IGFBP-7在结直肠癌实质—间质相互作用中对缝隙连接蛋白Cx43的影响
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摘要
结直肠癌是一类严重危害人类健康的恶性肿瘤。近年来,随着化疗、放疗和生物靶向治疗等多种手段的开展,死亡率有所下降,但发病率仍然很高。在中国,大肠癌发病率增长速度迅猛,尤其是苏浙沪三地。检出率低是影响大肠癌早期发现及治疗效果的重要因素之一。因此,提高大肠癌的早期诊断水平对治疗具有积极意义。
以往对大肠癌的研究主要集中在肿瘤细胞本身,而对肿瘤细胞和间质细胞相互作用对肿瘤影响的研究较少。成纤维细胞是间质微环境中的一个主要成分,它与肿瘤细胞之间存在直接作用和间接作用两种方式。
肿瘤细胞和间质成纤维细胞之间直接相互作用分为缝隙连接、中间连接、桥粒和紧密连接。缝隙连接蛋白43(Connexin43,Cx43)是缝隙连接通道蛋白的一种,与多种肿瘤的发生、发展及转移密切相关,其主要作用机制是通过促进相邻细胞凋亡而抑制肿瘤演进。
本实验首先检测4种结肠癌细胞系SW480、SW620、RKO和HT-29细胞Cx43的表达水平,发现RKO细胞Cx43高表达,而SW480、SW620和HT-29表达较低。由于SW480和SW620细胞具有相同的遗传背景,我们因此选择这两种细胞分别和HSF细胞进行细胞双层共培养和直接混合共培养,以观察它们相互作用对结肠癌细胞SW480和SW620的Cx43表达的影响以及对这两种细胞生长的影响,同时观察相互作用时间质成纤维细胞活化的影响。结果发现SW480和SW620细胞与HSF细胞共培养4d后Cx43表达均增加,同时HSF细胞被活化,并且这种活化的成纤维细胞可以明显促进SW480和SW620细胞的生长。
除了直接相互作用外,间接相互作用也发挥着积极影响,它是细胞因子通过旁分泌和内分泌等形式完成的。TGF-β信号通路是调节肿瘤实质-间质相互作用的一条通路,它在肿瘤早期起抑制癌症的作用,但晚期在外界因素作用下发挥促癌的作用,我们实验室早期研究发现IGFBP-7是一个在肿瘤实质间质相互作用后表达增加的分泌蛋白,它主要在结直肠癌中表达,通过调节IGFs和胰岛素的生物效应,直接参与调节细胞增殖、黏附等,具有促进肿瘤细胞凋亡、老化和减少肿瘤细胞转移等作用。我们前期实验结果表明在肿瘤组织浸润前沿处IGFBP-7表达明显强于实体内部,且这种高表达与病人的生存时间呈正相关。随后细胞学研究发现,结肠癌细胞与间质成纤维细胞相互作用能促进IGFBP-7表达。我们通过TGF-β1刺激SW480细胞和SW620细胞,发现IGFBP-7的表达升高,说明TGF-β1信号通路促进IGFBP-7的表达。
正如前面实验发现的结果,Cx43在肿瘤组织中的表达具有和IGFBP-7同样的改变趋势:浸润前沿的肿瘤细胞表达水平明显高于肿瘤中心区域的肿瘤细胞。随后我们在结肠癌细胞CW2和RKO以及转染IGFBP-7的CW2和RKO细胞中观察其对肿瘤细胞Cx43表达的影响。实验结果发现转染IGFBP-7的CW2细胞中Cx43在mRNA和蛋白水平表达都升高,而在同样转染IGFBP-7的RKO细胞Cx43在蛋白水平升高,而在mRNA水平却降低。对TGF-β1信号通路的Smad2蛋白磷酸化检测时发现转染IGFBP-7的CW2细胞和RKO细胞磷酸化程度都降低,说明Cx43的表达增加可能是通过抑制TGF-β1-Smad2信号通路并促进TGF-β1的其他信号通路来完成的。
Cx43在正常组织中主要表达在细胞膜上,但是在肿瘤组织中表达却在胞浆中。本实验研究发现转染IGFBP-7和空载体的RKO细胞都在胞浆表达Cx43,只是转染IGFBP-7的RKO细胞表达量要高些,但染料示踪实验对RKO-EV和RKO-RP细胞进行了细胞间缝隙连接通讯(GJIC)功能的检测还没有发现这种表达增高能重建GJIC。
本研究得到如下结论:
1.结肠癌细胞SW480/SW620和成纤维细胞HSF共培养促进结肠癌细胞Cx43表达,并促进SW480/SW620细胞生长,同时使成纤维细胞HSF活化。
2.TGF-β1促进SW480细胞IGFBP-7和Cx43 mRNA表达,诱导SW620细胞IGFBP-7 mRNA的表达。
3.IGFBP-7抑制TGF-β1信号通路中Smad2蛋白的磷酸化,促进Cx43的表达。
Colorectal cancer(CRC) is one of the prevalent malignant tumors that threaten our health.In spite of the development of radiotherapy,chemotherapy and bio-targeted therapy,the mortality declines indistinctively.In China,the incidence grows rapidly, especially in ZheJiang,ShangHai and JiangSu provinces.The low early detection rate is one of the important factors affect the cancer therapy.To improve the early detection rate will promote the cancer therapy.
Malignant tumors are composed of tumor cells and stromal cells.The researches mainly focused on the tumor cells.However,the stromal cells receive increasing attention because of their participation at tumor development,progression and metastasis,and of their response to therapy.Fibroblasts are ubiquitous stromal cells which have direct and indirect effects to the tumor cells.
Direct interaction includes gap junction,intermediate junction,desmosome and tight junctions,which play vital role in cell growth,differentiation and migration. Connexin 43(Cx43) is a component of gap junction(GJ) channels,related to tumor. development and progression.It also inhibits the development of cancer by inducing the apoptosis of the adjacent cells.
As Cx43 are expressed widely in SW480,SW620,RKO and HT-29 CRC lines, we chose SW480 and SW620 as our experiment models because they were derived from the different origin of single patient.We co-culture them with human skin fibroblast(HSF) respectively.By RT-PCR,we found Cx43 expression level got increased after co-culture,and HSF was also activated to be cancer-associated fibroblasts(CAFs) which could prompt tumor cells' growth.
For the indirect tumor-stroma interaction,we chose TGF-βsignaling pathway which has been reported to promote cell migration in tumor-stroma interaction.In our pervious study,we found a secreted protein -- IGFBP-7 was expressed intensively in CRC than normal colon mucosa.It had been confirmed that the mechanism for its tumor suppressor role is mainly promoting apoptosis and aging,inhibiting the metastasis of tumor cells,etc.We stimulated SW480 and SW620 with TGF-β1 and found IGFBP-7 expression was increased,implying that TGF-βsignaling played roles in IGFBP-7 expression.Meanwhile,we also found the treatment increased Cx43 expression in SW480 cells.
As we have found Cx43 and IGFBP-7 expressed intensively in tumor infiltrating front than in its center by immunohistochemistry,we chosed CW2 and RKO cell lines to see the effects of IGFBP-7 and Cx43.IGFBP-7 was transfected into those cells and the Cx43 mRNA and protein were detected.IGFBP-7 transfection increased Cx43 mRNA and protein expression in CW2 cells,but decreased mRNA expression in RKO cell lines.The expression of P-Smad2 in TGF-β1 signaling was decreased after transfection of IGFBP-7 into CW2 cells and RKO cells,implying that Cx43 expression was increased by inhibiting TGF-β1- Smad2 cell signaling while promoting other TGF-β1 cell signaling.
Cx43 locate at the cell membrane of normal cells while they move to cytoplasm in cancer cells.We found Cx43 expressed at cytoplasm in both IGFBP-7 transfected RKO cell and pre- IGFBP-7 transfected RKO cell.
We get conclusion from the above results:
1.SW480/SW620-HSF co-culture increased Cx43 expression,prompted growth of SW480 and SW620 and activation of HSF cells.
2.TGF-β1 increased expression of IGFBP-7 and Cx43 in SW480 cells mRNA level and the expression of IGFBP-7 in SW620 cells.
3.IGFBP-7 increased the expression of Cx43 in CW2 cells but decreased Cx43 mRNA level in RKO cells.
以往对大肠癌的研究主要集中在肿瘤细胞本身,而对肿瘤细胞和间质细胞相互作用对肿瘤影响的研究较少。成纤维细胞是间质微环境中的一个主要成分,它与肿瘤细胞之间存在直接作用和间接作用两种方式。
肿瘤细胞和间质成纤维细胞之间直接相互作用分为缝隙连接、中间连接、桥粒和紧密连接。缝隙连接蛋白43(Connexin43,Cx43)是缝隙连接通道蛋白的一种,与多种肿瘤的发生、发展及转移密切相关,其主要作用机制是通过促进相邻细胞凋亡而抑制肿瘤演进。
本实验首先检测4种结肠癌细胞系SW480、SW620、RKO和HT-29细胞Cx43的表达水平,发现RKO细胞Cx43高表达,而SW480、SW620和HT-29表达较低。由于SW480和SW620细胞具有相同的遗传背景,我们因此选择这两种细胞分别和HSF细胞进行细胞双层共培养和直接混合共培养,以观察它们相互作用对结肠癌细胞SW480和SW620的Cx43表达的影响以及对这两种细胞生长的影响,同时观察相互作用时间质成纤维细胞活化的影响。结果发现SW480和SW620细胞与HSF细胞共培养4d后Cx43表达均增加,同时HSF细胞被活化,并且这种活化的成纤维细胞可以明显促进SW480和SW620细胞的生长。
除了直接相互作用外,间接相互作用也发挥着积极影响,它是细胞因子通过旁分泌和内分泌等形式完成的。TGF-β信号通路是调节肿瘤实质-间质相互作用的一条通路,它在肿瘤早期起抑制癌症的作用,但晚期在外界因素作用下发挥促癌的作用,我们实验室早期研究发现IGFBP-7是一个在肿瘤实质间质相互作用后表达增加的分泌蛋白,它主要在结直肠癌中表达,通过调节IGFs和胰岛素的生物效应,直接参与调节细胞增殖、黏附等,具有促进肿瘤细胞凋亡、老化和减少肿瘤细胞转移等作用。我们前期实验结果表明在肿瘤组织浸润前沿处IGFBP-7表达明显强于实体内部,且这种高表达与病人的生存时间呈正相关。随后细胞学研究发现,结肠癌细胞与间质成纤维细胞相互作用能促进IGFBP-7表达。我们通过TGF-β1刺激SW480细胞和SW620细胞,发现IGFBP-7的表达升高,说明TGF-β1信号通路促进IGFBP-7的表达。
正如前面实验发现的结果,Cx43在肿瘤组织中的表达具有和IGFBP-7同样的改变趋势:浸润前沿的肿瘤细胞表达水平明显高于肿瘤中心区域的肿瘤细胞。随后我们在结肠癌细胞CW2和RKO以及转染IGFBP-7的CW2和RKO细胞中观察其对肿瘤细胞Cx43表达的影响。实验结果发现转染IGFBP-7的CW2细胞中Cx43在mRNA和蛋白水平表达都升高,而在同样转染IGFBP-7的RKO细胞Cx43在蛋白水平升高,而在mRNA水平却降低。对TGF-β1信号通路的Smad2蛋白磷酸化检测时发现转染IGFBP-7的CW2细胞和RKO细胞磷酸化程度都降低,说明Cx43的表达增加可能是通过抑制TGF-β1-Smad2信号通路并促进TGF-β1的其他信号通路来完成的。
Cx43在正常组织中主要表达在细胞膜上,但是在肿瘤组织中表达却在胞浆中。本实验研究发现转染IGFBP-7和空载体的RKO细胞都在胞浆表达Cx43,只是转染IGFBP-7的RKO细胞表达量要高些,但染料示踪实验对RKO-EV和RKO-RP细胞进行了细胞间缝隙连接通讯(GJIC)功能的检测还没有发现这种表达增高能重建GJIC。
本研究得到如下结论:
1.结肠癌细胞SW480/SW620和成纤维细胞HSF共培养促进结肠癌细胞Cx43表达,并促进SW480/SW620细胞生长,同时使成纤维细胞HSF活化。
2.TGF-β1促进SW480细胞IGFBP-7和Cx43 mRNA表达,诱导SW620细胞IGFBP-7 mRNA的表达。
3.IGFBP-7抑制TGF-β1信号通路中Smad2蛋白的磷酸化,促进Cx43的表达。
Colorectal cancer(CRC) is one of the prevalent malignant tumors that threaten our health.In spite of the development of radiotherapy,chemotherapy and bio-targeted therapy,the mortality declines indistinctively.In China,the incidence grows rapidly, especially in ZheJiang,ShangHai and JiangSu provinces.The low early detection rate is one of the important factors affect the cancer therapy.To improve the early detection rate will promote the cancer therapy.
Malignant tumors are composed of tumor cells and stromal cells.The researches mainly focused on the tumor cells.However,the stromal cells receive increasing attention because of their participation at tumor development,progression and metastasis,and of their response to therapy.Fibroblasts are ubiquitous stromal cells which have direct and indirect effects to the tumor cells.
Direct interaction includes gap junction,intermediate junction,desmosome and tight junctions,which play vital role in cell growth,differentiation and migration. Connexin 43(Cx43) is a component of gap junction(GJ) channels,related to tumor. development and progression.It also inhibits the development of cancer by inducing the apoptosis of the adjacent cells.
As Cx43 are expressed widely in SW480,SW620,RKO and HT-29 CRC lines, we chose SW480 and SW620 as our experiment models because they were derived from the different origin of single patient.We co-culture them with human skin fibroblast(HSF) respectively.By RT-PCR,we found Cx43 expression level got increased after co-culture,and HSF was also activated to be cancer-associated fibroblasts(CAFs) which could prompt tumor cells' growth.
For the indirect tumor-stroma interaction,we chose TGF-βsignaling pathway which has been reported to promote cell migration in tumor-stroma interaction.In our pervious study,we found a secreted protein -- IGFBP-7 was expressed intensively in CRC than normal colon mucosa.It had been confirmed that the mechanism for its tumor suppressor role is mainly promoting apoptosis and aging,inhibiting the metastasis of tumor cells,etc.We stimulated SW480 and SW620 with TGF-β1 and found IGFBP-7 expression was increased,implying that TGF-βsignaling played roles in IGFBP-7 expression.Meanwhile,we also found the treatment increased Cx43 expression in SW480 cells.
As we have found Cx43 and IGFBP-7 expressed intensively in tumor infiltrating front than in its center by immunohistochemistry,we chosed CW2 and RKO cell lines to see the effects of IGFBP-7 and Cx43.IGFBP-7 was transfected into those cells and the Cx43 mRNA and protein were detected.IGFBP-7 transfection increased Cx43 mRNA and protein expression in CW2 cells,but decreased mRNA expression in RKO cell lines.The expression of P-Smad2 in TGF-β1 signaling was decreased after transfection of IGFBP-7 into CW2 cells and RKO cells,implying that Cx43 expression was increased by inhibiting TGF-β1- Smad2 cell signaling while promoting other TGF-β1 cell signaling.
Cx43 locate at the cell membrane of normal cells while they move to cytoplasm in cancer cells.We found Cx43 expressed at cytoplasm in both IGFBP-7 transfected RKO cell and pre- IGFBP-7 transfected RKO cell.
We get conclusion from the above results:
1.SW480/SW620-HSF co-culture increased Cx43 expression,prompted growth of SW480 and SW620 and activation of HSF cells.
2.TGF-β1 increased expression of IGFBP-7 and Cx43 in SW480 cells mRNA level and the expression of IGFBP-7 in SW620 cells.
3.IGFBP-7 increased the expression of Cx43 in CW2 cells but decreased Cx43 mRNA level in RKO cells.
引文
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[47] Shiokawa-Sawada M, Mano H, Hanada K, et al. Down-regulation of gap junctional intercellular communication between osteoblastic MC3T3-E1 cells by basic fibroblast growth factor and a phorbol ester.(12-O-tetradecanoylphorbol-13-acetate). J Bone Miner Res. 1997;12(8):1165-73.
[48] Tacheau C, Fontaine J, Loy J, et al. TGF-beta induces connexin43 gene expression in normal murine mammary gland epithelial cells via activation of p38 and PI3K/AKT signaling pathways. J Cell Physiol. 2008;217(3):759-68.
[49] Leithe E, Rivedal E. Epidermal growth factor regulates ubiquitination,internalization and proteasome-dependent degradation of connexin43. J Cell Sci.2004; 117(Pt 7):1211-20.
[50] Burt JM, Steele TD. Selective effect of PDGF on connexin43 versus connexin40 comprised gap junction channels. Cell Commun Adhes. 2003; 10(4-6):287-91.
[51] Cushing P, Bhalla R, Johnson AM, et al. Nerve growth factor increases connexin43 phosphorylation and gap junctional intercellular communication. J Neurosci Res. 2005;82(6):788-801.
[52] Kang J, Kang N, Lovatt D, et al. Connexin 43 hemichannels are permeable to ATP. J Neurosci. 2008;28(18):4702-11.
[53] Eugenin EA, Braiies MC, Berman JW, et al. TNF-alpha plus IFN-gamma induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses. J Immunol.2003;170(3):1320-8.
[54] Wajapeyee N, Serra RW, Zhu X,et al. Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP-7.Cell. 2008;132(3):363-374.
[55] Guasch G, Schober M, Pasolli HA, et al. Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia.Cancer Cell. 2007;12(4):313-27.
[56] Lin SJ, Lerch TF, Cook RW, et al. The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding . Reproduction.2006;132(2):179-190.
[57] Gold LI. The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncog. 1999;10(4):303-360.
[58] Kutsukake M, Ishihara R, Momose K, et al. Circulating IGF-binding protein 7 (IGFBP-7) levels are elevated in patients with endometriosis or undergoing diabetic hemodialysis. Reprod Biol Endocrinol.2008;19(6):54.
[59] Xu HT, Li QC, Zhang YX, et al. Connexin 43 recruits E-cadherin expression and inhibits the malignant behaviour of lung cancer cells. Folia Histochem Cytobiol. 2008;46(3):315-21.
[60] Majoul IV, Onichtchouk D, Butkevich E, et al. Limiting transport steps and novel interactions of Connexin-43 along the secretory pathway. Histochem Cell Biol. 2009;132(3):263-80.
[61] Park DJ, Freitas TA, Wallick CJ, et al. Molecular dynamics and in vitro analysis of Connexin43: A new 14-3-3 mode-1 interacting protein. Protein Sci.2006;15(10):2344-55.
[1]Ozanne BW,Spence HJ,McGarry LC,et al.Transcription factors control invasion:AP-1 the first among equals.Oncogene,2007,26(1):1-10
[2]Milde-Langosch K The Fos family of transcription factors and their role in tumourigenesis.Eur J Cancer,2005,41(16):2449-61
[3]Gurzov EN,Bakiri L,Alfaro JM,et al.Targeting c-Jun and JunB proteins as potential anticancer cell therapy.Oncogene,2008,27(5):641-52
[4]Weitzman JB,Fiette L.Matsuo K,et al.JunD protects cells from p53-dependent senescence and Apoptosis.Mol Cell,2000,6(5):1109-19.
[5] Lam E, Kilani RT, Li Y,et al. Stratifin-Induced Matrix Metalloproteinase-1 in Fibroblast Is Mediated by c-fos and p38 Mitogen-Activated Protein Kinase Activation. J Invest Dermatol, 2005,125(2):230-8
[6] Heinrich R, Livne E, Ben-Izhak O,et al. The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene. J Biol Chem,2004,279(7):5708-15
[7] Belguise K, Kersual N, Galtier F,et al. FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells.Oncogene ,2005,24(8): 1434-44
[8] Hill R, Song Y, Cardiff RD,et al. Selective Evolution of Stromal Mesenchyme with p53 Loss in Response to Epithelial Tumorigenesis. Cell,2005,123(6):1001-11
[9] Ashida R, Tominaga K, Sasaki E,et al. AP-1 and colorectal cancer. Inflammopharmacology 2005, 13(1-3):113-25
[10] Wang Q, Sun Z, Yang HS,et al. Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both beta-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. Oncogene,2008, 27(11):1527-35
[11] Li W, Wu CL, Febbo P,et al. Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells. Am J Pathol,2007, 171(4): 1189-98
[12] Haiti M, Karagiannidis Al, Bister K. Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis. Oncogene, 2006 , 25(29):4043-55
[13] Singer CF, Kronsteiner N, Hudelist G,et al. Interleukin 1 System and Sex Steroid Receptor Expression in Human Breast Cancer: Interleukin la Protein Secretion Is Correlated with Malignant Phenotype. Clin Cancer Res,2003,9(13):4877-83
[14] Kajanne R, Miettinen P, Mehlem A,et al. EGF-R Regulates MMP Function in Fibroblasts Through MAPK and AP-1 Pathways. J Cell Physiol,2007, 212(2):489-97
[15]Westermarck J,Li S,Jaakkola P,et al.Activation of Fibroblast Collagenase-1Expression by Tumor Cells of Squamous Cell Carcinomas Is Mediated by p38Mitogen-activated Protein Kinase and c-Jun NH2-terminal Kinase-2.Cancer Res,2000,60(24):7156-62
[16]Ye Lin,Qingzhang Li.The Regulation of Development and Lactation of the Mammary Gland by Leptin.The Journal of American Science,2005,1(1):63-67
[17]Hirota T,Irie K,Okamoto R,et al.Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway.Oncogene,2005,24(13):2229-35
[18]Wajapeyee N,Serra RW,Zhu X,et al.Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP-7.Ce11,2008,132(3):363-74
[19]Guicheux J,Lemonnier J,Ghayor C,et al.Activation of p38 mitogen-activated protein kinase and c-jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation.J Bone Miner Res,2003,18(11):2060-8.
[20]Dewever O,Westbroek W,Verloes A,et al.Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-beta or wounding.J Cell Sci,2004,117(Pt 20):4691-703.
[21]Zhang Y,Feng XH,Derynck R.Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription.Nature,1998,394(6696):909-13
[22]Santibafiez JF.NK mediates TGF-betal-induced epithelial mesenchymal tran-sdifferentiation of mouse transformed keratinocytes.FEBS Letters,2006,580(22):5385-91
[23]Szabowski A,Maas-Szabowski N,ANDRECHT S,et al.c-Jun and JunB Antagonistically Control Cytokine-Regulated Mesenchymal-Epidermal Interaction in Skin.Cell,2000,103(5):745-55
[24]Nateri AS,Spencer-Dene B,Behrens A.Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development.Nature,2005,437(7056):281-5
[25]Schiller M,Brhm M,Dennler S,et al.Mitogen-and stress-activated protein kinase 1 is critical for interleukin-l-induced,CREB-mediated,c-fos gene expression in keratinocytes Oncogene,2006,25(32):4449-57
[26]胡勇斌,曾庆富,冯德云,等.激活蛋白-1调控转化生长因子β1诱导的人肺成纤维细胞I型胶原分泌.中南大学学报医学版,2007,32(5):776-781
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[45] Ogawa T, Hayashi T, Yorioka N, et al. Hexamethylene bisacetamide protects peritoneal mesothelial cells from glucose. Kidney Int. 2001;60(3):996-1008.
[46] Yao J, Hiramatsu N, Zhu Y, et al. Nitric oxide-mediated regulation of connexin43 expression and gap junctional intercellular communication in mesangial cells. J Am Soc Nephrol. 2005;16(1):58-67.
[47] Shiokawa-Sawada M, Mano H, Hanada K, et al. Down-regulation of gap junctional intercellular communication between osteoblastic MC3T3-E1 cells by basic fibroblast growth factor and a phorbol ester.(12-O-tetradecanoylphorbol-13-acetate). J Bone Miner Res. 1997;12(8):1165-73.
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[50] Burt JM, Steele TD. Selective effect of PDGF on connexin43 versus connexin40 comprised gap junction channels. Cell Commun Adhes. 2003; 10(4-6):287-91.
[51] Cushing P, Bhalla R, Johnson AM, et al. Nerve growth factor increases connexin43 phosphorylation and gap junctional intercellular communication. J Neurosci Res. 2005;82(6):788-801.
[52] Kang J, Kang N, Lovatt D, et al. Connexin 43 hemichannels are permeable to ATP. J Neurosci. 2008;28(18):4702-11.
[53] Eugenin EA, Braiies MC, Berman JW, et al. TNF-alpha plus IFN-gamma induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses. J Immunol.2003;170(3):1320-8.
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[1]Ozanne BW,Spence HJ,McGarry LC,et al.Transcription factors control invasion:AP-1 the first among equals.Oncogene,2007,26(1):1-10
[2]Milde-Langosch K The Fos family of transcription factors and their role in tumourigenesis.Eur J Cancer,2005,41(16):2449-61
[3]Gurzov EN,Bakiri L,Alfaro JM,et al.Targeting c-Jun and JunB proteins as potential anticancer cell therapy.Oncogene,2008,27(5):641-52
[4]Weitzman JB,Fiette L.Matsuo K,et al.JunD protects cells from p53-dependent senescence and Apoptosis.Mol Cell,2000,6(5):1109-19.
[5] Lam E, Kilani RT, Li Y,et al. Stratifin-Induced Matrix Metalloproteinase-1 in Fibroblast Is Mediated by c-fos and p38 Mitogen-Activated Protein Kinase Activation. J Invest Dermatol, 2005,125(2):230-8
[6] Heinrich R, Livne E, Ben-Izhak O,et al. The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene. J Biol Chem,2004,279(7):5708-15
[7] Belguise K, Kersual N, Galtier F,et al. FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells.Oncogene ,2005,24(8): 1434-44
[8] Hill R, Song Y, Cardiff RD,et al. Selective Evolution of Stromal Mesenchyme with p53 Loss in Response to Epithelial Tumorigenesis. Cell,2005,123(6):1001-11
[9] Ashida R, Tominaga K, Sasaki E,et al. AP-1 and colorectal cancer. Inflammopharmacology 2005, 13(1-3):113-25
[10] Wang Q, Sun Z, Yang HS,et al. Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both beta-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. Oncogene,2008, 27(11):1527-35
[11] Li W, Wu CL, Febbo P,et al. Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells. Am J Pathol,2007, 171(4): 1189-98
[12] Haiti M, Karagiannidis Al, Bister K. Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis. Oncogene, 2006 , 25(29):4043-55
[13] Singer CF, Kronsteiner N, Hudelist G,et al. Interleukin 1 System and Sex Steroid Receptor Expression in Human Breast Cancer: Interleukin la Protein Secretion Is Correlated with Malignant Phenotype. Clin Cancer Res,2003,9(13):4877-83
[14] Kajanne R, Miettinen P, Mehlem A,et al. EGF-R Regulates MMP Function in Fibroblasts Through MAPK and AP-1 Pathways. J Cell Physiol,2007, 212(2):489-97
[15]Westermarck J,Li S,Jaakkola P,et al.Activation of Fibroblast Collagenase-1Expression by Tumor Cells of Squamous Cell Carcinomas Is Mediated by p38Mitogen-activated Protein Kinase and c-Jun NH2-terminal Kinase-2.Cancer Res,2000,60(24):7156-62
[16]Ye Lin,Qingzhang Li.The Regulation of Development and Lactation of the Mammary Gland by Leptin.The Journal of American Science,2005,1(1):63-67
[17]Hirota T,Irie K,Okamoto R,et al.Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway.Oncogene,2005,24(13):2229-35
[18]Wajapeyee N,Serra RW,Zhu X,et al.Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP-7.Ce11,2008,132(3):363-74
[19]Guicheux J,Lemonnier J,Ghayor C,et al.Activation of p38 mitogen-activated protein kinase and c-jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation.J Bone Miner Res,2003,18(11):2060-8.
[20]Dewever O,Westbroek W,Verloes A,et al.Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-beta or wounding.J Cell Sci,2004,117(Pt 20):4691-703.
[21]Zhang Y,Feng XH,Derynck R.Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription.Nature,1998,394(6696):909-13
[22]Santibafiez JF.NK mediates TGF-betal-induced epithelial mesenchymal tran-sdifferentiation of mouse transformed keratinocytes.FEBS Letters,2006,580(22):5385-91
[23]Szabowski A,Maas-Szabowski N,ANDRECHT S,et al.c-Jun and JunB Antagonistically Control Cytokine-Regulated Mesenchymal-Epidermal Interaction in Skin.Cell,2000,103(5):745-55
[24]Nateri AS,Spencer-Dene B,Behrens A.Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development.Nature,2005,437(7056):281-5
[25]Schiller M,Brhm M,Dennler S,et al.Mitogen-and stress-activated protein kinase 1 is critical for interleukin-l-induced,CREB-mediated,c-fos gene expression in keratinocytes Oncogene,2006,25(32):4449-57
[26]胡勇斌,曾庆富,冯德云,等.激活蛋白-1调控转化生长因子β1诱导的人肺成纤维细胞I型胶原分泌.中南大学学报医学版,2007,32(5):776-781
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