重组人乳铁蛋白对口腔鳞癌Tca8113细胞的抑制作用及其机制研究
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摘要
口腔鳞状细胞癌(Oral squamous cell carcinoma,OSCC)是人类十大恶性肿瘤之一,占口腔颌面部恶性肿瘤的80%以上,长期以来口腔鳞状细胞癌的治疗一直是肿瘤治疗领域研究的重要课题,迫切需要肿瘤治疗的新方式。在抑制肿瘤的发生、发展方面,应用天然存在的化合物乳铁蛋白(lactoferrin,LF)进行癌症的化学预防和治疗逐渐成为重要的方法。
目前,国内关于乳铁蛋白抗肿瘤作用的研究还未见报道,本研究在吉林省科技发展计划项目(编号:200705346)的资助下,通过一系列体外实验,研究了重组人乳铁蛋白(Recombinate human lactoferrin,rhLF)对体外培养的口腔鳞癌Tca8113细胞的抑制作用,并且为了更好的研究rhLF介导的抗口腔鳞癌细胞的活性,观察了rhLF对细胞周期、周期调控因子、促炎症反应细胞因子、血管生成因子的影响。结果发现rhLF在体外可以直接抑制肿瘤细胞的生长;rhLF在体外抗肿瘤活性的机制为诱导肿瘤细胞周期抑制,减少肿瘤细胞释放的促炎症反应细胞因子和血管生成因子。表明直接抑制细胞生长是乳铁蛋白抑制癌细胞生长的机制之一,乳铁蛋白可以通过多种途径发挥抗肿瘤作用,达到预防和治疗肿瘤的目的。
本研究的创新点在于比较系统地研究了重组人乳铁蛋白在口腔癌治疗方面的作用,初步探讨了rhLF在体外对癌细胞的抑制作用,并利用FCM、Westernblot、ELISA、免疫组化等方法研究了rhLF对口腔鳞癌Tca8113细胞细胞周期、细胞因子等表达的影响,全面系统地评价了rhLF在体外抑制口腔鳞癌细胞的作用及机制;提出了rhLF可以通过直接抑制生血管因子的生成来减少肿瘤相关血管的发生进而抑制肿瘤细胞的生长;为今后进一步的动物实验和临床实验提供了依据,为口腔鳞癌的化学药物治疗提供新的思路和理论基础,也为其他恶性肿瘤的治疗提供参考。
Malignant tumors are extremely harmful to human health. The incidence rate of which shows an upward trend year after year, and its mortality rate stands forefront of various diseases. In all malignant tumors, oral squamous cell carcinoma (OSCC) accounted for 2% -3%. OSCC, which occupies more than 80% of malignant tumors in oral and maxillofacial region, is one of the top ten human malignant tumors. At present, we mainly rely on surgical resection, radiotherapy and chemotherapy as conventional therapy. After analysis of oral combination therapy studies and clinical significance, Chinese scholars propose a comprehensive individualized treatment plan of oral cancer. That is, ensure the quality of patient’s life while enhance tumor cure rate. Clinical and research workers in the country and abroad constantly sum up experience and improve existing treatment methods to carry out an active exploration of new ideas for cancer treatment. Nowadays, researchers promote using of natural foods as chemoprevention of oral cancer carcinogenesis. Chemoprevention aims to utilize a part of physiological activities of compounds from natural plants/animals. Chemoprevention and chemotherapy with naturally occurring compounds such as lactoferrin have become increasingly important strategies in inhibiting carcinogenesis and tumor growth.
Lactoferrin (LF), an 80-kDa basic glycoprotein, is a member of the transferrin family of iron-binding proteins which was originally isolated from human milk. Human lactoferrin consists of 691 amino acid residues. The complete amino acid sequence of bovine lactoferrin has been determined to contain 689 amino acids. The structure of human lactoferrin and bovine lactoferrin is similar. The protein is present in mammalian exocrine secretions, including breast milk, tears, nasal and bronchial mucus, cervical mucus, and seminal fluid. Recombinate human lactoferrin (rhLF) is structurally and functionally equivalent to native human LF in all material respects, as demonstrated by comparison of their 3D structures, molecular weights, biologic activities and other physicochemical properties, differing only in the nature of its glycosylation. Lactoferrin has multiple known biological activities, including iron regulation, cellular growth and differentiation, antimicrobial defense, antiinflammatory activity, and cancer protection. Immunoreactivity of Lf has been detected in many human neoplasms such as adenocarcinomas of the parotid gland and prostate, breast carcinoma, thyroid tumours, renal cell carcinoma, gastric and colorectal adenomas and carcinomas , gallbladder carcinomas,astrocytomas and multiforme glioblastomas and, recently, in skin nevi and melanomas; nevertheless, in these neoplastic conditions, the functional role of LF has not been fully elucidated. LF is a multifunctional protein,Although LF was originally identified as a mucosal host defense mediator and inflammatory immune modulator, it also displays antineoplastic activity. Recently, studies have suggested chemopreventive and antitumor activity for lactoferrin as well. bLF and its digested fragments have been found to remarkably inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Marked inhibition of tumor growth and reduced lung colonization by B16-F10 melanoma experimental metastasis were found in mice treated with hLF injected. Added to drinking water inhibited 4-nitroquinoline 1-oxide carcinogenesis in rats. Oral bLF reduced lung colonization by colon carcinoma cells in mice. Yoo et al demonstrated lactoferrin had the ability to inhibit metastasis of primary tumors in mice with cancer. Despite the evidence that LF possesses chemopreventive activity, little is known about the mechanisms by which its antitumor activity is mediated.
In order to test whether human recombinant lactoferrin has a chemotherapeutic effect on oral cancers ,we examined the effect of rhLF on Tca8113 cell lines. To study one possible mechanism of lactoferrin-mediated antitumor activity in head and neck cancer cells, we investigated how the cell cycle, proinflammatory cytokines, proangiogenics are affected by rhLF treatment.
Measurement of cell proliferation by MTT: Incubated Tca8113 cells and two normal cell lines CHO and 293T were treated with rhLF at different concentration, at the same time, morphology of cells were observed with microscope. During these seven experimental groups, rhLF has no inhibitory effect to the proliferation of CHO and 293T cells. Different doses of rhLF have inhibitory effects on Tca8113 cells. The result showed that rhLF1-rhLF7 group inhibitory rates were 16%, 28%, 30%, 36%, 43%, 56%, 63%. Groups add 50 and 100μg/ml rhLF had distinct difference when compared with cell culture group without rhLF (C group) (p <0.05), and with the increase of lactoferrin concentration, inhibition effect gradually increase. 35.7μg/ml rhLF treatment group, with the culture time extended showed no increasing inhibitory effect. rhLF can induce dose-dependent growth inhibition on the oral tumor cells cultivated in vitro.
Flow cytometric analysis: For cell analysis, 50μg/ml and 100μg/ml rhLF were added to medium, with augment of drug concentration, Tca8113 cells distribution in the cell cycle changed dramatically. During G 0/G1 phase, the number of cells increased, and during S and G2/M phase, cells reduced gradually. It can be seen, Tca8113 cells were arrested in the Go / Gl phase by rhLF, and there is a clear dose-effect relationship. Incubated with different concentration of rhLF for 24h, Tca8113 cells were respectively detected cyclinD1, p19, p27 gene mRNA expression, and then compared with no rhLF control group. CyclinD1 of 50μg/ml and 25μg/ml rhLF experimental groups mRNA has a statistically significant difference when compared with the control group (t = 9.107, p <0.05; t = 4.963, p <0.05). The level of p19, p27 mRNA expression did not change obviously. There was no statistically significant difference, compared with the control group (p19 :F = 0.309, p27: F = 2.573, p> 0.05).
RT-PCR and Western blot are used to detect rhLF influence on angiogenic factors VEGF, bFGF mRNA and protein expression, secreted by Tca8113 cells. After 24 hours constant stimulation of rhLF, VEGF and bFGF gene PCR product of Tca8113 cells were tested. It is obvious that there are statistical significance differences between 50μg/ml rhLF experimental group and control group, p <0.05 (VEGF: t = 8.530, bFGF: t = 7.056). Accordingly VEGF and bFGF protein expression of Tca8113 cells reduced with the increased concentration of rhLF and significant difference was found when compared 50μg/ml rhLF experimental group (E group) and the control group (A group),p <0.05(VEGF:t=4.324. bFGF:t=6.396).
Immunohistochemical methods were employed in normal oral mucosa (n = 10) and OSCC patients’(n = 65) tumor tissue to detect expression of proinflammatory cytokines IL-6 and IL-8 in oral squamous cell carcinoma, and there relationship with clinicopathological parameters. Quantitative analysis was made by image analysis system. The level of IL-6, IL-8 in patients with OSCC was significantly higher than normal oral mucosa. IL-6, IL-8 expression has nothing to do with tumor pathological grade, gender, age and size, but IL-6, IL-8 expression is closely related to lymph node metastasis.
Adhibit immunohistochemical method, enzyme linked immunosorbent assay to detect impact of recombinant human lactoferrin on IL-6, IL-8 protein . According to the results of immunohistochemical staining, IL-6, IL-8 were expressed by Tca8113 cells. Interestingly, in 50μg/ml rhLF group, IL-6, IL-8 expression seemed to be suppressed. There are only weak expression or no expression in this group. ELISA test results: Different conditioned medium (contains rhLF 50μg/ml and100μg/ml separately) separately cultivate Tca8113 cells for 24 h, levels of IL-6, IL-8 were significantly decreased in the culture supernatant of 100μg/ml rhLF group. Compared with the normal control group, the difference was significant (p <0.05).
Conclusion: Direct inhibition of cellular growth is one mechanism by which Lactoferrin may inhibit cancer growth. Lactoferrin induces direct cell cycle arrest which seemed to be modulated by down-regulation of cyclin D1. Lactoferrin can decrease cellular release of the proangiogenic cytokines, including VEGF and bFGF. Lactoferrin may also inhibit tumor mediated angiogenesis. Lactoferrin can decrease cellular release of the proinflammatory cytokines, including interleukin-6 and interleukin-8, which suppresses tumor growth.
This innovative point lies in that studies of recombinant human lactoferritin of oral cancer treatment is carried out for the first time in China. Inhibitory effect of rhLF on cancer cells was investigated in vitro, and take advantage of FCM, westernblot, ELISA, immunohistochemical methods, influences of rhLF in oral squamous cell carcinoma cells such as cell cycle and cytokine expression were studied. It is a comprehensive and systematic evaluation of inhibitory effect of rhLF on oral cancer cells and its mechanism. A basis for the subsequent further animal experiments and clinical trials, new ideas and theoretical foundation for oral squamous cell carcinoma of chemotherapy , and other malignant tumors treatment are provided.
目前,国内关于乳铁蛋白抗肿瘤作用的研究还未见报道,本研究在吉林省科技发展计划项目(编号:200705346)的资助下,通过一系列体外实验,研究了重组人乳铁蛋白(Recombinate human lactoferrin,rhLF)对体外培养的口腔鳞癌Tca8113细胞的抑制作用,并且为了更好的研究rhLF介导的抗口腔鳞癌细胞的活性,观察了rhLF对细胞周期、周期调控因子、促炎症反应细胞因子、血管生成因子的影响。结果发现rhLF在体外可以直接抑制肿瘤细胞的生长;rhLF在体外抗肿瘤活性的机制为诱导肿瘤细胞周期抑制,减少肿瘤细胞释放的促炎症反应细胞因子和血管生成因子。表明直接抑制细胞生长是乳铁蛋白抑制癌细胞生长的机制之一,乳铁蛋白可以通过多种途径发挥抗肿瘤作用,达到预防和治疗肿瘤的目的。
本研究的创新点在于比较系统地研究了重组人乳铁蛋白在口腔癌治疗方面的作用,初步探讨了rhLF在体外对癌细胞的抑制作用,并利用FCM、Westernblot、ELISA、免疫组化等方法研究了rhLF对口腔鳞癌Tca8113细胞细胞周期、细胞因子等表达的影响,全面系统地评价了rhLF在体外抑制口腔鳞癌细胞的作用及机制;提出了rhLF可以通过直接抑制生血管因子的生成来减少肿瘤相关血管的发生进而抑制肿瘤细胞的生长;为今后进一步的动物实验和临床实验提供了依据,为口腔鳞癌的化学药物治疗提供新的思路和理论基础,也为其他恶性肿瘤的治疗提供参考。
Malignant tumors are extremely harmful to human health. The incidence rate of which shows an upward trend year after year, and its mortality rate stands forefront of various diseases. In all malignant tumors, oral squamous cell carcinoma (OSCC) accounted for 2% -3%. OSCC, which occupies more than 80% of malignant tumors in oral and maxillofacial region, is one of the top ten human malignant tumors. At present, we mainly rely on surgical resection, radiotherapy and chemotherapy as conventional therapy. After analysis of oral combination therapy studies and clinical significance, Chinese scholars propose a comprehensive individualized treatment plan of oral cancer. That is, ensure the quality of patient’s life while enhance tumor cure rate. Clinical and research workers in the country and abroad constantly sum up experience and improve existing treatment methods to carry out an active exploration of new ideas for cancer treatment. Nowadays, researchers promote using of natural foods as chemoprevention of oral cancer carcinogenesis. Chemoprevention aims to utilize a part of physiological activities of compounds from natural plants/animals. Chemoprevention and chemotherapy with naturally occurring compounds such as lactoferrin have become increasingly important strategies in inhibiting carcinogenesis and tumor growth.
Lactoferrin (LF), an 80-kDa basic glycoprotein, is a member of the transferrin family of iron-binding proteins which was originally isolated from human milk. Human lactoferrin consists of 691 amino acid residues. The complete amino acid sequence of bovine lactoferrin has been determined to contain 689 amino acids. The structure of human lactoferrin and bovine lactoferrin is similar. The protein is present in mammalian exocrine secretions, including breast milk, tears, nasal and bronchial mucus, cervical mucus, and seminal fluid. Recombinate human lactoferrin (rhLF) is structurally and functionally equivalent to native human LF in all material respects, as demonstrated by comparison of their 3D structures, molecular weights, biologic activities and other physicochemical properties, differing only in the nature of its glycosylation. Lactoferrin has multiple known biological activities, including iron regulation, cellular growth and differentiation, antimicrobial defense, antiinflammatory activity, and cancer protection. Immunoreactivity of Lf has been detected in many human neoplasms such as adenocarcinomas of the parotid gland and prostate, breast carcinoma, thyroid tumours, renal cell carcinoma, gastric and colorectal adenomas and carcinomas , gallbladder carcinomas,astrocytomas and multiforme glioblastomas and, recently, in skin nevi and melanomas; nevertheless, in these neoplastic conditions, the functional role of LF has not been fully elucidated. LF is a multifunctional protein,Although LF was originally identified as a mucosal host defense mediator and inflammatory immune modulator, it also displays antineoplastic activity. Recently, studies have suggested chemopreventive and antitumor activity for lactoferrin as well. bLF and its digested fragments have been found to remarkably inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Marked inhibition of tumor growth and reduced lung colonization by B16-F10 melanoma experimental metastasis were found in mice treated with hLF injected. Added to drinking water inhibited 4-nitroquinoline 1-oxide carcinogenesis in rats. Oral bLF reduced lung colonization by colon carcinoma cells in mice. Yoo et al demonstrated lactoferrin had the ability to inhibit metastasis of primary tumors in mice with cancer. Despite the evidence that LF possesses chemopreventive activity, little is known about the mechanisms by which its antitumor activity is mediated.
In order to test whether human recombinant lactoferrin has a chemotherapeutic effect on oral cancers ,we examined the effect of rhLF on Tca8113 cell lines. To study one possible mechanism of lactoferrin-mediated antitumor activity in head and neck cancer cells, we investigated how the cell cycle, proinflammatory cytokines, proangiogenics are affected by rhLF treatment.
Measurement of cell proliferation by MTT: Incubated Tca8113 cells and two normal cell lines CHO and 293T were treated with rhLF at different concentration, at the same time, morphology of cells were observed with microscope. During these seven experimental groups, rhLF has no inhibitory effect to the proliferation of CHO and 293T cells. Different doses of rhLF have inhibitory effects on Tca8113 cells. The result showed that rhLF1-rhLF7 group inhibitory rates were 16%, 28%, 30%, 36%, 43%, 56%, 63%. Groups add 50 and 100μg/ml rhLF had distinct difference when compared with cell culture group without rhLF (C group) (p <0.05), and with the increase of lactoferrin concentration, inhibition effect gradually increase. 35.7μg/ml rhLF treatment group, with the culture time extended showed no increasing inhibitory effect. rhLF can induce dose-dependent growth inhibition on the oral tumor cells cultivated in vitro.
Flow cytometric analysis: For cell analysis, 50μg/ml and 100μg/ml rhLF were added to medium, with augment of drug concentration, Tca8113 cells distribution in the cell cycle changed dramatically. During G 0/G1 phase, the number of cells increased, and during S and G2/M phase, cells reduced gradually. It can be seen, Tca8113 cells were arrested in the Go / Gl phase by rhLF, and there is a clear dose-effect relationship. Incubated with different concentration of rhLF for 24h, Tca8113 cells were respectively detected cyclinD1, p19, p27 gene mRNA expression, and then compared with no rhLF control group. CyclinD1 of 50μg/ml and 25μg/ml rhLF experimental groups mRNA has a statistically significant difference when compared with the control group (t = 9.107, p <0.05; t = 4.963, p <0.05). The level of p19, p27 mRNA expression did not change obviously. There was no statistically significant difference, compared with the control group (p19 :F = 0.309, p27: F = 2.573, p> 0.05).
RT-PCR and Western blot are used to detect rhLF influence on angiogenic factors VEGF, bFGF mRNA and protein expression, secreted by Tca8113 cells. After 24 hours constant stimulation of rhLF, VEGF and bFGF gene PCR product of Tca8113 cells were tested. It is obvious that there are statistical significance differences between 50μg/ml rhLF experimental group and control group, p <0.05 (VEGF: t = 8.530, bFGF: t = 7.056). Accordingly VEGF and bFGF protein expression of Tca8113 cells reduced with the increased concentration of rhLF and significant difference was found when compared 50μg/ml rhLF experimental group (E group) and the control group (A group),p <0.05(VEGF:t=4.324. bFGF:t=6.396).
Immunohistochemical methods were employed in normal oral mucosa (n = 10) and OSCC patients’(n = 65) tumor tissue to detect expression of proinflammatory cytokines IL-6 and IL-8 in oral squamous cell carcinoma, and there relationship with clinicopathological parameters. Quantitative analysis was made by image analysis system. The level of IL-6, IL-8 in patients with OSCC was significantly higher than normal oral mucosa. IL-6, IL-8 expression has nothing to do with tumor pathological grade, gender, age and size, but IL-6, IL-8 expression is closely related to lymph node metastasis.
Adhibit immunohistochemical method, enzyme linked immunosorbent assay to detect impact of recombinant human lactoferrin on IL-6, IL-8 protein . According to the results of immunohistochemical staining, IL-6, IL-8 were expressed by Tca8113 cells. Interestingly, in 50μg/ml rhLF group, IL-6, IL-8 expression seemed to be suppressed. There are only weak expression or no expression in this group. ELISA test results: Different conditioned medium (contains rhLF 50μg/ml and100μg/ml separately) separately cultivate Tca8113 cells for 24 h, levels of IL-6, IL-8 were significantly decreased in the culture supernatant of 100μg/ml rhLF group. Compared with the normal control group, the difference was significant (p <0.05).
Conclusion: Direct inhibition of cellular growth is one mechanism by which Lactoferrin may inhibit cancer growth. Lactoferrin induces direct cell cycle arrest which seemed to be modulated by down-regulation of cyclin D1. Lactoferrin can decrease cellular release of the proangiogenic cytokines, including VEGF and bFGF. Lactoferrin may also inhibit tumor mediated angiogenesis. Lactoferrin can decrease cellular release of the proinflammatory cytokines, including interleukin-6 and interleukin-8, which suppresses tumor growth.
This innovative point lies in that studies of recombinant human lactoferritin of oral cancer treatment is carried out for the first time in China. Inhibitory effect of rhLF on cancer cells was investigated in vitro, and take advantage of FCM, westernblot, ELISA, immunohistochemical methods, influences of rhLF in oral squamous cell carcinoma cells such as cell cycle and cytokine expression were studied. It is a comprehensive and systematic evaluation of inhibitory effect of rhLF on oral cancer cells and its mechanism. A basis for the subsequent further animal experiments and clinical trials, new ideas and theoretical foundation for oral squamous cell carcinoma of chemotherapy , and other malignant tumors treatment are provided.
引文
[1]邱蔚六.我国口腔颌面肿瘤的诊治和研究现状[J].中华口腔医学杂志, 2003,38(1):1-2.
[2] Pan MH, Ho CT. Chemopreventive effects of natural dietary compounds on cancer development[J]. Chem Soc Rev, 2008,37(11):2558-74.
[3] Krishnan K, Campbell S, Abdel-Rahman F, et al. Cancer chemoprevention drug targets[J]. Curr Drug Targets, 2003,4(1):45-54.
[4] Qui W, Zheng J. Development of oral and maxillofacial oncology in China[J]. Chin Med J (Engl), 2003,116(10):1567-73.
[5]颌面外科专业委员会口腔颌面肿瘤学组.我国口腔颌面部肿瘤学科现状[J].中华口腔医学杂志, 2006,41(8):481-2.
[6]杨湛.口腔颌面部肿瘤综合治疗设计中的平衡理念[J].华西口腔医学杂志, 2008,26(1):4-7.
[7] Guilford JM, Pezzuto JM. Natural products as inhibitors of carcinoge- nesis[J]. Expert Opin Investig Drugs, 2008,17(9):1341-52.
[8] Kelloff GJ, Crowell JA, Steele VE, et al. Progress in cancer chemopreven- tion[J]. Ann N Y Acad Sci, 1999,889:1-13.
[9] Kelloff GJ, Crowell JA, Steele VE, et al. Progress in cancer chemopreven- tion: development of diet-derived chemopreventive agents[J]. J Nutr, 2000,130(2S Suppl):467S-71S.
[10] Zou DM, Brewer M, Garcia F, et al. Cactus pear: a natural product in cancer chemoprevention[J]. Nutr J, 2005,4:25.
[11] Michels KB, Willett WC, Fuchs CS, et al. Coffee, tea, and caffeine consumption and incidence of colon and rectal cancer[J]. J Natl Cancer Inst, 2005,97(4):282-92.
[12] Tsuda H, Ohshima Y, Nomoto H, et al. Cancer prevention by natural compounds[J]. Drug Metab Pharmacokinet, 2004,19(4):245-63.
[13] Levay PF, Viljoen M. Lactoferrin: a general review[J]. Haematologica,1995,80(3):252-67.
[14] Mason DY, Taylor CR. Distribution of transferrin, ferritin, and lactoferrin in human tissues[J]. J Clin Pathol, 1978,31(4):316-27.
[15] van der Strate BW, Beljaars L, Molema G, et al. Antiviral activities of lactoferrin[J]. Antiviral Res, 2001,52(3):225-39.
[16] Keiichi SZ. Lactoferrin: A Marverlors Protein in Milk?[J]. Anim Sci, 2000,71(4):329-47.
[17]陈历俊,姜铁民.乳铁蛋白生物功能及基因表达[M].北京:科学出版社. 2007.
[18] Marshall K. Therapeutic applications of whey protein[J]. Altern Med Rev, 2004,9(2):136-56.
[19] Pierce A, Colavizza D, Benaissa M, et al. Molecular cloning and sequence analysis of bovine lactotransferrin[J]. Eur J Biochem, 1991, 196(1):177-84.
[20] Baker EN, Baker HM. Molecular structure, binding properties and dynamics of lactoferrin[J]. Cell Mol Life Sci, 2005,62(22):2531-9.
[21] Ellison RT, 3rd, Giehl TJ, LaForce FM. Damage of the outer membrane of enteric gram-negative bacteria by lactoferrin and transferrin[J]. Infect Immun, 1988,56(11):2774-81.
[22] Bellamy W, Takase M, Yamauchi K, et al. Identification of the bactericidal domain of lactoferrin[J]. Biochim Biophys Acta, 1992,1121(1-2):130-6.
[23]冯兴军,王建华,杨雅麟.乳铁蛋白肽作用机制研究进展[J].中国生物工程杂志, 2004,24(1):23-6.
[24]凌雪萍,庞广昌,李国强.乳铁蛋白的最新研究进展[J].食品科学, 2003,24(1):160-3.
[25]陈车生,袁勤生.乳铁蛋白的研究进展[J].食品与药品, 2008,10(1):62-6.
[26]王觐,薛长勇.乳铁蛋白的生理功能及研究进展[J].中国食物与营养, 2008,9:52-4.
[27] Letchoumy PV, Mohan KV, Stegeman JJ, et al. In vitro antioxidativepotential of lactoferrin and black tea polyphenols and protective effects in vivo on carcinogen activation, DNA damage, proliferation, invasion, and angiogenesis during experimental oral carcinogenesis[J]. Oncol Res, 2008,17(5):193-203.
[28]郝高峰,林焕彩.唾液乳铁蛋白和溶菌酶含量与乳牙[J].中华口腔医学杂志, 2009,44(2):82-4.
[29]肖晖,刘宁.乳铁蛋白对大鼠成骨细胞增殖与分化的影响.[J].国际骨科学杂志, 2008,29(3):198-201.
[30]徐红萌,刘小立.乳铁蛋白对SNL神经病理性疼痛大鼠的镇痛作用[J].中国疼痛医学杂志, 2008,14(6):360-3.
[31] Tsuda H, Sekine K, Fujita K, et al. Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies[J]. Biochem Cell Biol, 2002,80(1):131-6.
[32] Masuda C, Wanibuchi H, Sekine K, et al. Chemopreventive effects of bovine lactoferrin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis[J]. Jpn J Cancer Res, 2000,91(6):582-8.
[33] Xu Y. Isolation and Characterization of Whey components[D]. Australia: School of Food Science; 1996.
[34] Tsuda H, Sekine K, Ushida Y, et al. Milk and dairy products in cancer prevention: focus on bovine lactoferrin[J]. Mutat Res, 2000,462(2-3): 227-33.
[35] Tsuda H, Sekine K, Nakamura J, et al. Inhibition of azoxymethane initiated colon tumor and aberrant crypt foci development by bovine lactoferrin administration in F344 rats[J]. Adv Exp Med Biol, 1998,443: 273-84.
[36] Varadhachary A, Wolf JS, Petrak K, et al. Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy[J]. Int J Cancer, 2004,111(3):398-403.
[37] Nishiya K, Horwitz DA. Contrasting effects of lactoferrin on humanlymphocyte and monocyte natural killer activity and antibody-dependent cell-mediated cytotoxicity[J]. J Immunol, 1982,129(6):2519-23.
[38] Sawatzki G, Rich IN. Lactoferrin stimulates colony stimulating factor production in vitro and in vivo[J]. Blood Cells, 1989,15(2):371-85.
[39] Gahr M, Speer CP, Damerau B, et al. Influence of lactoferrin on the function of human polymorphonuclear leukocytes and monocytes[J]. J Leukoc Biol, 1991,49(5):427-33.
[40] Iigo M, Shimamura M, Matsuda E, et al. Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa: a possible explanation for inhibition of carcinogenesis and metastasis[J]. Cytokine, 2004,25(1):36-44.
[41] Shimamura M, Yamamoto Y, Ashino H, et al. Bovine lactoferrin inhibits tumor-induced angiogenesis[J]. Int J Cancer, 2004,111(1):111-6.
[42] Norrby K, Mattsby-Baltzer I, Innocenti M, et al. Orally administered bovine lactoferrin systemically inhibits VEGF(165)-mediated angiogenesis in the rat[J]. Int J Cancer, 2001,91(2):236-40.
[43] Damiens E, El Yazidi I, Mazurier J, et al. Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells[J]. J Cell Biochem, 1999,74(3):486-98.
[44] Xiao Y, Monitto CL, Minhas KM, et al. Lactoferrin down-regulates G1 cyclin-dependent kinases during growth arrest of head and neck cancer cells[J]. Clin Cancer Res, 2004,10(24):8683-6.
[45] Fujita K, Matsuda E, Sekine K, et al. Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats[J]. Carcinogenesis, 2004,25(10):1961-6.
[46] Mignogna MD, Fedele S, Lo Russo L. The World Cancer Report and the burden of oral cancer[J]. Eur J Cancer Prev, 2004,13(2):139-42.
[47] Wolf JS, Li D, Taylor RJ, et al. Lactoferrin inhibits growth of malignant tumors of the head and neck[J]. ORL J Otorhinolaryngol Relat Spec,2003,65(5):245-9.
[48] Wolf JS, Li G, Varadhachary A, et al. Oral lactoferrin results in T cell-dependent tumor inhibition of head and neck squamous cell carcinoma in vivo[J]. Clin Cancer Res, 2007,13(5):1601-10.
[49] McKeown ST, Lundy FT, Nelson J, et al. The cytotoxic effects of human neutrophil peptide-1 (HNP1) and lactoferrin on oral squamous cell carcinoma (OSCC) in vitro[J]. Oral Oncol, 2006,42(7):685-90.
[50] Sakai T, Banno Y, Kato Y, et al. Pepsin-digested bovine lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells[J]. J Pharmacol Sci, 2005,98(1):41-8.
[51] Salgado R, Junius S, Benoy I, et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer[J]. Int J Cancer, 2003,103(5):642-6.
[52] Culig Z, Steiner H, Bartsch G, et al. Interleukin-6 regulation of prostate cancer cell growth[J]. J Cell Biochem, 2005,95(3):497-505.
[53] Kishimoto T. Interleukin-6: discovery of a pleiotropic cytokine[J]. Arthritis Res Ther, 2006,8 Suppl 2:S2.
[54] Scheller J, Rose-John S. Interleukin-6 and its receptor: from bench to bedside[J]. Med Microbiol Immunol, 2006,195(4):173-83.
[55] Rose-John S, Waetzig GH, Scheller J, et al. The IL-6/sIL-6R complex as a novel target for therapeutic approaches[J]. Expert Opin Ther Targets, 2007,11(5):613-24.
[56] Rose-John S, Scheller J, Elson G, et al. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer[J]. J Leukoc Biol, 2006,80(2):227-36.
[57] Hsu HC, Lee YM, Tsai WH, et al. Circulating levels of thrombopoietic and inflammatory cytokines in patients with acute myeloblastic leukemia and myelodysplastic syndrome[J]. Oncology, 2002,63(1):64-9.
[58] Huang SP, Wu MS, Shun CT, et al. Interleukin-6 increases vascularendothelial growth factor and angiogenesis in gastric carcinoma[J]. J Biomed Sci, 2004,11(4):517-27.
[59] Bartsch R, Woehrer S, Raderer M, et al. Serum interleukin-6 levels in patients with gastric MALT lymphoma compared to gastric and pancreatic cancer[J]. Anticancer Res, 2006,26(4B):3187-90.
[60] Bellone S, Watts K, Cane S, et al. High serum levels of interleukin-6 in endometrial carcinoma are associated with uterine serous papillary histology, a highly aggressive and chemotherapy-resistant variant of endometrial cancer[J]. Gynecol Oncol, 2005,98(1):92-8.
[61] Songur N, Kuru B, Kalkan F, et al. Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer[J]. Tumori, 2004,90(2):196-200.
[62] Belluco C, Nitti D, Frantz M, et al. Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer[J]. Ann Surg Oncol, 2000,7(2):133-8.
[63] Negrier S, Perol D, Menetrier-Caux C, et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6--from the Groupe Francais d'Immunotherapie[J]. J Clin Oncol, 2004,22(12):2371-8.
[64] Zakrzewska I, Poznanski J. [Changes of serum il-6 and CRP after chemotherapy in patients with ovarian carcinoma][J]. Pol Merkur Lekarski, 2001,11(63):210-3.
[65] Oka M, Yamamoto K, Takahashi M, et al. Relationship between serum levels of interleukin 6, various disease parameters and malnutrition in patients with esophageal squamous cell carcinoma[J]. Cancer Res, 1996,56(12):2776-80.
[66] Karczewska A, Nawrocki S, Breborowicz D, et al. Expression of interleukin-6, interleukin-6 receptor, and glycoprotein 130 correlates with good prognoses for patients with breast carcinoma[J]. Cancer,2000,88(9):2061-71.
[67] Garcia-Tunon I, Ricote M, Ruiz A, et al. IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma[J]. Histopathology, 2005,47(1):82-9.
[68] Miyamoto Y, Hosotani R, Doi R, et al. Interleukin-6 inhibits radiation induced apoptosis in pancreatic cancer cells[J]. Anticancer Res, 2001,21(4A):2449-56.
[69] Zhang GJ, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma[J]. Anticancer Res, 1999,19(2B):1427-32.
[70] Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine[J]. Cancer Res, 2005,65(23):10794-800.
[71] Yuan H, Liddle FJ, Mahajan S, et al. IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor[J]. Carcinogenesis, 2004,25(11):2247-55.
[72]王越,杨洁,高燕.卵巢癌细胞IL-6、IL-8及其受体表达的研究[J].免疫学杂志, 2006,22(5):475-9.
[73] Ashizawa T, Okada R, Suzuki Y, et al. Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor[J]. Gastric Cancer, 2005,8(2):124-31.
[74]赵向阳,李玉红,许倩. IL-6及其受体和凋亡相关基因在胃癌中的表达[J].承德医学院学报, 2005,22(3):194-5.
[75] el-Far M, Fouda M, Yahya R, et al. Serum IL-10 and IL-6 levels at diagnosis as independent predictors of outcome in non-Hodgkin's lymphoma[J]. J Physiol Biochem, 2004,60(4):253-8.
[76] Lai R, O'Brien S, Maushouri T, et al. Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia[J]. Cancer, 2002,95(5):1071-5.
[77] Guo YQ, Chen SL. [The significance of IGF-1, VEGF, IL-6 in multiple myeloma progression][J]. Zhonghua Xue Ye Xue Za Zhi, 2006,27(4):231-4.
[78] Brozek W, Bises G, Girsch T, et al. Differentiation-dependent expression and mitogenic action of interleukin-6 in human colon carcinoma cells: relevance for tumour progression[J]. Eur J Cancer, 2005,41(15):2347-54.
[79] Pfitzenmaier J, Vessella R, Higano CS, et al. Elevation of cytokine levels in cachectic patients with prostate carcinoma[J]. Cancer, 2003,97(5): 1211-6.
[80] Mehmet N, Refik M, Harputluoglu M, et al. Serum and gastric fluid levels of cytokines and nitrates in gastric diseases infected with Helicobacter pylori[J]. New Microbiol, 2004,27(2):139-48.
[81] Kaminska J, Nowacki MP, Kowalska M, et al. Clinical significance of serum cytokine measurements in untreated colorectal cancer patients: soluble tumor necrosis factor receptor type I--an independent prognostic factor[J]. Tumour Biol, 2005,26(4):186-94.
[82] Nikiteas NI, Tzanakis N, Gazouli M, et al. Serum IL-6, TNFalpha and CRP levels in Greek colorectal cancer patients: prognostic implications[J]. World J Gastroenterol, 2005,11(11):1639-43.
[83] Esfandi F, Mohammadzadeh Ghobadloo S, Basati G. Interleukin-6 level in patients with colorectal cancer[J]. Cancer Lett, 2006,244(1):76-8.
[84] Tan EL, Selvaratnam G, Kananathan R, et al. Quantification of Epstein-Barr virus DNA load, interleukin-6, interleukin-10, transforming growth factor-beta1 and stem cell factor in plasma of patients with nasopharyngeal carcinoma[J]. BMC Cancer, 2006,6:227.
[85] Steiner H, Cavarretta IT, Moser PL, et al. Regulation of growth of prostate cancer cells selected in the presence of interleukin-6 by the anti-interleukin-6 antibody CNTO 328[J]. Prostate, 2006,66(16):1744-52.
[86] Dimitriu C, Martignoni ME, Bachmann J, et al. Clinical impact of cachexia on survival and outcome of cancer patients[J]. Rom J Intern Med,2005,43(3-4):173-85.
[87] Kovacs E. Multiple myeloma and B cell lymphoma. Investigation of IL-6, IL-6 receptor antagonist (IL-6RA), and GP130 antagonist (GP130A) using various parameters in an in vitro model[J]. ScientificWorldJournal, 2006,6:888-98.
[88] Yoshio-Hoshino N, Adachi Y, Aoki C, et al. Establishment of a new interleukin-6 (IL-6) receptor inhibitor applicable to the gene therapy for IL-6-dependent tumor[J]. Cancer Res, 2007,67(3):871-5.
[89] Chakravarti N, Myers JN, Aggarwal BB. Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane)[J]. Int J Cancer, 2006,119(6):1268-75.
[90] Woods KV, El-Naggar A, Clayman GL, et al. Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens[J]. Cancer Res, 1998,58(14):3132-41.
[91] Nakano Y, Kobayashi W, Sugai S, et al. Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma[J]. Jpn J Cancer Res, 1999,90(8):858-66.
[92] Mann EA, Spiro JD, Chen LL, et al. Cytokine expression by head and neck squamous cell carcinomas[J]. Am J Surg, 1992,164(6):567-73.
[93] Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer[J]. Clin Cancer Res, 1999,5(6):1369-79.
[94] Knerer B, Formanek M, Temmel A, et al. The role of fibroblasts from oropharyngeal mucosa in producing proinflammatory and mitogenic cytokines without prior stimulation[J]. Eur Arch Otorhinolaryngol, 1999,256(5):266-70.
[95] Hong SH, Ondrey FG, Avis IM, et al. Cyclooxygenase regulates humanoropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation?[J]. FASEB J, 2000,14(11):1499-507.
[96] Wang LS, Chow KC, Wu CW. Expression and up-regulation of interleukin-6 in oesophageal carcinoma cells by n-sodium butyrate[J]. Br J Cancer, 1999,80(10):1617-22.
[97] Wang YF, Chang SY, Tai SK, et al. Clinical significance of interleukin-6 and interleukin-6 receptor expressions in oral squamous cell carcinoma[J]. Head Neck, 2002,24(9):850-8.
[98] Hess S, Smola H, Sandaradura De Silva U, et al. Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte chemoattractant protein-1 production[J]. J Immunol, 2000,165(4):1939-48.
[99] Zhong Z, Wen Z, Darnell JE, Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6[J]. Science, 1994,264(5155):95-8.
[100] Rubin Grandis J, Zeng Q, Drenning SD. Epidermal growth factor receptor--mediated stat3 signaling blocks apoptosis in head and neck cancer[J]. Laryngoscope, 2000,110(5 Pt 1):868-74.
[101] Kanazawa T, Nishino H, Hasegawa M, et al. Interleukin-6 directly influences proliferation and invasion potential of head and neck cancer cells[J]. Eur Arch Otorhinolaryngol, 2007,264(7):815-21.
[102] Vairaktaris E, Yapijakis C, Serefoglou Z, et al. Gene expression polymorphisms of interleukins-1 beta, -4, -6, -8, -10, and tumor necrosis factors-alpha, -beta: regression analysis of their effect upon oral squamous cell carcinoma[J]. J Cancer Res Clin Oncol, 2008,134(8):821-32.
[103] Vucicevic Boras V, Cikes N, Lukac J, et al. Salivary and serum interleukin 6 and basic fibroblast growth factor levels in patients with oral squamous cell carcinoma[J]. Minerva Stomatol, 2005,54(10):569-73.
[104] St John MA, Li Y, Zhou X, et al. Interleukin 6 and interleukin 8 aspotential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma[J]. Arch Otolaryngol Head Neck Surg, 2004,130(8):929-35.
[105] Kademani D. Oral cancer[J]. Mayo Clin Proc, 2007,82(7):878-87.
[106] Cumberbatch M, Dearman RJ, Uribe-Luna S, et al. Regulation of epidermal Langerhans cell migration by lactoferrin[J]. Immunology, 2000,100(1):21-8.
[107] Guillen C, McInnes IB, Vaughan DM, et al. Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice[J]. J Immunol, 2002,168(8):3950-7.
[108] Bezault J, Bhimani R, Wiprovnick J, et al. Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice[J]. Cancer Res, 1994,54(9):2310-2.
[109] Son HJ, Lee SH, Choi SY. Human lactoferrin controls the level of retinoblastoma protein and its activity[J]. Biochem Cell Biol, 2006,84(3): 345-50.
[110] Weinberg ED. The role of iron in cancer[J]. Eur J Cancer Prev, 1996,5(1):19-36.
[111] Ziere B, Van Veen H, Koopman J. Safety, tolerability, and pharmacokinetics of I.V. administered rhLF in humans. 5th International Conference on Lactoferrin 2001[C]; Alberta (Canada): Pharming Techno- logies.
[112] Hayes TG, Falchook GF, Varadhachary GR, et al. Phase I trial of oral talactoferrin alfa in refractory solid tumors[J]. Invest New Drugs, 2006,24(3):233-40.
[113]汪堃仁,薛绍白,柳惠图.细胞生物学[M].北京:师范大学出版社. 1998:436-511.
[114]沈珝琁,方福德.真核基因表达调控[M].北京:高等教育出版社. 1997:1-14.
[115]宋今丹.医学细胞生物学[M].北京:人民卫生出版社. 2002.
[116] Bartek J, Lukas J. Mammalian G1- and S-phase checkpoints in response to DNA damage[J]. Curr Opin Cell Biol, 2001,13(6):738-47.
[117]桂建芳. RNA加工与细胞周期调控[M].北京:科学出版社. 1998:78-136.
[118] Baldin V, Lukas J, Marcote MJ, et al. Cyclin D1 is a nuclear protein required for cell cycle progression in G1[J]. Genes Dev, 1993,7(5):812-21.
[119] Liu T, Zhu E, Wang L, et al. Abnormal expression of Rb pathway-related proteins in salivary gland acinic cell carcinoma[J]. Hum Pathol, 2005,36(9):962-70.
[120]曹雷,王莉红,刘婷娇等. p27Kip1、cyclin D1蛋白和Ki-67在口腔鳞癌中的表达及其意义[J].广东医学, 2008,30(11):1655-7.
[121] Joe AK, Liu H, Suzui M, et al. Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines[J]. Clin Cancer Res, 2002,8(3):893-903.
[122]张诗式,刘亚敏. p27 kip1 , p21waf1在肿瘤细胞周期调控过程的作用[J].武警医学院学报, 2004,13(3):162-5.
[123] Okabe M, Inagaki H, Murase T, et al. Prognostic significance of p27 and Ki-67 expression in mucoepidermoid carcinoma of the intraoral minor salivary gland[J]. Mod Pathol, 2001,14(10):1008-14.
[124] Hayashi H, Ogawa N, Ishiwa N, et al. High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients[J]. Lung Cancer, 2001,34(1):59-65.
[125] Alkarain A, Slingerland J. Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer[J]. Breast Cancer Res, 2004,6(1):13-21.
[126]侯波,高岩.口腔鳞状细胞癌和癌前病变中细胞周期相关蛋白p27表达的研究[J].中华口腔医学杂志, 2006,41(2):102-5.
[127] Chan FK, Zhang J, Cheng L, et al. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4[J]. Mol Cell Biol, 1995,15(5):2682-8.
[128] Xu JC, Feng ZZ, Zhao SF. [Expression of vascular endothelial growth factor, vascular endothelial growth factor receptor-3 and nm23-H1 in oral squamous cell carcinoma][J]. Zhonghua Kou Qiang Yi Xue Za Zhi, 2007,42(11):681-3.
[129] Hase T, Kawashiri S, Tanaka A, et al. Correlation of basic fibroblast growth factor expression with the invasion and the prognosis of oral squamous cell carcinoma[J]. J Oral Pathol Med, 2006,35(3):136-9.
[130] Shinkaruk S, Bayle M, Lain G, et al. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy[J]. Curr Med Chem Anticancer Agents, 2003,3(2):95-117.
[131] Rusnati M, Presta M. Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies[J]. Curr Pharm Des, 2007,13(20):2025-44.
[132] Presta M, Dell'Era P, Mitola S, et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis[J]. Cytokine Growth Factor Rev, 2005,16(2):159-78.
[133] Pradeep CR, Sunila ES, Kuttan G. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies[J]. Integr Cancer Ther, 2005,4(4):315-21.
[134]王雷,陈应新,高文信.血管内皮细胞生长因子、碱性成纤维细胞生长因子在口腔鳞状细胞癌中的表达研究[J].现代口腔医学杂志, 2004,18(4):299-301.
[135] Cattini PA, Nickel B, Bock M, et al. Immunolocalization of basic fibroblast growth factor (bFGF) in growing and growth-inhibited placental cells: a possible role for bFGF in placental cell development[J]. Placenta, 1991,12(4):341-52.
[136] Yamamoto N, Matsutani S, Yoshitake Y, et al. Immunohistochemical localization of basic fibroblast growth factor in A431 human epidermoid carcinoma cells[J]. Histochemistry, 1991,96(6):479-85.
[137] Lin FF, Chen HZ, Xie X, et al. [Down-regulation of vascular endothelial growth factor expression in ovarian cancer cell line SKOV3 by interferon-gamma][J]. Zhonghua Fu Chan Ke Za Zhi, 2003,38(3):150-3, 3-1.
[138] Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 expression in vitro[J]. World J Gastroenterol, 2004,10(3):393-9.
[139] Mader JS, Smyth D, Marshall J, et al. Bovine lactoferricin inhibits basic fibroblast growth factor- and vascular endothelial growth factor165-induced angiogenesis by competing for heparin-like binding sites on endothelial cells[J]. Am J Pathol, 2006,169(5):1753-66.
[140] Gura T. Chemokines take center stage in inflammatory ills[J]. Science, 1996,272(5264):954-6.
[141] Hermanek P, Sobin LN. TNM classification of malignant tumors of oral and maxillofacial rigion[M]. Geneva:World Health Organization. 2002.
[142] Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis[J]. Neuro Oncol, 2005,7(2):122-33.
[143] Waugh DJ, Wilson C. The interleukin-8 pathway in cancer[J]. Clin Cancer Res, 2008,14(21):6735-41.
[144] Horikawa T, Kaizaki Y, Kato H, et al. Expression of interleukin-8 receptor A predicts poor outcome in patients with nasopharyngeal carcinoma[J]. Laryngoscope, 2005,115(1):62-7.
[145] Jenkins GJ, Harries K, Doak SH, et al. The bile acid deoxycholic acid (DCA) at neutral pH activates NF-kappaB and induces IL-8 expression in oesophageal cells in vitro[J]. Carcinogenesis, 2004,25(3):317-23.
[146]徐文华.白细胞介素8与头颈部鳞癌[J].国外医学口腔医学分册, 2005,32(6):440-2.
[147]贾忠,贺冠海,封光华.趋化因子IL - 8与胃癌组织中浸润炎性细胞相关性分析[J].医学研究杂志, 2007,36(2):42-4.
[148] Millar HJ, Nemeth JA, McCabe FL, et al. Circulating human interleukin-8 as an indicator of cancer progression in a nude rat orthotopic human non-small cell lung carcinoma model[J]. Cancer Epidemiol Biomarkers Prev, 2008,17(8):2180-7.
[149] Maruyama K, Zhang JZ, Nihei Y, et al. Regulatory effects of gamma-interferon on IL-6 and IL-8 secretion by cultured human keratinocytes and dermal fibroblasts[J]. J Dermatol, 1995,22(12):901-6.
[150] Melnikova VO, Bar-Eli M. Bioimmunotherapy for melanoma using fully human antibodies targeting MCAM/MUC18 and IL-8[J]. Pigment Cell Res, 2006,19(5):395-405.
[151] Watanabe H, Iwase M, Ohashi M, et al. Role of interleukin-8 secreted from human oral squamous cell carcinoma cell lines[J]. Oral Oncol, 2002,38(7):670-9.
[152]徐承平,卞修武,王清良.非小细胞肺癌组织芯片中白介素-8的表达及其临床病理意义[J].中国肺癌杂志, 2007,10(5):386-90.
[153] Wolf JS, Chen Z, Dong G, et al. IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas[J]. Clin Cancer Res, 2001,7(6):1812-20.
[154] Kuhara T, Iigo M, Itoh T, et al. Orally administered lactoferrin exerts an antimetastatic effect and enhances production of IL-18 in the intestinal epithelium[J]. Nutr Cancer, 2000,38(2):192-9.
[155] Wang WP, Iigo M, Sato J, et al. Activation of intestinal mucosal immunity in tumor-bearing mice by lactoferrin[J]. Jpn J Cancer Res, 2000,91(10): 1022-7.
[156] Artym J, Zimecki M, Kruzel ML. Reconstitution of the cellular immune response by lactoferrin in cyclophosphamide-treated mice is correlatedwith renewal of T cell compartment[J]. Immunobiology, 2003,207(3):197 -205.
[157] Talukder MJ, Takeuchi T, Harada E. Characteristics of lactoferrin receptor in bovine intestine: higher binding activity to the epithelium overlying Peyer's patches[J]. J Vet Med A Physiol Pathol Clin Med, 2003,50(3):123-31.
[158] Suzuki YA, Shin K, Lonnerdal B. Molecular cloning and functional expression of a human intestinal lactoferrin receptor[J]. Biochemistry, 2001,40(51):15771-9.
[159] Crouch SP, Slater KJ, Fletcher J. Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin[J]. Blood, 1992,80(1):235-40.
[160] Mattsby-Baltzer I, Roseanu A, Motas C, et al. Lactoferrin or a fragment thereof inhibits the endotoxin-induced interleukin-6 response in human monocytic cells[J]. Pediatr Res, 1996,40(2):257-62.
[161] Haversen L, Ohlsson BG, Hahn-Zoric M, et al. Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-kappa B[J]. Cell Immunol, 2002,220(2):83-95.
[2] Pan MH, Ho CT. Chemopreventive effects of natural dietary compounds on cancer development[J]. Chem Soc Rev, 2008,37(11):2558-74.
[3] Krishnan K, Campbell S, Abdel-Rahman F, et al. Cancer chemoprevention drug targets[J]. Curr Drug Targets, 2003,4(1):45-54.
[4] Qui W, Zheng J. Development of oral and maxillofacial oncology in China[J]. Chin Med J (Engl), 2003,116(10):1567-73.
[5]颌面外科专业委员会口腔颌面肿瘤学组.我国口腔颌面部肿瘤学科现状[J].中华口腔医学杂志, 2006,41(8):481-2.
[6]杨湛.口腔颌面部肿瘤综合治疗设计中的平衡理念[J].华西口腔医学杂志, 2008,26(1):4-7.
[7] Guilford JM, Pezzuto JM. Natural products as inhibitors of carcinoge- nesis[J]. Expert Opin Investig Drugs, 2008,17(9):1341-52.
[8] Kelloff GJ, Crowell JA, Steele VE, et al. Progress in cancer chemopreven- tion[J]. Ann N Y Acad Sci, 1999,889:1-13.
[9] Kelloff GJ, Crowell JA, Steele VE, et al. Progress in cancer chemopreven- tion: development of diet-derived chemopreventive agents[J]. J Nutr, 2000,130(2S Suppl):467S-71S.
[10] Zou DM, Brewer M, Garcia F, et al. Cactus pear: a natural product in cancer chemoprevention[J]. Nutr J, 2005,4:25.
[11] Michels KB, Willett WC, Fuchs CS, et al. Coffee, tea, and caffeine consumption and incidence of colon and rectal cancer[J]. J Natl Cancer Inst, 2005,97(4):282-92.
[12] Tsuda H, Ohshima Y, Nomoto H, et al. Cancer prevention by natural compounds[J]. Drug Metab Pharmacokinet, 2004,19(4):245-63.
[13] Levay PF, Viljoen M. Lactoferrin: a general review[J]. Haematologica,1995,80(3):252-67.
[14] Mason DY, Taylor CR. Distribution of transferrin, ferritin, and lactoferrin in human tissues[J]. J Clin Pathol, 1978,31(4):316-27.
[15] van der Strate BW, Beljaars L, Molema G, et al. Antiviral activities of lactoferrin[J]. Antiviral Res, 2001,52(3):225-39.
[16] Keiichi SZ. Lactoferrin: A Marverlors Protein in Milk?[J]. Anim Sci, 2000,71(4):329-47.
[17]陈历俊,姜铁民.乳铁蛋白生物功能及基因表达[M].北京:科学出版社. 2007.
[18] Marshall K. Therapeutic applications of whey protein[J]. Altern Med Rev, 2004,9(2):136-56.
[19] Pierce A, Colavizza D, Benaissa M, et al. Molecular cloning and sequence analysis of bovine lactotransferrin[J]. Eur J Biochem, 1991, 196(1):177-84.
[20] Baker EN, Baker HM. Molecular structure, binding properties and dynamics of lactoferrin[J]. Cell Mol Life Sci, 2005,62(22):2531-9.
[21] Ellison RT, 3rd, Giehl TJ, LaForce FM. Damage of the outer membrane of enteric gram-negative bacteria by lactoferrin and transferrin[J]. Infect Immun, 1988,56(11):2774-81.
[22] Bellamy W, Takase M, Yamauchi K, et al. Identification of the bactericidal domain of lactoferrin[J]. Biochim Biophys Acta, 1992,1121(1-2):130-6.
[23]冯兴军,王建华,杨雅麟.乳铁蛋白肽作用机制研究进展[J].中国生物工程杂志, 2004,24(1):23-6.
[24]凌雪萍,庞广昌,李国强.乳铁蛋白的最新研究进展[J].食品科学, 2003,24(1):160-3.
[25]陈车生,袁勤生.乳铁蛋白的研究进展[J].食品与药品, 2008,10(1):62-6.
[26]王觐,薛长勇.乳铁蛋白的生理功能及研究进展[J].中国食物与营养, 2008,9:52-4.
[27] Letchoumy PV, Mohan KV, Stegeman JJ, et al. In vitro antioxidativepotential of lactoferrin and black tea polyphenols and protective effects in vivo on carcinogen activation, DNA damage, proliferation, invasion, and angiogenesis during experimental oral carcinogenesis[J]. Oncol Res, 2008,17(5):193-203.
[28]郝高峰,林焕彩.唾液乳铁蛋白和溶菌酶含量与乳牙[J].中华口腔医学杂志, 2009,44(2):82-4.
[29]肖晖,刘宁.乳铁蛋白对大鼠成骨细胞增殖与分化的影响.[J].国际骨科学杂志, 2008,29(3):198-201.
[30]徐红萌,刘小立.乳铁蛋白对SNL神经病理性疼痛大鼠的镇痛作用[J].中国疼痛医学杂志, 2008,14(6):360-3.
[31] Tsuda H, Sekine K, Fujita K, et al. Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies[J]. Biochem Cell Biol, 2002,80(1):131-6.
[32] Masuda C, Wanibuchi H, Sekine K, et al. Chemopreventive effects of bovine lactoferrin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis[J]. Jpn J Cancer Res, 2000,91(6):582-8.
[33] Xu Y. Isolation and Characterization of Whey components[D]. Australia: School of Food Science; 1996.
[34] Tsuda H, Sekine K, Ushida Y, et al. Milk and dairy products in cancer prevention: focus on bovine lactoferrin[J]. Mutat Res, 2000,462(2-3): 227-33.
[35] Tsuda H, Sekine K, Nakamura J, et al. Inhibition of azoxymethane initiated colon tumor and aberrant crypt foci development by bovine lactoferrin administration in F344 rats[J]. Adv Exp Med Biol, 1998,443: 273-84.
[36] Varadhachary A, Wolf JS, Petrak K, et al. Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy[J]. Int J Cancer, 2004,111(3):398-403.
[37] Nishiya K, Horwitz DA. Contrasting effects of lactoferrin on humanlymphocyte and monocyte natural killer activity and antibody-dependent cell-mediated cytotoxicity[J]. J Immunol, 1982,129(6):2519-23.
[38] Sawatzki G, Rich IN. Lactoferrin stimulates colony stimulating factor production in vitro and in vivo[J]. Blood Cells, 1989,15(2):371-85.
[39] Gahr M, Speer CP, Damerau B, et al. Influence of lactoferrin on the function of human polymorphonuclear leukocytes and monocytes[J]. J Leukoc Biol, 1991,49(5):427-33.
[40] Iigo M, Shimamura M, Matsuda E, et al. Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa: a possible explanation for inhibition of carcinogenesis and metastasis[J]. Cytokine, 2004,25(1):36-44.
[41] Shimamura M, Yamamoto Y, Ashino H, et al. Bovine lactoferrin inhibits tumor-induced angiogenesis[J]. Int J Cancer, 2004,111(1):111-6.
[42] Norrby K, Mattsby-Baltzer I, Innocenti M, et al. Orally administered bovine lactoferrin systemically inhibits VEGF(165)-mediated angiogenesis in the rat[J]. Int J Cancer, 2001,91(2):236-40.
[43] Damiens E, El Yazidi I, Mazurier J, et al. Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells[J]. J Cell Biochem, 1999,74(3):486-98.
[44] Xiao Y, Monitto CL, Minhas KM, et al. Lactoferrin down-regulates G1 cyclin-dependent kinases during growth arrest of head and neck cancer cells[J]. Clin Cancer Res, 2004,10(24):8683-6.
[45] Fujita K, Matsuda E, Sekine K, et al. Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats[J]. Carcinogenesis, 2004,25(10):1961-6.
[46] Mignogna MD, Fedele S, Lo Russo L. The World Cancer Report and the burden of oral cancer[J]. Eur J Cancer Prev, 2004,13(2):139-42.
[47] Wolf JS, Li D, Taylor RJ, et al. Lactoferrin inhibits growth of malignant tumors of the head and neck[J]. ORL J Otorhinolaryngol Relat Spec,2003,65(5):245-9.
[48] Wolf JS, Li G, Varadhachary A, et al. Oral lactoferrin results in T cell-dependent tumor inhibition of head and neck squamous cell carcinoma in vivo[J]. Clin Cancer Res, 2007,13(5):1601-10.
[49] McKeown ST, Lundy FT, Nelson J, et al. The cytotoxic effects of human neutrophil peptide-1 (HNP1) and lactoferrin on oral squamous cell carcinoma (OSCC) in vitro[J]. Oral Oncol, 2006,42(7):685-90.
[50] Sakai T, Banno Y, Kato Y, et al. Pepsin-digested bovine lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells[J]. J Pharmacol Sci, 2005,98(1):41-8.
[51] Salgado R, Junius S, Benoy I, et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer[J]. Int J Cancer, 2003,103(5):642-6.
[52] Culig Z, Steiner H, Bartsch G, et al. Interleukin-6 regulation of prostate cancer cell growth[J]. J Cell Biochem, 2005,95(3):497-505.
[53] Kishimoto T. Interleukin-6: discovery of a pleiotropic cytokine[J]. Arthritis Res Ther, 2006,8 Suppl 2:S2.
[54] Scheller J, Rose-John S. Interleukin-6 and its receptor: from bench to bedside[J]. Med Microbiol Immunol, 2006,195(4):173-83.
[55] Rose-John S, Waetzig GH, Scheller J, et al. The IL-6/sIL-6R complex as a novel target for therapeutic approaches[J]. Expert Opin Ther Targets, 2007,11(5):613-24.
[56] Rose-John S, Scheller J, Elson G, et al. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer[J]. J Leukoc Biol, 2006,80(2):227-36.
[57] Hsu HC, Lee YM, Tsai WH, et al. Circulating levels of thrombopoietic and inflammatory cytokines in patients with acute myeloblastic leukemia and myelodysplastic syndrome[J]. Oncology, 2002,63(1):64-9.
[58] Huang SP, Wu MS, Shun CT, et al. Interleukin-6 increases vascularendothelial growth factor and angiogenesis in gastric carcinoma[J]. J Biomed Sci, 2004,11(4):517-27.
[59] Bartsch R, Woehrer S, Raderer M, et al. Serum interleukin-6 levels in patients with gastric MALT lymphoma compared to gastric and pancreatic cancer[J]. Anticancer Res, 2006,26(4B):3187-90.
[60] Bellone S, Watts K, Cane S, et al. High serum levels of interleukin-6 in endometrial carcinoma are associated with uterine serous papillary histology, a highly aggressive and chemotherapy-resistant variant of endometrial cancer[J]. Gynecol Oncol, 2005,98(1):92-8.
[61] Songur N, Kuru B, Kalkan F, et al. Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer[J]. Tumori, 2004,90(2):196-200.
[62] Belluco C, Nitti D, Frantz M, et al. Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer[J]. Ann Surg Oncol, 2000,7(2):133-8.
[63] Negrier S, Perol D, Menetrier-Caux C, et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6--from the Groupe Francais d'Immunotherapie[J]. J Clin Oncol, 2004,22(12):2371-8.
[64] Zakrzewska I, Poznanski J. [Changes of serum il-6 and CRP after chemotherapy in patients with ovarian carcinoma][J]. Pol Merkur Lekarski, 2001,11(63):210-3.
[65] Oka M, Yamamoto K, Takahashi M, et al. Relationship between serum levels of interleukin 6, various disease parameters and malnutrition in patients with esophageal squamous cell carcinoma[J]. Cancer Res, 1996,56(12):2776-80.
[66] Karczewska A, Nawrocki S, Breborowicz D, et al. Expression of interleukin-6, interleukin-6 receptor, and glycoprotein 130 correlates with good prognoses for patients with breast carcinoma[J]. Cancer,2000,88(9):2061-71.
[67] Garcia-Tunon I, Ricote M, Ruiz A, et al. IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma[J]. Histopathology, 2005,47(1):82-9.
[68] Miyamoto Y, Hosotani R, Doi R, et al. Interleukin-6 inhibits radiation induced apoptosis in pancreatic cancer cells[J]. Anticancer Res, 2001,21(4A):2449-56.
[69] Zhang GJ, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma[J]. Anticancer Res, 1999,19(2B):1427-32.
[70] Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine[J]. Cancer Res, 2005,65(23):10794-800.
[71] Yuan H, Liddle FJ, Mahajan S, et al. IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor[J]. Carcinogenesis, 2004,25(11):2247-55.
[72]王越,杨洁,高燕.卵巢癌细胞IL-6、IL-8及其受体表达的研究[J].免疫学杂志, 2006,22(5):475-9.
[73] Ashizawa T, Okada R, Suzuki Y, et al. Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor[J]. Gastric Cancer, 2005,8(2):124-31.
[74]赵向阳,李玉红,许倩. IL-6及其受体和凋亡相关基因在胃癌中的表达[J].承德医学院学报, 2005,22(3):194-5.
[75] el-Far M, Fouda M, Yahya R, et al. Serum IL-10 and IL-6 levels at diagnosis as independent predictors of outcome in non-Hodgkin's lymphoma[J]. J Physiol Biochem, 2004,60(4):253-8.
[76] Lai R, O'Brien S, Maushouri T, et al. Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia[J]. Cancer, 2002,95(5):1071-5.
[77] Guo YQ, Chen SL. [The significance of IGF-1, VEGF, IL-6 in multiple myeloma progression][J]. Zhonghua Xue Ye Xue Za Zhi, 2006,27(4):231-4.
[78] Brozek W, Bises G, Girsch T, et al. Differentiation-dependent expression and mitogenic action of interleukin-6 in human colon carcinoma cells: relevance for tumour progression[J]. Eur J Cancer, 2005,41(15):2347-54.
[79] Pfitzenmaier J, Vessella R, Higano CS, et al. Elevation of cytokine levels in cachectic patients with prostate carcinoma[J]. Cancer, 2003,97(5): 1211-6.
[80] Mehmet N, Refik M, Harputluoglu M, et al. Serum and gastric fluid levels of cytokines and nitrates in gastric diseases infected with Helicobacter pylori[J]. New Microbiol, 2004,27(2):139-48.
[81] Kaminska J, Nowacki MP, Kowalska M, et al. Clinical significance of serum cytokine measurements in untreated colorectal cancer patients: soluble tumor necrosis factor receptor type I--an independent prognostic factor[J]. Tumour Biol, 2005,26(4):186-94.
[82] Nikiteas NI, Tzanakis N, Gazouli M, et al. Serum IL-6, TNFalpha and CRP levels in Greek colorectal cancer patients: prognostic implications[J]. World J Gastroenterol, 2005,11(11):1639-43.
[83] Esfandi F, Mohammadzadeh Ghobadloo S, Basati G. Interleukin-6 level in patients with colorectal cancer[J]. Cancer Lett, 2006,244(1):76-8.
[84] Tan EL, Selvaratnam G, Kananathan R, et al. Quantification of Epstein-Barr virus DNA load, interleukin-6, interleukin-10, transforming growth factor-beta1 and stem cell factor in plasma of patients with nasopharyngeal carcinoma[J]. BMC Cancer, 2006,6:227.
[85] Steiner H, Cavarretta IT, Moser PL, et al. Regulation of growth of prostate cancer cells selected in the presence of interleukin-6 by the anti-interleukin-6 antibody CNTO 328[J]. Prostate, 2006,66(16):1744-52.
[86] Dimitriu C, Martignoni ME, Bachmann J, et al. Clinical impact of cachexia on survival and outcome of cancer patients[J]. Rom J Intern Med,2005,43(3-4):173-85.
[87] Kovacs E. Multiple myeloma and B cell lymphoma. Investigation of IL-6, IL-6 receptor antagonist (IL-6RA), and GP130 antagonist (GP130A) using various parameters in an in vitro model[J]. ScientificWorldJournal, 2006,6:888-98.
[88] Yoshio-Hoshino N, Adachi Y, Aoki C, et al. Establishment of a new interleukin-6 (IL-6) receptor inhibitor applicable to the gene therapy for IL-6-dependent tumor[J]. Cancer Res, 2007,67(3):871-5.
[89] Chakravarti N, Myers JN, Aggarwal BB. Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane)[J]. Int J Cancer, 2006,119(6):1268-75.
[90] Woods KV, El-Naggar A, Clayman GL, et al. Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens[J]. Cancer Res, 1998,58(14):3132-41.
[91] Nakano Y, Kobayashi W, Sugai S, et al. Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma[J]. Jpn J Cancer Res, 1999,90(8):858-66.
[92] Mann EA, Spiro JD, Chen LL, et al. Cytokine expression by head and neck squamous cell carcinomas[J]. Am J Surg, 1992,164(6):567-73.
[93] Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer[J]. Clin Cancer Res, 1999,5(6):1369-79.
[94] Knerer B, Formanek M, Temmel A, et al. The role of fibroblasts from oropharyngeal mucosa in producing proinflammatory and mitogenic cytokines without prior stimulation[J]. Eur Arch Otorhinolaryngol, 1999,256(5):266-70.
[95] Hong SH, Ondrey FG, Avis IM, et al. Cyclooxygenase regulates humanoropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation?[J]. FASEB J, 2000,14(11):1499-507.
[96] Wang LS, Chow KC, Wu CW. Expression and up-regulation of interleukin-6 in oesophageal carcinoma cells by n-sodium butyrate[J]. Br J Cancer, 1999,80(10):1617-22.
[97] Wang YF, Chang SY, Tai SK, et al. Clinical significance of interleukin-6 and interleukin-6 receptor expressions in oral squamous cell carcinoma[J]. Head Neck, 2002,24(9):850-8.
[98] Hess S, Smola H, Sandaradura De Silva U, et al. Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte chemoattractant protein-1 production[J]. J Immunol, 2000,165(4):1939-48.
[99] Zhong Z, Wen Z, Darnell JE, Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6[J]. Science, 1994,264(5155):95-8.
[100] Rubin Grandis J, Zeng Q, Drenning SD. Epidermal growth factor receptor--mediated stat3 signaling blocks apoptosis in head and neck cancer[J]. Laryngoscope, 2000,110(5 Pt 1):868-74.
[101] Kanazawa T, Nishino H, Hasegawa M, et al. Interleukin-6 directly influences proliferation and invasion potential of head and neck cancer cells[J]. Eur Arch Otorhinolaryngol, 2007,264(7):815-21.
[102] Vairaktaris E, Yapijakis C, Serefoglou Z, et al. Gene expression polymorphisms of interleukins-1 beta, -4, -6, -8, -10, and tumor necrosis factors-alpha, -beta: regression analysis of their effect upon oral squamous cell carcinoma[J]. J Cancer Res Clin Oncol, 2008,134(8):821-32.
[103] Vucicevic Boras V, Cikes N, Lukac J, et al. Salivary and serum interleukin 6 and basic fibroblast growth factor levels in patients with oral squamous cell carcinoma[J]. Minerva Stomatol, 2005,54(10):569-73.
[104] St John MA, Li Y, Zhou X, et al. Interleukin 6 and interleukin 8 aspotential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma[J]. Arch Otolaryngol Head Neck Surg, 2004,130(8):929-35.
[105] Kademani D. Oral cancer[J]. Mayo Clin Proc, 2007,82(7):878-87.
[106] Cumberbatch M, Dearman RJ, Uribe-Luna S, et al. Regulation of epidermal Langerhans cell migration by lactoferrin[J]. Immunology, 2000,100(1):21-8.
[107] Guillen C, McInnes IB, Vaughan DM, et al. Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice[J]. J Immunol, 2002,168(8):3950-7.
[108] Bezault J, Bhimani R, Wiprovnick J, et al. Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice[J]. Cancer Res, 1994,54(9):2310-2.
[109] Son HJ, Lee SH, Choi SY. Human lactoferrin controls the level of retinoblastoma protein and its activity[J]. Biochem Cell Biol, 2006,84(3): 345-50.
[110] Weinberg ED. The role of iron in cancer[J]. Eur J Cancer Prev, 1996,5(1):19-36.
[111] Ziere B, Van Veen H, Koopman J. Safety, tolerability, and pharmacokinetics of I.V. administered rhLF in humans. 5th International Conference on Lactoferrin 2001[C]; Alberta (Canada): Pharming Techno- logies.
[112] Hayes TG, Falchook GF, Varadhachary GR, et al. Phase I trial of oral talactoferrin alfa in refractory solid tumors[J]. Invest New Drugs, 2006,24(3):233-40.
[113]汪堃仁,薛绍白,柳惠图.细胞生物学[M].北京:师范大学出版社. 1998:436-511.
[114]沈珝琁,方福德.真核基因表达调控[M].北京:高等教育出版社. 1997:1-14.
[115]宋今丹.医学细胞生物学[M].北京:人民卫生出版社. 2002.
[116] Bartek J, Lukas J. Mammalian G1- and S-phase checkpoints in response to DNA damage[J]. Curr Opin Cell Biol, 2001,13(6):738-47.
[117]桂建芳. RNA加工与细胞周期调控[M].北京:科学出版社. 1998:78-136.
[118] Baldin V, Lukas J, Marcote MJ, et al. Cyclin D1 is a nuclear protein required for cell cycle progression in G1[J]. Genes Dev, 1993,7(5):812-21.
[119] Liu T, Zhu E, Wang L, et al. Abnormal expression of Rb pathway-related proteins in salivary gland acinic cell carcinoma[J]. Hum Pathol, 2005,36(9):962-70.
[120]曹雷,王莉红,刘婷娇等. p27Kip1、cyclin D1蛋白和Ki-67在口腔鳞癌中的表达及其意义[J].广东医学, 2008,30(11):1655-7.
[121] Joe AK, Liu H, Suzui M, et al. Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines[J]. Clin Cancer Res, 2002,8(3):893-903.
[122]张诗式,刘亚敏. p27 kip1 , p21waf1在肿瘤细胞周期调控过程的作用[J].武警医学院学报, 2004,13(3):162-5.
[123] Okabe M, Inagaki H, Murase T, et al. Prognostic significance of p27 and Ki-67 expression in mucoepidermoid carcinoma of the intraoral minor salivary gland[J]. Mod Pathol, 2001,14(10):1008-14.
[124] Hayashi H, Ogawa N, Ishiwa N, et al. High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients[J]. Lung Cancer, 2001,34(1):59-65.
[125] Alkarain A, Slingerland J. Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer[J]. Breast Cancer Res, 2004,6(1):13-21.
[126]侯波,高岩.口腔鳞状细胞癌和癌前病变中细胞周期相关蛋白p27表达的研究[J].中华口腔医学杂志, 2006,41(2):102-5.
[127] Chan FK, Zhang J, Cheng L, et al. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4[J]. Mol Cell Biol, 1995,15(5):2682-8.
[128] Xu JC, Feng ZZ, Zhao SF. [Expression of vascular endothelial growth factor, vascular endothelial growth factor receptor-3 and nm23-H1 in oral squamous cell carcinoma][J]. Zhonghua Kou Qiang Yi Xue Za Zhi, 2007,42(11):681-3.
[129] Hase T, Kawashiri S, Tanaka A, et al. Correlation of basic fibroblast growth factor expression with the invasion and the prognosis of oral squamous cell carcinoma[J]. J Oral Pathol Med, 2006,35(3):136-9.
[130] Shinkaruk S, Bayle M, Lain G, et al. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy[J]. Curr Med Chem Anticancer Agents, 2003,3(2):95-117.
[131] Rusnati M, Presta M. Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies[J]. Curr Pharm Des, 2007,13(20):2025-44.
[132] Presta M, Dell'Era P, Mitola S, et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis[J]. Cytokine Growth Factor Rev, 2005,16(2):159-78.
[133] Pradeep CR, Sunila ES, Kuttan G. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies[J]. Integr Cancer Ther, 2005,4(4):315-21.
[134]王雷,陈应新,高文信.血管内皮细胞生长因子、碱性成纤维细胞生长因子在口腔鳞状细胞癌中的表达研究[J].现代口腔医学杂志, 2004,18(4):299-301.
[135] Cattini PA, Nickel B, Bock M, et al. Immunolocalization of basic fibroblast growth factor (bFGF) in growing and growth-inhibited placental cells: a possible role for bFGF in placental cell development[J]. Placenta, 1991,12(4):341-52.
[136] Yamamoto N, Matsutani S, Yoshitake Y, et al. Immunohistochemical localization of basic fibroblast growth factor in A431 human epidermoid carcinoma cells[J]. Histochemistry, 1991,96(6):479-85.
[137] Lin FF, Chen HZ, Xie X, et al. [Down-regulation of vascular endothelial growth factor expression in ovarian cancer cell line SKOV3 by interferon-gamma][J]. Zhonghua Fu Chan Ke Za Zhi, 2003,38(3):150-3, 3-1.
[138] Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 expression in vitro[J]. World J Gastroenterol, 2004,10(3):393-9.
[139] Mader JS, Smyth D, Marshall J, et al. Bovine lactoferricin inhibits basic fibroblast growth factor- and vascular endothelial growth factor165-induced angiogenesis by competing for heparin-like binding sites on endothelial cells[J]. Am J Pathol, 2006,169(5):1753-66.
[140] Gura T. Chemokines take center stage in inflammatory ills[J]. Science, 1996,272(5264):954-6.
[141] Hermanek P, Sobin LN. TNM classification of malignant tumors of oral and maxillofacial rigion[M]. Geneva:World Health Organization. 2002.
[142] Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis[J]. Neuro Oncol, 2005,7(2):122-33.
[143] Waugh DJ, Wilson C. The interleukin-8 pathway in cancer[J]. Clin Cancer Res, 2008,14(21):6735-41.
[144] Horikawa T, Kaizaki Y, Kato H, et al. Expression of interleukin-8 receptor A predicts poor outcome in patients with nasopharyngeal carcinoma[J]. Laryngoscope, 2005,115(1):62-7.
[145] Jenkins GJ, Harries K, Doak SH, et al. The bile acid deoxycholic acid (DCA) at neutral pH activates NF-kappaB and induces IL-8 expression in oesophageal cells in vitro[J]. Carcinogenesis, 2004,25(3):317-23.
[146]徐文华.白细胞介素8与头颈部鳞癌[J].国外医学口腔医学分册, 2005,32(6):440-2.
[147]贾忠,贺冠海,封光华.趋化因子IL - 8与胃癌组织中浸润炎性细胞相关性分析[J].医学研究杂志, 2007,36(2):42-4.
[148] Millar HJ, Nemeth JA, McCabe FL, et al. Circulating human interleukin-8 as an indicator of cancer progression in a nude rat orthotopic human non-small cell lung carcinoma model[J]. Cancer Epidemiol Biomarkers Prev, 2008,17(8):2180-7.
[149] Maruyama K, Zhang JZ, Nihei Y, et al. Regulatory effects of gamma-interferon on IL-6 and IL-8 secretion by cultured human keratinocytes and dermal fibroblasts[J]. J Dermatol, 1995,22(12):901-6.
[150] Melnikova VO, Bar-Eli M. Bioimmunotherapy for melanoma using fully human antibodies targeting MCAM/MUC18 and IL-8[J]. Pigment Cell Res, 2006,19(5):395-405.
[151] Watanabe H, Iwase M, Ohashi M, et al. Role of interleukin-8 secreted from human oral squamous cell carcinoma cell lines[J]. Oral Oncol, 2002,38(7):670-9.
[152]徐承平,卞修武,王清良.非小细胞肺癌组织芯片中白介素-8的表达及其临床病理意义[J].中国肺癌杂志, 2007,10(5):386-90.
[153] Wolf JS, Chen Z, Dong G, et al. IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas[J]. Clin Cancer Res, 2001,7(6):1812-20.
[154] Kuhara T, Iigo M, Itoh T, et al. Orally administered lactoferrin exerts an antimetastatic effect and enhances production of IL-18 in the intestinal epithelium[J]. Nutr Cancer, 2000,38(2):192-9.
[155] Wang WP, Iigo M, Sato J, et al. Activation of intestinal mucosal immunity in tumor-bearing mice by lactoferrin[J]. Jpn J Cancer Res, 2000,91(10): 1022-7.
[156] Artym J, Zimecki M, Kruzel ML. Reconstitution of the cellular immune response by lactoferrin in cyclophosphamide-treated mice is correlatedwith renewal of T cell compartment[J]. Immunobiology, 2003,207(3):197 -205.
[157] Talukder MJ, Takeuchi T, Harada E. Characteristics of lactoferrin receptor in bovine intestine: higher binding activity to the epithelium overlying Peyer's patches[J]. J Vet Med A Physiol Pathol Clin Med, 2003,50(3):123-31.
[158] Suzuki YA, Shin K, Lonnerdal B. Molecular cloning and functional expression of a human intestinal lactoferrin receptor[J]. Biochemistry, 2001,40(51):15771-9.
[159] Crouch SP, Slater KJ, Fletcher J. Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin[J]. Blood, 1992,80(1):235-40.
[160] Mattsby-Baltzer I, Roseanu A, Motas C, et al. Lactoferrin or a fragment thereof inhibits the endotoxin-induced interleukin-6 response in human monocytic cells[J]. Pediatr Res, 1996,40(2):257-62.
[161] Haversen L, Ohlsson BG, Hahn-Zoric M, et al. Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-kappa B[J]. Cell Immunol, 2002,220(2):83-95.
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