课题一：MMP-7在肺癌患者肿瘤组织中的表达和外周血中蛋白水平及其临床意义 课题二：傅里叶变换红外光谱技术鉴别肺组织良恶性的研究
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摘要
研究背景：肺癌是目前世界发病率和死亡率最高的恶性肿瘤,严重威胁人类健康,据不完全统计,2008年,全球新发肺癌患者160多万,死亡140多万,且近年来,其发病率和死亡率呈逐年上升趋势。目前,所有肺癌患者的5年生存率在15%左右,但早期肺癌患者行根治性手术切除后5年生存率可达70%以上。所以,研究肺癌的生物学特性、找到能够早期发现肺癌的方法显得尤为重要,而肿瘤标志物的研究是近年来研究的一个热点。本实验室在前期的工作中建立了分析肺癌组织释放到体液中的游离蛋白的新模型,建立了包含1200多种蛋白的肺癌相关蛋白数据库,为肺癌肿瘤标志物的寻找提供了新的线索。本研究对其中的基质金属蛋白酶7(Matrix metalloproteinase7, MMP-7)在肺癌患者肿瘤组织中的表达和外周血血浆中的蛋白水平及其临床意义进行研究。
材料和方法：①采用酶联免疫吸附试验(Enzyme linked immunosorbent assay, ELISA)检测214例外周血血浆样本(114例肺癌患者、100例正常对照)以测定其MMP-7蛋白的血浆浓度,检验其诊断肺癌的敏感性、特异性和准确度,并分析其浓度与肺癌患者的临床特征之间的关系。②对97例肺癌组织标本(来自上述114例肺癌患者石蜡包埋组织切片)进行免疫组织化学(Immunohistochemisty,IHC)染色,以分析MMP-7蛋白在肺癌组织和正常支气管、肺泡组织中的表达隋况及其与肺癌患者临床特征之间的关系。
实验结果：①ELISA检测结果显示：肺癌患者外周血血浆中MMP-7蛋白浓度(n=114, Median=0.72ng/ml)显著高于正常人外周血血浆中MMP-7蛋白浓度(n=100,Median=0.30ng/ml, P<0.001),当cutoff值为0.56ng/ml时,MMP-7检测肺癌的敏感性为62.3%,特异性为76.0%；肺癌患者外周血血浆中MMP-7蛋白浓度与肺癌患者的年龄、性别、吸烟史、肿瘤大小、病理类型、肿瘤分化程度、淋巴结转移及分期比较均无统计学意义(P>0.05)；②免疫组化染色的结果显示：肺癌组织中MMP-7(62.91%)的蛋白表达明显高于正常支气管(10%)和肺泡组织(0%)(P<0.001),且肺癌组织中MMP-7蛋白表达与肺癌患者的肿瘤分化程度呈负相关,与淋巴结转移呈正相关(P值分别为0.025和0.017),与肺癌患者的其他临床特征无明显相关(P>0.05)。
结论：(DMMP-7在肺癌患者外周血血浆中的蛋白水平和肿瘤组织中的表达均显著升高,提示MMP-7与其他MMPs家族成员一样,在肿瘤的生长、侵袭、转移中起重要作用,我们认为,MMP-7可能为肺癌的一种很好的肿瘤标志物,且因肺癌组织中MMP-7的蛋白表达与肿瘤的分化程度呈负相关,而与有无淋巴结转移呈正相关,所以,MMP-7可能成为预测肺癌患者预后的重要检测指标和将来新的肺癌靶向药物的靶标。②肺癌患者外周血血浆中MMP-7蛋白浓度与肺癌患者的临床特征之间无相关性,这一结论也证实了肿瘤标志物具有辅助诊断肿瘤作用,但与肿瘤患者的临床资料特征无明显相关性。
研究背景：随着影像学技术的发展,目前临床上诊断的孤立性肺结节越来越多,但由于临床各诊断方法的局限性而影响了诊断的可靠性及诊断效率,绝大多数患者最终需手术切除,根据术中快速冰冻结果明确诊断和决定手术方案,但由于术中快速冰冻亦有一定的局限性,有时,并不能达到快速准确判断的目的。傅里叶变换红外光谱技术(Fourier Transform Infrared Spectroscopy, FTIR Spectroscopy)通过探测分子的构成和结构变化,可在疾病早期快速有效区分组织的良恶性。本研究旨在应用FTIR光谱技术扫描离体肺组织,通过建立判别方程式初步达到区分肺良恶性组织的目的。
材料与方法：术中获取30例肺癌组织和30例正常肺组织标本,应用FTIR光谱仪并联合衰减全反射探头(Attenuated total reflection, ATR)对离体肺组织进行扫描。应用OMNIC软件(Thermo Nicolet, Boston)进行光谱获取。对获得的肺组织图谱应用Spapro2.2软件(北京大学化学与分子工程学院,北京)分析,测定参数包括组织图谱峰强、峰位、半峰宽,并计算峰强比值,1460cm-1是峰强中最稳定的谱带参数,因而使用此点的峰强进行相对峰强比值的计算。比较两组各参数,应用SPSS19.0软件进行数据分析,对正态分布数据行t检验,非正态分布行Mann-Whitney U检验,P<0.05为具有统计学差异。建立区分肺良、恶性组织的典则判别方程式。应用wilk lambda stepwise选择对判别方程式贡献最大的变量参数,并应用回顾验证和逐次剔除验证的方法衡量典则判别方程式的判别效力。计算敏感性和特异性,并将判别分类结果同病理金标准进行比较,检验此判别方程式的准确性。
结果：在60个标本的光谱判别中,30例为恶性,另30例为非恶性。两组统计学比较中,峰位1640cm-1,1303cm-1,1120cm-1和1085cm-1有显著统计学差异；峰强1546cm-1,1460cm-1,1400cm-1,1165cm-1和1120cm-’有显著统计学差异；相对峰强比值1743/1460,1640/1460,1546/1460,1240/1460和1120/1460有显著统计学差异；半峰宽在1640cm-1,1460cm-1,1400cm-1,1303cm-1,1240cm-1,1165cm-1,1120cm-1,和1085cm-1处有显著统计学差异。典则判别方程式建立如下：
Lmalignant=3.241X1+3.687X2+106.193X3+116.557X4-137.103
=3.613X,+3.200X2+79.639X3+151.923X4-131.738
X1表示1303cm-1处半峰宽； X2表示1240cm-1处半峰宽；X3表示1120cm-1处相对峰强比值；X4表示1546cm-1处峰强。
ATR-FTIR光谱判别结果同病理金标准相比,其判别敏感性和特异性均为96.7%。
结论：FTIR光谱技术联合典则判别统计学方法,可以达到快速而准确的鉴别良恶性肺组织的目的。
BACKGROUND&AIM:As we all know, Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death throughout the world. According to statistics, it accounts for13%(1.6million) of the total cancer cases and18%(1.4million) of the deaths in2008. Lung cancer rates are increasing in countries such as China and several other countries. Overall, the5-year survival rate is approximately15%, whereas the5-year survival rate for patients of stage I with radically surgical resection is over70%. Therefore we need a more thorough study to know the biological behavior of lung cancer and to find some new detecting methods at the early stage. In order to achieve this, we use tumor marker in the present study.
In previous study of our lab, we provide a novel method to detect free proteins that released to plasma by lung cancer tumor cells to establish lung cancer-related protein profiles in peripheral blood. First, we analyzed the proteins released into serum-free conditioned medium (CM) by lung cancer cells and its adjacent normal bronchial cells through short-time culture, and then we established lung cancer related protein database (over1200proteins), which includes Matrix metalloproteinase7(MMP-7). MMP-7has been found to perform several biological functions in tumor promotion, growth and metastasis. The aim of this study is to examine the protein levels of MMP-7in tumor tissue and peripheral blood of lung cancer patients, and evaluate its potential clinical value.
METHODS:①Peripheral blood samples were obtained from114lung cancer patients and100healthy control subjects. MMP-7protein levels in the plasma were measured by enzyme-linked immunosorbent assay.②97lung cancer tissue specimens (found from the same114patients) were also examined by immunohistochemistry to determine the protein express of MMP-7.
RESULTS:①ELISA results:The plasma protein levels of MMP-7in lung cancer patients(median=0.72ng/mL) were significantly higher than those in healthy control subjects (median=0.30ng/mL)(P<0.001).When the cutoff of MMP-7protein level was set at0.56ng/mL, the sensitivity and specificity of detecting lung cancer were62.3%and76.0%, respectively. However, the plasma protein levels of MMP-7in lung cancer patients did not statistically differ in age, sex, smoking status, tumor size, pathological classification, as well as lymphatic metastasis and stage (P>0.05).②IHC results:The MMP-7positive rates in lung cancer tissues was62.91%, and it is significantly higher than normal alveoli and bronchial tissues(P<0.001). The positive rates of MMP-7in lymphatic metastasis and low classification of tumor were significantly higher than those in non lymphatic metastasis and high+mediate classification (P value is0.017and0.025, respectively). But there are no other correlations between the MMP-7expression and the patients'other clinical characteristics, such as age, sex, smoking status, tumor size and stages (P>0.05).
CONCLUSION:①The plasma protein levels and the expression of MMP-7increase in the peripheral blood of lung cancer patients and tumor tissues. It indicates that MMP-7plays a big role in tumor's growth and metastasis as well as other members of MMPs. The expression of MMP-7in lung cancer tissues is higher in lymphatic metastasis and low classification patients. All of this shows that MMP-7is a potential outstanding tumor marker and prognostic factor for lung cancer patients and maybe a new target for drug thearapy.②The fact that no significant correlation between the protein levels of MMP-7and lung cancer patients'clinical characteristics were observed in this study warrants further analysis in larger samples.
BACKGROUND:With the development of radiological techniques, more and more solitary pulmonary nodules (SPN) have been found. However, the diagnostic accuracy and diagnostic efficient are not satisfactory as the result of limited current diagnosis methods. Most patients still need surgical treatment and surgeons generally rely on intra-operative fast frozen section (FSD) technique to help deciding corrected diagnosis and operation strategy. But FSD also has its limitations. Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) Spectroscopy could serve as a diagnostic tool for detecting and discriminating different diseases, with the absorption of electromagnetic radiation from400cm-1-4000cm-1, is sensitive to changes in molecular compositions and structures. The aim of this preliminary study was to distinguish malignant and non-malignant lung tissues with ATR-FTIR spectroscopy.
METHODS:60lung tissue samples were obtained from30patients underwent pulmonary lobectomy. Samples were examined with ATR-FTIR spectroscopy before histological diagnosis. Peak positions, intensities and full width at half maximum (FWHM) of each absorbent band were measured, and the relative intensity ratios were calculated. FTIR parameterrs of malignant and non-malignant samples of the two groups were compared. Normally, distributed data were analyzed with the t test; otherwise the Mann-Whitney U test was used. P<0.05was considered statistically significant. Canonical discriminant analysis (CDA) was used to distinguish malignant and non-malignant lung samples. Wilk's lambda stepwise discriminant program was applied to help select variables that contribute most to the discriminant function. Two discriminant equations were established. Retrospective validation and leave-one-out cross-validation were also used to evaluate the discriminant power of the CD A. Sensitivity, specificity were calculated. Pathologic results as gold standard were compared with the CDA classification later.
RESULTS:Of the two groups, peak positions of1640cm-1,1303cm-1,1120cm-1,1085cm-1were significantly different; peak intensities of1546cm-1,1460cm-1,1400cm-1,1165cm-1,1120cm-1, and relative intensity ratios of1743cm-1,1640cm-1,1546cm-1,1240cm-1,1120cm-1of the two groups were distinctly different from each other; The differences of FWHM1640cm-1,1460cm-1,1400cm-1,1303cm-1,1240cm-1,1165cm-1,1120cm-1,1085cm-1between the malignant and non-malignant sample groups were statistically significant.
Functions of Canonical Discriminant Analysis were established as follows: Lmalignant=3.241X1+3.687X2+106.193X3+116.557X4-137.103Lnon-malignant=3.613X1+3.200X2+79.639X3+151.923X4-131.738X1represents FWHM at1303cm-1; X2signifies FWHM at1240cm-1; X3indicates peak intensity ratio at1120cm-1; X4presents as peak intensity at1546cm-1. The sensitivity and specificity of the CDA were all96.7%.
CONCLUSIONS:ATR-FTIR spectroscopy is a promising method for detection of malignant lung tissue, and could be proved useful in lung tumor surgery.
材料和方法：①采用酶联免疫吸附试验(Enzyme linked immunosorbent assay, ELISA)检测214例外周血血浆样本(114例肺癌患者、100例正常对照)以测定其MMP-7蛋白的血浆浓度,检验其诊断肺癌的敏感性、特异性和准确度,并分析其浓度与肺癌患者的临床特征之间的关系。②对97例肺癌组织标本(来自上述114例肺癌患者石蜡包埋组织切片)进行免疫组织化学(Immunohistochemisty,IHC)染色,以分析MMP-7蛋白在肺癌组织和正常支气管、肺泡组织中的表达隋况及其与肺癌患者临床特征之间的关系。
实验结果：①ELISA检测结果显示：肺癌患者外周血血浆中MMP-7蛋白浓度(n=114, Median=0.72ng/ml)显著高于正常人外周血血浆中MMP-7蛋白浓度(n=100,Median=0.30ng/ml, P<0.001),当cutoff值为0.56ng/ml时,MMP-7检测肺癌的敏感性为62.3%,特异性为76.0%；肺癌患者外周血血浆中MMP-7蛋白浓度与肺癌患者的年龄、性别、吸烟史、肿瘤大小、病理类型、肿瘤分化程度、淋巴结转移及分期比较均无统计学意义(P>0.05)；②免疫组化染色的结果显示：肺癌组织中MMP-7(62.91%)的蛋白表达明显高于正常支气管(10%)和肺泡组织(0%)(P<0.001),且肺癌组织中MMP-7蛋白表达与肺癌患者的肿瘤分化程度呈负相关,与淋巴结转移呈正相关(P值分别为0.025和0.017),与肺癌患者的其他临床特征无明显相关(P>0.05)。
结论：(DMMP-7在肺癌患者外周血血浆中的蛋白水平和肿瘤组织中的表达均显著升高,提示MMP-7与其他MMPs家族成员一样,在肿瘤的生长、侵袭、转移中起重要作用,我们认为,MMP-7可能为肺癌的一种很好的肿瘤标志物,且因肺癌组织中MMP-7的蛋白表达与肿瘤的分化程度呈负相关,而与有无淋巴结转移呈正相关,所以,MMP-7可能成为预测肺癌患者预后的重要检测指标和将来新的肺癌靶向药物的靶标。②肺癌患者外周血血浆中MMP-7蛋白浓度与肺癌患者的临床特征之间无相关性,这一结论也证实了肿瘤标志物具有辅助诊断肿瘤作用,但与肿瘤患者的临床资料特征无明显相关性。
研究背景：随着影像学技术的发展,目前临床上诊断的孤立性肺结节越来越多,但由于临床各诊断方法的局限性而影响了诊断的可靠性及诊断效率,绝大多数患者最终需手术切除,根据术中快速冰冻结果明确诊断和决定手术方案,但由于术中快速冰冻亦有一定的局限性,有时,并不能达到快速准确判断的目的。傅里叶变换红外光谱技术(Fourier Transform Infrared Spectroscopy, FTIR Spectroscopy)通过探测分子的构成和结构变化,可在疾病早期快速有效区分组织的良恶性。本研究旨在应用FTIR光谱技术扫描离体肺组织,通过建立判别方程式初步达到区分肺良恶性组织的目的。
材料与方法：术中获取30例肺癌组织和30例正常肺组织标本,应用FTIR光谱仪并联合衰减全反射探头(Attenuated total reflection, ATR)对离体肺组织进行扫描。应用OMNIC软件(Thermo Nicolet, Boston)进行光谱获取。对获得的肺组织图谱应用Spapro2.2软件(北京大学化学与分子工程学院,北京)分析,测定参数包括组织图谱峰强、峰位、半峰宽,并计算峰强比值,1460cm-1是峰强中最稳定的谱带参数,因而使用此点的峰强进行相对峰强比值的计算。比较两组各参数,应用SPSS19.0软件进行数据分析,对正态分布数据行t检验,非正态分布行Mann-Whitney U检验,P<0.05为具有统计学差异。建立区分肺良、恶性组织的典则判别方程式。应用wilk lambda stepwise选择对判别方程式贡献最大的变量参数,并应用回顾验证和逐次剔除验证的方法衡量典则判别方程式的判别效力。计算敏感性和特异性,并将判别分类结果同病理金标准进行比较,检验此判别方程式的准确性。
结果：在60个标本的光谱判别中,30例为恶性,另30例为非恶性。两组统计学比较中,峰位1640cm-1,1303cm-1,1120cm-1和1085cm-1有显著统计学差异；峰强1546cm-1,1460cm-1,1400cm-1,1165cm-1和1120cm-’有显著统计学差异；相对峰强比值1743/1460,1640/1460,1546/1460,1240/1460和1120/1460有显著统计学差异；半峰宽在1640cm-1,1460cm-1,1400cm-1,1303cm-1,1240cm-1,1165cm-1,1120cm-1,和1085cm-1处有显著统计学差异。典则判别方程式建立如下：
Lmalignant=3.241X1+3.687X2+106.193X3+116.557X4-137.103
=3.613X,+3.200X2+79.639X3+151.923X4-131.738
X1表示1303cm-1处半峰宽； X2表示1240cm-1处半峰宽；X3表示1120cm-1处相对峰强比值；X4表示1546cm-1处峰强。
ATR-FTIR光谱判别结果同病理金标准相比,其判别敏感性和特异性均为96.7%。
结论：FTIR光谱技术联合典则判别统计学方法,可以达到快速而准确的鉴别良恶性肺组织的目的。
BACKGROUND&AIM:As we all know, Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death throughout the world. According to statistics, it accounts for13%(1.6million) of the total cancer cases and18%(1.4million) of the deaths in2008. Lung cancer rates are increasing in countries such as China and several other countries. Overall, the5-year survival rate is approximately15%, whereas the5-year survival rate for patients of stage I with radically surgical resection is over70%. Therefore we need a more thorough study to know the biological behavior of lung cancer and to find some new detecting methods at the early stage. In order to achieve this, we use tumor marker in the present study.
In previous study of our lab, we provide a novel method to detect free proteins that released to plasma by lung cancer tumor cells to establish lung cancer-related protein profiles in peripheral blood. First, we analyzed the proteins released into serum-free conditioned medium (CM) by lung cancer cells and its adjacent normal bronchial cells through short-time culture, and then we established lung cancer related protein database (over1200proteins), which includes Matrix metalloproteinase7(MMP-7). MMP-7has been found to perform several biological functions in tumor promotion, growth and metastasis. The aim of this study is to examine the protein levels of MMP-7in tumor tissue and peripheral blood of lung cancer patients, and evaluate its potential clinical value.
METHODS:①Peripheral blood samples were obtained from114lung cancer patients and100healthy control subjects. MMP-7protein levels in the plasma were measured by enzyme-linked immunosorbent assay.②97lung cancer tissue specimens (found from the same114patients) were also examined by immunohistochemistry to determine the protein express of MMP-7.
RESULTS:①ELISA results:The plasma protein levels of MMP-7in lung cancer patients(median=0.72ng/mL) were significantly higher than those in healthy control subjects (median=0.30ng/mL)(P<0.001).When the cutoff of MMP-7protein level was set at0.56ng/mL, the sensitivity and specificity of detecting lung cancer were62.3%and76.0%, respectively. However, the plasma protein levels of MMP-7in lung cancer patients did not statistically differ in age, sex, smoking status, tumor size, pathological classification, as well as lymphatic metastasis and stage (P>0.05).②IHC results:The MMP-7positive rates in lung cancer tissues was62.91%, and it is significantly higher than normal alveoli and bronchial tissues(P<0.001). The positive rates of MMP-7in lymphatic metastasis and low classification of tumor were significantly higher than those in non lymphatic metastasis and high+mediate classification (P value is0.017and0.025, respectively). But there are no other correlations between the MMP-7expression and the patients'other clinical characteristics, such as age, sex, smoking status, tumor size and stages (P>0.05).
CONCLUSION:①The plasma protein levels and the expression of MMP-7increase in the peripheral blood of lung cancer patients and tumor tissues. It indicates that MMP-7plays a big role in tumor's growth and metastasis as well as other members of MMPs. The expression of MMP-7in lung cancer tissues is higher in lymphatic metastasis and low classification patients. All of this shows that MMP-7is a potential outstanding tumor marker and prognostic factor for lung cancer patients and maybe a new target for drug thearapy.②The fact that no significant correlation between the protein levels of MMP-7and lung cancer patients'clinical characteristics were observed in this study warrants further analysis in larger samples.
BACKGROUND:With the development of radiological techniques, more and more solitary pulmonary nodules (SPN) have been found. However, the diagnostic accuracy and diagnostic efficient are not satisfactory as the result of limited current diagnosis methods. Most patients still need surgical treatment and surgeons generally rely on intra-operative fast frozen section (FSD) technique to help deciding corrected diagnosis and operation strategy. But FSD also has its limitations. Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) Spectroscopy could serve as a diagnostic tool for detecting and discriminating different diseases, with the absorption of electromagnetic radiation from400cm-1-4000cm-1, is sensitive to changes in molecular compositions and structures. The aim of this preliminary study was to distinguish malignant and non-malignant lung tissues with ATR-FTIR spectroscopy.
METHODS:60lung tissue samples were obtained from30patients underwent pulmonary lobectomy. Samples were examined with ATR-FTIR spectroscopy before histological diagnosis. Peak positions, intensities and full width at half maximum (FWHM) of each absorbent band were measured, and the relative intensity ratios were calculated. FTIR parameterrs of malignant and non-malignant samples of the two groups were compared. Normally, distributed data were analyzed with the t test; otherwise the Mann-Whitney U test was used. P<0.05was considered statistically significant. Canonical discriminant analysis (CDA) was used to distinguish malignant and non-malignant lung samples. Wilk's lambda stepwise discriminant program was applied to help select variables that contribute most to the discriminant function. Two discriminant equations were established. Retrospective validation and leave-one-out cross-validation were also used to evaluate the discriminant power of the CD A. Sensitivity, specificity were calculated. Pathologic results as gold standard were compared with the CDA classification later.
RESULTS:Of the two groups, peak positions of1640cm-1,1303cm-1,1120cm-1,1085cm-1were significantly different; peak intensities of1546cm-1,1460cm-1,1400cm-1,1165cm-1,1120cm-1, and relative intensity ratios of1743cm-1,1640cm-1,1546cm-1,1240cm-1,1120cm-1of the two groups were distinctly different from each other; The differences of FWHM1640cm-1,1460cm-1,1400cm-1,1303cm-1,1240cm-1,1165cm-1,1120cm-1,1085cm-1between the malignant and non-malignant sample groups were statistically significant.
Functions of Canonical Discriminant Analysis were established as follows: Lmalignant=3.241X1+3.687X2+106.193X3+116.557X4-137.103Lnon-malignant=3.613X1+3.200X2+79.639X3+151.923X4-131.738X1represents FWHM at1303cm-1; X2signifies FWHM at1240cm-1; X3indicates peak intensity ratio at1120cm-1; X4presents as peak intensity at1546cm-1. The sensitivity and specificity of the CDA were all96.7%.
CONCLUSIONS:ATR-FTIR spectroscopy is a promising method for detection of malignant lung tissue, and could be proved useful in lung tumor surgery.
引文
1. Siegel R, Naishadham D, Jemal A. Cancer Statistics,2012. CA Cancer J Clin,2012; 62(5):10-29.
2. Cersosimo RJ. Lung cancer:a review. Am J Health Syst Pharm.2002; 59(7):611-642.
3. Martin J, Ginsberg RJ, Venkatraman ES, et al. Long-term results of combined-modality therapy in resectable non-small cell lung cancer. J Clin Oncol.2002; 20(8):1989-1995.
4. Reed CC, Waterhouse A, Kirby S, et al. Decorin prevents metastatic spreading of breast cancer. Oncogene.2005; 24(6):1104-1110.
5. Xiao T, Ying W, Li L, et al. An approach to studying lung cancer-related proteins in human blood. Mol Cell Proteomics.2005; 4(10):1480-1486.
6. Deryugina El, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev,2006; 25(1):9-34.
7. Rebecca Siegel, Deepa Naishadham, Ahmedin Jemal. Cancer Statistics,2012. Cancer J Clic,2012; 62:10-29.
8. 陈万青,张思维,邹小农.中国肺癌发病死亡的估计和流行趋势研究.中国肺癌杂志,2010；13(5)：488-493.
9. Ahmedin Jemal, Freddie Bray, Melissa M. Center, et al. Global Cancer Statistics. Cancer J Clic,2011; 61:69-90.
10. Bar-Or A, Nuttall RK, Duddy M, et al. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain,2003; 126(12):2738-2749.
11. Muller D, Quantin B, Gesnel MC, et al. The collagenase gene family in humans consists of at least four members. Biochem J,1988; 253(1):187-192.
12. Yamamoto H, Adachi Y, Itoh F, et al. Association of matrilysin expression with recurrence and poor prognosis in human esophageal squamous cell carcinoma. Cancer Res,1999; 59(14):3313-3316.
13. Aihara R, Mochiki E, Nakabayashi T, et al. Clinical significance of mucin phenotype, beta-catenin and matrix metalloproteinase 7 in early undifferentiated gastric carcinoma. Br J Surg,2005; 92(4):454-462.
14. Adachi Y, Yamamoto H, Itoh F, et al. Clinicopathologic and prognostic significance of matrilysin expression at the invasive front in human colorectal cancers. Int J Cancer,2001; 95(5):290-294.
15. Yamamoto H, Iku S, Adachi Y, et al. Association of trypsin expression with tumour progression and matrilysin expression in human colorectal cancer. J Pathol,2003; 199(2):176-184.
16. Jones LE, Humphreys MJ, Campbell F, et al. Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer:increased expression of matrix metalloproteinase-7 predicts poor survival. Clin Cancer Res, 2004; 10(8):2832-2845.
17. Deryugina El, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev.2006; 25(1):9-34.
18.郭伟.外周血MMP-7mRNA表达与非小细胞肺癌侵袭、转移的关系研究[D].太原：山西医科大学,2010.
19.刘一臻,王明荣.肺癌早期诊断研究进展.中国肺癌杂志.2011；14(5)：429-434.
20.宋宝辉,杨清波,张金涛,等.MMP-7和uPAR在非小细胞肺癌的表达及其意义.临床肿瘤学杂志.2009；14(12)：1069-1072.
21.张扬,李才,张莲珠,等.MMP-26和MMP-7在非小细胞肺癌中的表达及其临床意义.现代生物医学进展.2009；9(18)：3471-3474.
22. Liu D, Nakano J, Ishikawa S, et al. Overexpression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer. Lung Cancer,2007; 58(3):384-391.
23.梅同华,罗彬,马英.基质金属蛋白酶-2、-7在肺癌中的表达.重庆医学.2004；33(3)：376-378.
24. Wang Y, Addess KJ, Chen J, et al. MMDB:annotating protein sequences with Entrez's 3D-structure database. Nucleic Acids Res.2007; 35:298-300.
25. Wilson CL, Matrisian LM. Matrilysin:an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol.1996; 28(2):123-136.
26. Shiomi T, Okada Y. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev.2003; 22(2-3):145-152.
27. Matono H, Oda Y, Nakamori M, et al. Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. Hum Pathol.2008; 39(12):1802-1808.
28. Mohan MJ, Seaton T, Mitchell J, et al. The tumor necrosis factor-alpha converting enzyme (TACE):a unique metalloproteinase with highly defined substrate selectivity. Biochemistry.2002; 41(30):9462-9469.
29. Vargo-Gogola T, Crawford HC, Fingleton B, et al. Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. Arch Biochem Biophys.2002; 408(2):155-161.
30. Yu WH, Woessner JF Jr, McNeish JD, et al. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev.2002; 16(3):307-323.
31. Noe V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci.2001; 114(Pt 1):111-118.
32. von Bredow DC, Nagle RB, Bowden GT, et al. Cleavage of beta 4 integrin by matrilysin. Exp Cell Res.1997; 236(1):341-345.
33. Hulboy DL, Gautam S, Fingleton B, et al. The influence of matrix metalloproteinase-7 on early mammary tumorigenesis in the multiple intestinal neoplasia mouse. Oncol Rep.2004; 12(1):13-17.
34. Tsunezumi J, Yamamoto K, Higashi S, et al. Matrilysin (matrix metalloprotease-7) cleaves membrane-bound annexin II and enhances binding of tissue-type plasminogen activator to cancer cell surfaces. FEBS J.2008; 275(19):4810-4823.
35. Powell WC, Fingleton B, Wilson CL, et al. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol.1999; 9(24):1441-1447.
36. Liu H, Huang J, Wu B, et al. Matrilysin inhibits proliferation and modulates sensitivity of lung cancer cells to FasL-mediated apoptosis. Med Oncol.2008; 25(4):419-430.
37. Liu H, Zhang T, Wu B, et al. Chronic exposure to exogenous matrilysin induces chemoresistance and enhances Bcl-2 expression in A549 lung adenocarcinoma cells. Mol Biol Rep.2009; 36(8):2099-2109.
38. Ikeda S, Inagaki M, Takabe K, et al. Rapid detection of matrix metalloproteinase-7 and carcinoembryonic antigen mRNA expression in intraoperative pleural lavage samples using the reverse transcriptase loop-mediated isothermal amplification method. Acta Cytol.2009; 53(3):283-291.
39. Blackhall FH, Shepherd FA. Small cell lung cancer and targeted therapies. Curr Opin Oncol.2007,19(2):103-108.
40. Yuan J, Dutton CM, Scully SP. RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion. J Orthop Res.2005; 23(6):1467-1474.
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2. Cersosimo RJ. Lung cancer:a review. Am J Health Syst Pharm.2002; 59(7):611-642.
3. Martin J, Ginsberg RJ, Venkatraman ES, et al. Long-term results of combined-modality therapy in resectable non-small cell lung cancer. J Clin Oncol.2002; 20(8):1989-1995.
4. Reed CC, Waterhouse A, Kirby S, et al. Decorin prevents metastatic spreading of breast cancer. Oncogene.2005; 24(6):1104-1110.
5. Xiao T, Ying W, Li L, et al. An approach to studying lung cancer-related proteins in human blood. Mol Cell Proteomics.2005; 4(10):1480-1486.
6. Deryugina El, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev,2006; 25(1):9-34.
7. Rebecca Siegel, Deepa Naishadham, Ahmedin Jemal. Cancer Statistics,2012. Cancer J Clic,2012; 62:10-29.
8. 陈万青,张思维,邹小农.中国肺癌发病死亡的估计和流行趋势研究.中国肺癌杂志,2010；13(5)：488-493.
9. Ahmedin Jemal, Freddie Bray, Melissa M. Center, et al. Global Cancer Statistics. Cancer J Clic,2011; 61:69-90.
10. Bar-Or A, Nuttall RK, Duddy M, et al. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain,2003; 126(12):2738-2749.
11. Muller D, Quantin B, Gesnel MC, et al. The collagenase gene family in humans consists of at least four members. Biochem J,1988; 253(1):187-192.
12. Yamamoto H, Adachi Y, Itoh F, et al. Association of matrilysin expression with recurrence and poor prognosis in human esophageal squamous cell carcinoma. Cancer Res,1999; 59(14):3313-3316.
13. Aihara R, Mochiki E, Nakabayashi T, et al. Clinical significance of mucin phenotype, beta-catenin and matrix metalloproteinase 7 in early undifferentiated gastric carcinoma. Br J Surg,2005; 92(4):454-462.
14. Adachi Y, Yamamoto H, Itoh F, et al. Clinicopathologic and prognostic significance of matrilysin expression at the invasive front in human colorectal cancers. Int J Cancer,2001; 95(5):290-294.
15. Yamamoto H, Iku S, Adachi Y, et al. Association of trypsin expression with tumour progression and matrilysin expression in human colorectal cancer. J Pathol,2003; 199(2):176-184.
16. Jones LE, Humphreys MJ, Campbell F, et al. Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer:increased expression of matrix metalloproteinase-7 predicts poor survival. Clin Cancer Res, 2004; 10(8):2832-2845.
17. Deryugina El, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev.2006; 25(1):9-34.
18.郭伟.外周血MMP-7mRNA表达与非小细胞肺癌侵袭、转移的关系研究[D].太原：山西医科大学,2010.
19.刘一臻,王明荣.肺癌早期诊断研究进展.中国肺癌杂志.2011；14(5)：429-434.
20.宋宝辉,杨清波,张金涛,等.MMP-7和uPAR在非小细胞肺癌的表达及其意义.临床肿瘤学杂志.2009；14(12)：1069-1072.
21.张扬,李才,张莲珠,等.MMP-26和MMP-7在非小细胞肺癌中的表达及其临床意义.现代生物医学进展.2009；9(18)：3471-3474.
22. Liu D, Nakano J, Ishikawa S, et al. Overexpression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer. Lung Cancer,2007; 58(3):384-391.
23.梅同华,罗彬,马英.基质金属蛋白酶-2、-7在肺癌中的表达.重庆医学.2004；33(3)：376-378.
24. Wang Y, Addess KJ, Chen J, et al. MMDB:annotating protein sequences with Entrez's 3D-structure database. Nucleic Acids Res.2007; 35:298-300.
25. Wilson CL, Matrisian LM. Matrilysin:an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol.1996; 28(2):123-136.
26. Shiomi T, Okada Y. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev.2003; 22(2-3):145-152.
27. Matono H, Oda Y, Nakamori M, et al. Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. Hum Pathol.2008; 39(12):1802-1808.
28. Mohan MJ, Seaton T, Mitchell J, et al. The tumor necrosis factor-alpha converting enzyme (TACE):a unique metalloproteinase with highly defined substrate selectivity. Biochemistry.2002; 41(30):9462-9469.
29. Vargo-Gogola T, Crawford HC, Fingleton B, et al. Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. Arch Biochem Biophys.2002; 408(2):155-161.
30. Yu WH, Woessner JF Jr, McNeish JD, et al. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev.2002; 16(3):307-323.
31. Noe V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci.2001; 114(Pt 1):111-118.
32. von Bredow DC, Nagle RB, Bowden GT, et al. Cleavage of beta 4 integrin by matrilysin. Exp Cell Res.1997; 236(1):341-345.
33. Hulboy DL, Gautam S, Fingleton B, et al. The influence of matrix metalloproteinase-7 on early mammary tumorigenesis in the multiple intestinal neoplasia mouse. Oncol Rep.2004; 12(1):13-17.
34. Tsunezumi J, Yamamoto K, Higashi S, et al. Matrilysin (matrix metalloprotease-7) cleaves membrane-bound annexin II and enhances binding of tissue-type plasminogen activator to cancer cell surfaces. FEBS J.2008; 275(19):4810-4823.
35. Powell WC, Fingleton B, Wilson CL, et al. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol.1999; 9(24):1441-1447.
36. Liu H, Huang J, Wu B, et al. Matrilysin inhibits proliferation and modulates sensitivity of lung cancer cells to FasL-mediated apoptosis. Med Oncol.2008; 25(4):419-430.
37. Liu H, Zhang T, Wu B, et al. Chronic exposure to exogenous matrilysin induces chemoresistance and enhances Bcl-2 expression in A549 lung adenocarcinoma cells. Mol Biol Rep.2009; 36(8):2099-2109.
38. Ikeda S, Inagaki M, Takabe K, et al. Rapid detection of matrix metalloproteinase-7 and carcinoembryonic antigen mRNA expression in intraoperative pleural lavage samples using the reverse transcriptase loop-mediated isothermal amplification method. Acta Cytol.2009; 53(3):283-291.
39. Blackhall FH, Shepherd FA. Small cell lung cancer and targeted therapies. Curr Opin Oncol.2007,19(2):103-108.
40. Yuan J, Dutton CM, Scully SP. RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion. J Orthop Res.2005; 23(6):1467-1474.
1. Goldstraw P, Crowley J, Chansky K, et al. International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project:proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2:706-714.
2. International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355:1763-1771.
3. Van't Westeinde SC, van Klaveren RJ. Screening and early detection of lung cancer. Cancer J 2011; 1:3-10.
4. Mazzone P, Jain P, Arroliga AC. Bronchoscopy and needle biopsy techniques for diagnosis and staging of lung cancer. Clin Chest Med 2002; 23:137-158, ix.
5. Nakamura H, Kawasaki N, Hagiwara M, et al. Endoscopic evaluation of centrally located early squamous cell carcinoma of the lung. Cancer 2001; 91:1142-1147.
6. Marchevsky AM, Changsri C, Gupta I, et al. Frozen section diagnoses of small pulmonary nodules:accuracy and clinical implications. Ann Thorac Surg 2004; 78: 1755-1759.
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