摘要
[背景]特发性肺纤维化(IPF)是一类原因未明的慢性进展性间质性肺疾病,以成纤维细胞的异常增殖和分化以及细胞外基质的堆积为特点,目前缺乏有效的治疗手段。近年来逐渐发现IPF与肺癌无论是在临床还是发病机制方面均存在许多相关性,有学者提出从肿瘤学的角度出发研究IPF,可能会对IPF有更全面认识。表观遗传学尤其是DNA甲基化引起的抑癌基因失活参与肿瘤的发生发展,DNA甲基化在IPF中的研究正逐步展开。肌成纤维母细胞是IPF发病中重要的效应细胞,肺泡上皮间充质转化是形成肌成纤维母细胞的一个重要来源。已知CDHl以及RUNX3缺失促进上皮间充质转化过程,同时CDH1及RUNX3也是重要的肿瘤抑制基因,多种肿瘤中存在CDHl及RUNX3甲基化现象。但是IPF中CDH1及RUNX3是否也存在甲基化现象目前尚无相关报道。
[目的]本研究拟检测IPF组织学标本中CDHl及RUNX3甲基化状态,并分析与临床指标相关性。
[方法]本实验应用甲基化特异性PCR(Methylation specific PCR, MSP)方法检测10株细胞系、16例IPF患者和17对肺癌及切缘正常组织中CDH1及RUNX3启动子的甲基化状态。利用real-time qPCR技术检测10株细胞系中CDH1及RUNX3mRNA表达水平。利用Western Blot方法检测10株细胞系中CDH1蛋白(E-cadherin)表达并利用免疫组织化学方法检测17对肺癌及切缘正常组织以及16例IPF组织E-cadherin表达。回顾16例IPF患者临床资料,分析CDH1及RUNX3甲基化状态与其临床指标相关性;分析17例肺癌患者E-cadherin表达与CDH1甲基化相关性。
[结果]
1、发生CDH1甲基化细胞系(293T, BGC823, RKO, MGC803, Hela, MKN45)比未发生甲基化细胞系(MKN74, MCF7, HCT116, AGS)其mRNA表达水平明显降低。
2、发生CDH1完全甲基化细胞系(RKO, Hela, MGC803)无CDH1蛋白(E-cadherin)表达。
3、发生RUNX3甲基化细胞系(RKO,293T, MCF7, MKN74, AGS, MGC803, Hela)比未发生甲基化细胞系(BGC823, HCT116, MKN45)其mRNA表达水平明显降低。
4、11例(68.75%)IPF组织有CDHl启动子甲基化,7例(41.18%)肺癌组织中有CDHl启动子甲基化,切缘正常组织无CDHl甲基化。IPF中CDHl启动子甲基化与病人年龄、性别、吸烟、病程无关。
5、9例(52.94%)肺癌组织E-cadherin表达异常,CDHl甲基化患者中E-cadherin异常表达的比例(71.4%)比正常表达比例(28.6%)高。2例CDHl甲基化的IPF患者,其成纤维细胞灶表面被覆的上皮细胞中E-cadherin表达减弱或缺失。
6、7例(43.75%)IPF组织中有RUNX3启动子甲基化,9例(52.94%)肺癌组织中有RUNX3启动子甲基化,3例(17.65%)切缘正常组织有RUNX3启动子甲基化。IPF中RUNX3启动子甲基化与病人年龄、性别、吸烟、病程无关。
[结论]
1、细胞系试验表明CDHl及RUNX3启动子区域高甲基化在转录水平上抑制目的基因表达。
2、IPF同肺癌一样,存在CDH1及RUNX3启动子区域甲基化现象,其中CDHl甲基化发生率显著高于切缘正常组织。IPF发生抑癌基因甲基化可能是IPF容易合并肺癌的原因之一。
3、IPF组织成纤维细胞灶表面被覆的肺泡上皮细胞E-cadherin表达缺失或减弱可能与CDHl甲基化有关。CDHl甲基化引起蛋白表达缺失,促进EMT进程,参与IPF发病。
Backgroud
Idiopathic pulmonary fibrosis(IPF)is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, without effective therapy. Its pathological character is the fibroblastic foci which comprises of aggregates of mesenchymal cells and extra cellular matrix(ECM). More and more evidences from clinic and basic research show that IPF is a diseae with similarities and links to cancer. Further research on IPF from an oncologist's view will help us get a more comprehensive understanding of IPF. Epigenetic alterations, espeically DNA methylation, participate in the pathogenesis of cancer. DNA methylation research in IPF is gradually conducted. Myofibroblasts are key effector cells in pulmonary fibrosis and one of their cellular origins is considered to be pulmonary epithelial cell which go under epithelial mesenchymal transition(EMT). The loss of CDH1and RUNX3promotes EMT process. CDH1and RUNX3are thought to be function as tumor suppressor genes and are inactivated or downregulated by promoter hypermethylation in a variety of tumors. However, the promoter hypermethylation of CDH1and RUNX3in IPF have not been reported.
Objective
To detect the methylation status of CDH1and RUNX3promoter region CpG islands in IPF and analyse the relationship between genes'methylation frequency and clinic parameters.
Methods
In the present study, we examined the methylation status of CDH1and RUNX3promoter region CpG islands in10cell lines,16cases of IPF,17cases of lung cancer and17cases of matching non-neoplastic tissue by methylation-specific PCR. CDH1and RUNX3gene expression were examined in10cell lines by real-time quantitative PCR. The protein expression of CDH1(E-cadherin) was examined in10cell lines by Western Blot and in17cases of lung cancer,17cases of matching non-neoplastic tissues and16cases of IPF tissues which have CDH1promoter hypermethylation by immunohistochemistry. We also reviewed the clinic data of IPF patients and analysed the correlations between the two genes'methylation frequency and clinic parameters. We also analysed the correlations between E-cadherin expression and CDH1promoter methylation status in17cases of lung cancer.
Results
1. The expression of CDH1mRNA were lower in those cell lines which were promoter hypermethylation, including293T, BGC823, RKO,MGC803, Hela, MKN45than in those cell lines which were promoter unmethylaion, including MKN74, MCF7, HCT116,AGS.
2. Those cell lines which were completely methylated, including RKO, Hela, MGC803, were not detected in expression of CDH1protein level(E-cadherin).
3. The expression of RUNX3mRNA were lower in those cell lines which were promoter hypermethylation, including RKO,293T, MCF7, MKN74, AGS, MGC803, Hela than in those cell lines which were promoter unmethylaion, including BGC823, HCT116,MKN45.
4. Aberrant hypermethylation of CDH1was detected in11of16(68.75%) IPF tissues,7of17(41.18%) lung cancer tissues. Whereas none of the matched normal lung tissues presented hypermethylation of CDH1. Statistical analyses of the correlation between CDH1promoter hypermethylation and clinic parameters demonstrated that there was no significant difference between methylated and unmethylated patients with regard to age, gender, smoke history and duration of disease.
5. Aberrant CDH1protein(E-cadherin) expression was detected in9/17(52.94%) lung cancer tissues. In CDH1methylated lung cacer patients, aberrant E-cadherin expression(71.4%)is higher than normal expression(28.6%). Alveolar epithelial cells covering fibroblastic foci showed negative or slight positive immunoreactivity to E-cadherin in two cases of IPF tissues which are CDH1promoter hypermethylation.
6. Aberrant hypermethylation of RUNX3was detected in7of16(43.75%) IPF tissues,9of17(52.94%) lung cancer tissues and3of17(17.65%) matched normal lung tissues. Statistical analyses of the correlation between RUNX3promoter hypermethylation and clinic parameters demonstrated that there was no significant difference between methylated and unmethylated patients with regard to age, gender, smoke history and duration of disease.
Conclusions
1. The cell lines experiments show that the transcription of CDH1and RUNX3may be downregulated by promoter hypermethylation.
2. Promoter hypermethylation of CDH1and RUNX3are observed in IPF, similar to lung cancer.The gene CDH1methylation incidence shows significantly higher when it compares to matching normal lung tissues. Tumor suppressor genes'promoter hypermethylation in IPF tissues is one of the reasons that IPF patients are susceptible to tumor.
3. Alveolar epithelial cells covering fibroblastic foci showed negative or slight positive immunoreactivity to E-cadherin in IPF tissues may be related with CDH1promoter hypermethylation. The loss of E-cadherin due to CDH1methylation may take part in EMT process of IPF.
引文
[1]. Bouros, D., et al., Association of malignancy with diseases causing interstitial pulmonary changes. Chest,2002.121(4):p.1278-89.
[2]. Nagai, A., et al., Lung cancer in patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med,1992.167(3):p.231-7.
[3]. Harris, J.M., et al., Cryptogenic fibrosing alveolitis and lung cancer:the BTS study. Thorax,2010.65(1):p.70-6.
[4]. Kropski, J.A., et al., Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis. Dis Model Mech,2013.6(1):p.9-17.
[5]. Rabinovich, E.I., et al., Global methylation patterns in idiopathic pulmonary fibrosis. PLoS One,2012.7(4):p. e33770.
[6]. Kage, H. and Z. Borok, EMT and interstitial lung disease:a mysterious relationship. Curr Opin Pulm Med,2012.18(5):p.517-23.
[7]. Phan, S.H., The myofibroblast in pulmonary fibrosis. Chest,2002.122(6 Suppl): p.286S-289S.
[8]. Vancheri, C., Idiopathic pulmonary fibrosis:an altered fibroblast proliferation linked to cancer biology. Proc Am Thorac Soc,2012.9(3):p.153-7.
[9]. Bird, A., Perceptions of epigenetics. Nature,2007.447(7143):p.396-8.
[10]. Feinberg, A.P. and B. Vogelstein, Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature,1983.301(5895):p.89-92.
[11]. Herman, J.G. and S.B. Baylin, Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med,2003.349(21):p.2042-54.
[12]. Sanders, Y.Y., et al., Thy-1 promoter hypermethylation:a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol,2008.39(5):p. 610-8.
[13]. Huang, S.K., et al., Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. Am J Pathol,2010.177(5):p. 2245-55.
[14]. Cisneros, J., et al., Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2012.303(4):p. L295-303.
[15]. Hu, B., et al., Epigenetic regulation of myofibroblast differentiation by DNA methylation. Am J Pathol,2010.177(1):p.21-8.
[16]. Tepass, U., et al., Cadherins in embryonic and neural morphogenesis. Nat Rev Mol Cell Biol,2000.1(2):p.91-100.
[17]. Thiery, J.P., Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer,2002.2(6):p.442-54.
[18]. Foty, R.A. and M.S. Steinberg, Cadherin-mediated cell-cell adhesion and tissue segregation in relation to malignancy. Int J Dev Biol,2004.48(5-6):p.397-409.
[19]. Kang, Y. and J. Massague, Epithelial-mesenchymal transitions:twist in development and metastasis. Cell,2004.118(3):p.277-9.
[20]. Kim, D.S., et al., Aberrant methylation of E-cadherin and H-cadherin genes in nonsmall cell lung cancer and its relation to clinicopathologic features. Cancer,2007. 110(12):p.2785-92.
[21]. Luo, J., et al., [Methylation status of CDH1 gene in preoperative abdominal lavage of patients with gastric cancer and its clinical significance]. Zhonghua Wei Chang Wai Ke Za Zhi,2012.15(7):p.710-4.
[22]. Sebova, K., et al., RASSF1A and CDH1 hypermethylation as potential epimarkers in breast cancer. Cancer Biomark,2011.10(1):p.13-26.
[23]. Takino, H., et al., Thymic extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue:a gene methylation study. Leuk Lymphoma,2013.
[24]. Jayaraj, P., et al., Epigenetic inactivation of the E-cadherin gene in eyelid sebaceous gland carcinoma. Br J Dermatol,2012.167(3):p.583-90.
[25]. Ito, K., RUNX3 in oncogenic and anti-oncogenic signaling in gastrointestinal cancers. J Cell Biochem,2011.112(5):p.1243-9.
[26]. Voon, D.C., et al., Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity. Stem Cells,2012.30(10):p.2088-99.
[27]. Bangsow, C., et al., The RUNX3 gene--sequence, structure and regulated expression. Gene,2001.279(2):p.221-32.
[28]. Tang, Y., F. Wu and C. Hu, [RUNX3 promoter hypermethylation and prognosis of early surgically resected non-small cell lung cancers]. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2011.36(7):p.650-4.
[29]. Kang, K.A., et al., Epigenetic changes induced by oxidative stress in colorectal cancer cells:methylation of tumor suppressor RUNX3. Tumour Biol,2012.33(2):p. 403-12.
[30]. Li, W.Q., et al., RUNX3 methylation and expression associated with advanced precancerous gastric lesions in a Chinese population. Carcinogenesis,2011.32(3):p. 406-10.
[31]. Lau, Q.C., et al., RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res, 2006.66(13):p.6512-20.
[32]. Herman, J.G., et al., Methylation-specific PCR:a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A,1996.93(18):p.9821-6.
[33]. Kroepil, F., et al., Down-regulation of CDH1 is associated with expression of SNAI1 in colorectal adenomas. PLoS One,2012.7(9):p. e46665.
[34]. Kitago, M., et al., Regulation of RUNX3 tumor suppressor gene expression in cutaneous melanoma. Clin Cancer Res,2009.15(9):p.2988-94.
[35]. 邱雪杉等,上皮性钙黏附蛋白和β-连环素的表达与非小细胞肺癌预后的关系.中华病理学杂志,2002.31(4):第318-321页.
[36]. Raghu, G., et al., An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis:evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med,2011.183(6):p.788-824.
[37]. Archontogeorgis, K., et al., Lung cancer and interstitial lung diseases:a systematic review. Pulm Med,2012.2012:p.315918.
[38]. Feinberg, A.P. and B. Vogelstein, Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature,1983.301(5895):p.89-92.
[39]. Sakai, T., et al., Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet,1991.48(5):p.880-8.
[40]. Herman, J.G., et al., Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A,1994.91(21):p.9700-4.
[41]. Herman, J.G., et al., Inactivation of the CDKN2/pl6/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res, 1995.55(20):p.4525-30.
[42]. Jeronimo, C., et al., Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. J Natl Cancer Inst,2001. 93(22):p.1747-52.
[43]. Schulz, W., Qualified promise:DNA methylation assays for the detection and classification of human cancers. J Biomed Biotechnol,2005.2005(3):p.227-9.
[44]. Hegi, M.E., et al., MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med,2005.352(10):p.997-1003.
[45]. Jirtle, R.L. and M.K. Skinner, Environmental epigenomics and disease susceptibility. Nat Rev Genet,2007.8(4):p.253-62.
[46]. Baccarelli, A., et al., Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med,2009.179(7):p.572-8.
[47]. Fraga, M.F., et al., Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A,2005.102(30):p.10604-9.
[48]. Rege, T.A. and J.S. Hagood, Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J,2006.20(8):p.1045-54.
[49]. Sanders, Y.Y., P. Kumbla and J.S. Hagood, Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. Am J Respir Cell Mol Biol, 2007.36(2):p.226-35.
[50]. Robinson, C.M., et al., Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. Respir Res,2012.13:p.74.
[51]. Lung, H.L., et al., THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. Oncogene,2005.24(43):p.6525-32.
[52]. Kang, Y. and J. Massague, Epithelial-mesenchymal transitions:twist in development and metastasis. Cell,2004.118(3):p.277-9.
[53]. Savagner, P., Leaving the neighborhood:molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays,2001.23(10):p.912-23.
[54]. Vernon, A.E. and C. LaBonne, Tumor metastasis:a new twist on epithelial-mesenchymal transitions. Curr Biol,2004.14(17):p. R719-21.
[55]. Shiozaki, H., et al., E-cadherin mediated adhesion system in cancer cells. Cancer, 1996.77(8 Suppl):p.1605-13.
[56]. Zaidi, S.K., et al., Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites. Proc Natl Acad Sci U S A,2002.99(12):p. 8048-53.
[57]. Wei, D., et al., Loss of RUNX3 expression significantly affects the clinical outcome of gastric cancer patients and its restoration causes drastic suppression of tumor growth and metastasis. Cancer Res,2005.65(11):p.4809-16.
[58]. Ito, K., et al., RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell,2008.14(3):p.226-37.
[59]. Azarschab, P., et al., Epigenetic control of E-cadherin (CDH1) by CpG methylation in metastasising laryngeal cancer. Oncol Rep,2003.10(2):p.501-3.
[60]. Yoshiura, K., et al., Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci U S A,1995.92(16):p. 7416-9.
[61]. Gonzalgo, M.L., et al., The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines. Cancer Res,1998.58(6):p.1245-52.
[62]. Goffin, J. and E. Eisenhauer, DNA methyltransferase inhibitors-state of the art. Ann Oncol,2002.13(11):p.1699-716.
[63]. Behrens, J., et al., The E-cadherin promoter:functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. Proc Natl Acad Sci U S A,1991.88(24):p.11495-9.
[64]. Ku, J.L., et al., Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Oncogene,2004.23(40):p.6736-42.
[65]. Osaki, M., et al., Expression of RUNX3 protein in human gastric mucosa, intestinal metaplasia and carcinoma. Eur J Clin Invest,2004.34(9):p.605-12.
[66]. Shimamoto, T., et al., Hypermethylation of E-cadherin gene is frequent and independent of p16INK4A methylation in non-small cell lung cancer:potential prognostic implication. Oncol Rep,2004.12(2):p.389-95.
[67]. Yanagawa, N., et al., Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers. Cancer Sci,2003.94(7):p.589-92.
[68]. Nakata, S., et al., The methylation status and protein expression of CDH1, p16(INK4A), and fragile histidine triad in nonsmall cell lung carcinoma:epigenetic silencing, clinical features, and prognostic significance. Cancer,2006.106(10):p. 2190-9.
[69]. Yoo, J.Y., et al., E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model. J Neurooncol,2012.109(2):p.219-27.
[70]. Willis, B.C., et al., Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1:potential role in idiopathic pulmonary fibrosis. Am J Pathol,2005.166(5):p.1321-32.
[71]. Harada, T., et al., Epithelial-mesenchymal transition in human lungs with usual interstitial pneumonia:quantitative immunohistochemistry. Pathol Int,2010.60(1):p. 14-21.
[72]. Kim, T.Y., et al., Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Invest,2004.84(4):p.479-84.
[1]. Raghu, G., et al., An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis:evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med,2011.183(6):p.788-824.
[2]. Jemal, A., et al., Global cancer statistics. CA Cancer J Clin,2011.61(2):p. 69-90.
[3]. Haddad, R. and D. Massaro, Idiopathic diffuse interstitial pulmonary fibrosis (fibrosing alveolitis), atypical epithelial proliferation and lung cancer. Am J Med,1968. 45(2):p.211-9.
[4]. Bouros, D., et al., Association of malignancy with diseases causing interstitial pulmonary changes. Chest,2002.121(4):p.1278-89.
[5]. Wells, C. and D.M. Mannino, Pulmonary fibrosis and lung cancer in the United States:analysis of the multiple cause of death mortality data,1979 through 1991. South Med J,1996.89(5):p.505-10.
[6]. Le Jeune, I., et al., The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med,2007.101(12):p.2534-40.
[7]. 张德平,特发性肺纤维化合并肺癌.中华结核和呼吸杂志,2012.35(9):第647-649页.
[8]. Nagai, A., et al., Lung cancer in patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med,1992.167(3):p.231-7.
[9]. Park, J., et al., Lung cancer in patients with idiopathic pulmonary fibrosis. Eur Respir J,2001.17(6):p.1216-9. [10]. Aubry, M.C., et al., Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clin Proc,2002.77(8):p.763-70.
[11]. 李建东与李继成,特发性肺间质纤维化合并肺癌2例.山西医科大学学报,2000.31(5):第400-400页.
[12]. 1.朱亚茜与刘昌起,特发性肺间质纤维化合并肺癌的临床分析.天津医药,2005.33(4):第235-236页.
[13]. 倪健,张捷与周彩存,间质性肺纤维化并发支气管肺癌的病例报告及文献 复习.国外医学(呼吸系统分册),2005.25(5):第396-397页.
[14].王优,林涛与林爱俊,特发性肺间质纤维化合并肺癌六例.肿瘤研究与临床,2007.19(10):第708-709页.
[15].秦超,李宏云与翟红娟,特发性肺间质纤维化合并肺癌21例临床分析.中原医刊,2007.34(17):第41-42页.
[16].宋晓萍,特发性肺间质纤维化合并肺癌临床特点总结.中国医药指南,2011.09(33):第175-176页.
[17]. Mizushima, Y. and M. Kobayashi, Clinical characteristics of synchronous multiple lung cancer associated with idiopathic pulmonary fibrosis. A review of Japanese cases. Chest,1995.108(5):p.1272-7.
[18]. Turner-Warwick, M., et al., Cryptogenic fibrosing alveolitis and lung cancer. Thorax,1980.35(7):p.496-9.
[19].柴晶晶等,肿瘤标志物与特发性肺纤维化关系初步探讨.中国呼吸与危重监护杂志,2011.10(1):第38-41页.
[20]. Takahashi, H., et al., Carcinoembryonic antigen in bronchoalveolar lavage fluid in patients with idiopathic pulmonary fibrosis. Jpn J Med,1985.24(3):p.236-43.
[21]. Shiota, Y., et al., [CEA and CA19-9 in BALF from patients with idiopathic interstitial pneumonia]. Nihon Kyobu Shikkan Gakkai Zasshi,1989.27(8):p.887-93.
[22]. Fahim, A., et al., Serum carcinoembryonic antigen correlates with severity of idiopathic pulmonary fibrosis. Respirology,2012.17(8):p.1247-52.
[23]. Takata, T., et al., Lymphocytic interstitial pneumonia associated with a marked increase in monoclonal IgM-kappa-type rheumatoid factor and serum CA19-9. Jpn J Med, 1991.30(1):p.92-6.
[24]. Fujita, J., et al., Marked elevation of CA19-9 in a patient with idiopathic pulmonary fibrosis:CA19-9 as a bad prognostic factor. Respirology,1998.3(3):p. 211-4.
[25]. Mukae, H., et al., Elevation of tumor-associated carbohydrate antigens in patients with diffuse panbronchiolitis. Am Rev Respir Dis,1993.148(3):p.744-51.
[26]. Totani, Y., et al., [Silicosis characterized by increasing serum CA 19-9 in parallel with progression of lung fibrosis]. Nihon Kokyuki Gakkai Zasshi,2000.38(2):p. 137-42.
[27]. Totani, Y., et al., Serum CA19-9 levels reflect bronchoalveolar lavage fluid neutrophil levels in idiopathic pulmonary fibrosis. Respiration,2001.68(4):p.438.
[28]. Obayashi, Y., et al., Role of carbohydrate antigens sialyl Lewis (a) (CA19-9) in bronchoalveolar lavage in patients with pulmonary fibrosis. Respiration,2000.67(2):p. 146-52.
[29]. Totani, Y., et al., [Clinical characterization of CA19-9 in patients with interstitial pneumonia showing pathological nonspecific interstitial pneumonia pattern]. Nihon Kokyuki Gakkai Zasshi,2005.43(2):p.77-83.
[30]. Kodama, T., et al., Serum levels of CA19-9 in patients with nonmalignant respiratory diseases. J Clin Lab Anal,2007.21(2):p.103-6.
[31]. Kohno, N., et al., KL-6, a mucin-like glycoprotein, in bronchoalveolar lavage fluid from patients with interstitial lung disease. Am Rev Respir Dis,1993.148(3):p. 637-42.
[32]. Hirasawa, Y., et al., KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. Am J Respir Cell Mol Biol,1997.17(4):p.501-7.
[33]. Kohno, N., et al., New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6. Chest,1989.96(1):p.68-73.
[34]. Kohno, N., [Clinical usefulness of KL-6 as a serum marker of idiopathic interstitial pneumonia]. Nihon Kyobu Shikkan Gakkai Zasshi,1996.34 Suppl:p.186-9.
[35]. Yokoyama, A., et al., Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology,2006.11(2):p.164-8.
[36]. Ishikawa, N., et al., Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig,2012.50(1):p.3-13.
[37]. Yokoyama, A., et al., Comparative evaluation of sialylated carbohydrate antigens, KL-6, CA19-9 and SLX as serum markers for interstitial pneumonia. Respirology,1998.3(3):p.199-202.
[38]. Shimizu, Y., et al., Colocalization of CA19-9 and KL-6 to epithelial cells in dilated bronchioles in a patient with idiopathic pulmonary fibrosis complicated by diffuse alveolar damage. Respirology,2002.7(3):p.281-4.
[39]. Ohnishi, H., et al., Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med,2002.165(3):p.378-81.
[40]. Ricci, A., et al., Serum CA 15-3 is increased in pulmonary fibrosis. Sarcoidosis Vase Diffuse Lung Dis,2009.26(1):p.54-63.
[41]. Calabrese, F., et al., Overexpression of squamous cell carcinoma antigen in idiopathic pulmonary fibrosis:clinicopathological correlations. Thorax,2008.63(9):p. 795-802.
[42]. Kanazawa, H., et al., CYFRA 21-1, a cytokeratin subunit 19 fragment, in bronchoalveolar lavage fluid from patients with interstitial lung disease. Clin Sci (Lond), 1998.94(5):p.531-5.
[43]. Dobashi, N., et al., Elevated serum and BAL cytokeratin 19 fragment in pulmonary fibrosis and acute interstitial pneumonia. Eur Respir J,1999.14(3):p.574-8.
[44]. Inage, M., et al., Levels of cytokeratin 19 fragments in bronchoalveolar lavage fluid correlate to the intensity of neutrophil and eosinophil-alveolitis in patients with idiopathic pulmonary fibrosis. Respir Med,2000.94(2):p.155-60.
[45]. Lloyd, C.R., S.L. Walsh and D.M. Hansell, High-resolution CT of complications of idiopathic fibrotic lung disease. Br J Radiol,2011.84(1003):p.581-92.
[46]. Potts, J. and D. Yogaratnam, Pirfenidone:a novel agent for the treatment of idiopathic pulmonary fibrosis. Ann Pharmacother,2013.47(3):p.361-7.
[47]. King, T.J., et al., Effect of interferon gamma-lb on survival in patients with idiopathic pulmonary fibrosis (INSPIRE):a multicentre, randomised, placebo-controlled trial. Lancet,2009.374(9685):p.222-8.
[48]. King, T.J., et al., BUILD-1:a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med,2008.177(1):p.75-81.
[49]. Raghu, G., et al., Treatment of idiopathic pulmonary fibrosis with etanercept:an exploratory, placebo-controlled trial. Am J Respir Crit Care Med,2008.178(9):p. 948-55.
[50]. Azuma, A., et al., Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med,2005.171(9):p. 1040-7.
[51]. Demedts, M., et al., High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med,2005.353(21):p.2229-42.
[52]. Raghu, G., et al., A placebo-controlled trial of interferon gamma-lb in patients with idiopathic pulmonary fibrosis. N Engl J Med,2004.350(2):p.125-33.
[53]. Suzuki, H., et al., Risk of acute exacerbation of interstitial pneumonia after pulmonary resection for lung cancer in patients with idiopathic pulmonary fibrosis based on preoperative high-resolution computed tomography. Surg Today,2011.41(7):p. 914-21.
[54]. Bando, T. and H. Date, [Surgical treatment of lung cancer in patients with pulmonary fibrosis]. Kyobu Geka,2012.65(8):p.714-9.
[55]. Sekine, Y. and E. Ko, [The influence of intraoperative oxygen inhalation on patients with idiopathic pulmonary fibrosis]. Masui,2011.60(3):p.307-13.
[56]. Yano, M., et al., Post-operative acute exacerbation of pulmonary fibrosis in lung cancer patients undergoing lung resection. Interact Cardiovasc Thorac Surg,2012.14(2): p.146-50.
[57]. Kushibe, K., et al., [Lung resections for lung cancer with idiopathic pulmonary fibrosis]. Kyobu Geka,2005.58(1):p.26-30.
[58]. Mizuno, Y., et al., The importance of intraoperative fluid balance for the prevention of postoperative acute exacerbation of idiopathic pulmonary fibrosis after pulmonary resection for primary lung cancer. Eur J Cardiothorac Surg,2012.41(6):p. e161-5.
[59]. Yamauchi, Y., et al., Safety of postoperative administration of human urinary trypsin inhibitor in lung cancer patients with idiopathic pulmonary fibrosis. PLoS One, 2011.6(12):p.e29053.
[60]. Hyzy, R., et al., Acute exacerbation of idiopathic pulmonary fibrosis. Chest, 2007.132(5):p.1652-8.
[61]. Kudoh, S., et al., Interstitial lung disease in Japanese patients with lung cancer:a cohort and nested case-control study. Am J Respir Crit Care Med,2008.177(12):p. 1348-57.
[62]. Takeuchi, E., et al., [Characteristics and management of patients with lung cancer and idiopathic interstitial pneumonia]. Nihon Kyobu Shikkan Gakkai Zasshi,1996. 34(6):p.653-8.
[63]. Minegishi, Y., et al., Exacerbation of idiopathic interstitial pneumonias associated with lung cancer therapy. Intern Med,2009.48(9):p.665-72.
[64]. Minegishi, Y., et al., The feasibility study of Carboplatin plus Etoposide for advanced small cell lung cancer with idiopathic interstitial pneumonias. J Thorac Oncol, 2011.6(4):p.801-7.
[65]. Takeda, A., et al., Acute exacerbation of subclinical idiopathic pulmonary fibrosis triggered by hypofractionated stereotactic body radiotherapy in a patient with primary lung cancer and slightly focal honeycombing. Radiat Med,2008.26(8):p. 504-7.
[66]. Steele, M.P., et al., Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med,2005.172(9):p.1146-52.
[67]. Baumgartner, K.B., et al., Cigarette smoking:a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med,1997.155(1):p.242-8.
[68]. Hubbard, R., et al., Occupational exposure to metal or wood dust and aetiology of cryptogenic fibrosing alveolitis. Lancet,1996.347(8997):p.284-9.
[69]. Miyake, Y., et al., Occupational and environmental factors and idiopathic pulmonary fibrosis in Japan. Ann Occup Hyg,2005.49(3):p.259-65.
[70]. Iwai, K., et al., Idiopathic pulmonary fibrosis. Epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med,1994.150(3):p.670-5.
[71]. Consonni, D., et al., Lung cancer and occupation in a population-based case-control study. Am J Epidemiol,2010.171(3):p.323-33.
[72]. Corbin, M., et al., Lung cancer and occupation:A New Zealand cancer registry-based case-control study. Am J Ind Med,2011.54(2):p.89-101.
[73]. Neuberger, J.S. and R.W. Field, Occupation and lung cancer in nonsmokers. Rev Environ Health,2003.18(4):p.251-67.
[74]. Raghu, G., et al., High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J,2006.27(1):p.136-42.
[75]. Tobin, R.W., et al., Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med,1998.158(6):p.1804-8.
[76]. Vereczkei, A., et al., Gastroesophageal reflux disease and non-small cell lung cancer. Results of a pilot study. Dis Esophagus,2008.21(5):p.457-60.
[77]. Kuwano, K., et al., P21Waf1/Cipl/Sdil and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med,1996. 154(2 Pt1):p.477-83.
[78]. Hojo, S., et al., Heterogeneous point mutations of the p53 gene in pulmonary fibrosis. Eur Respir J,1998.12(6):p.1404-8.
[79]. Saed, G.M., et al., Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing. Arch Dermatol,1998.134(8):p.963-7.
[80]. Uematsu, K., et al., Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis. Cancer Res,2001.61(23):p.8527-33.
[81]. Demopoulos, K., et al., MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. J Cell Mol Med,2002.6(2):p. 215-22.
[82]. Tsang, A.R., et al., hTERT mutations associated with idiopathic pulmonary fibrosis affect telomerase activity, telomere length, and cell growth by distinct mechanisms. Aging Cell,2012.11(3):p.482-90.
[83]. Alder, J.K., et al., Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet,2011. 7(3):p.e1001352.
[84]. Waisberg, D.R., et al., Abnormal expression of telomerase/apoptosis limits type II alveolar epithelial cell replication in the early remodeling of usual interstitial pneumonia/idiopathic pulmonary fibrosis. Hum Pathol,2010.41(3):p.385-91.
[85]. Diaz, D.L.A., et al., Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS One,2010.5(5):p. e10680.
[86]. Alder, J.K., et al., Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A,2008.105(35):p.13051-6.
[87]. Armanios, M.Y., et al., Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med,2007.356(13):p.1317-26.
[88]. Tsakiri, K.D., et al., Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A,2007.104(18):p.7552-7.
[89]. Cronkhite, J.T., et al., Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med,2008.178(7):p.729-37.
[90]. Amin, R.S., et al., Surfactant protein deficiency in familial interstitial lung disease. J Pediatr,2001.139(1):p.85-92.
[91]. Kropski, J.A., et al., Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis. Dis Model Mech,2013.6(1):p.9-17.
[92]. Zhang, Y., et al., A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med,2011.364(16):p.1576-7.
[93]. Bird, A., Perceptions of epigenetics. Nature,2007.447(7143):p.396-8.
[94]. Rege, T.A. and J.S. Hagood, Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J,2006.20(8):p.1045-54.
[95]. Sanders, Y.Y., P. Kumbla and J.S. Hagood, Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. Am J Respir Cell Mol Biol, 2007.36(2):p.226-35.
[96]. Sanders, Y.Y., et al., Thy-1 promoter hypermethylation:a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol,2008.39(5):p. 610-8.
[97]. Robinson, C.M., et al., Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. Respir Res,2012.13:p.74.
[98]. Huang, S.K., et al., Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. Am J Pathol,2010.177(5):p. 2245-55.
[99]. Hu, B., et al., Epigenetic regulation of myofibroblast differentiation by DNA methylation. Am J Pathol,2010.177(1):p.21-8.
[100]. Hu, B., et al., Essential role of MeCP2 in the regulation of myofibroblast differentiation during pulmonary fibrosis. Am J Pathol,2011.178(4):p.1500-8.
[101]. Cisneros, J., et al., Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2012.303(4):p. L295-303.
[102]. Rabinovich, E.I., et al., Global methylation patterns in idiopathic pulmonary fibrosis. PLoS One,2012.7(4):p. e33770.
[103]. Yang, I.V. and D.A. Schwartz, Epigenetic control of gene expression in the lung. Am J Respir Crit Care Med,2011.183(10):p.1295-301.
[104]. Sanders, Y.Y., et al., Altered DNA methylation profile in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med,2012.186(6):p.525-35.
[105]. Coward, W.R., et al., Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis. Mol Cell Biol,2009.29(15):p.4325-39.
[106]. Coward, W.R., et al., Repression of IP-10 by interactions between histone deacetylation and hypermethylation in idiopathic pulmonary fibrosis. Mol Cell Biol, 2010.30(12):p.2874-86.
[107]. Sanders, Y.Y., et al., Epigenetic regulation of thy-1 by histone deacetylase inhibitor in rat lung fibroblasts. Am J Respir Cell Mol Biol,2011.45(1):p.16-23.
[108]. Guo, W., et al., Abrogation of TGF-betal-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition. Am J Physiol Lung Cell Mol Physiol, 2009.297(5):p. L864-70.
[109]. Pandit, K.V., et al., Inhibition and role of let-7d in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med,2010.182(2):p.220-9.
[110]. Liu, G., et al., miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med,2010.207(8):p.1589-97.
[111]. Cushing, L., et al., miR-29 is a major regulator of genes associated with pulmonary fibrosis. Am J Respir Cell Mol Biol,2011.45(2):p.287-94.
[112]. Pottier, N., et al., Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts:implication in epithelial-mesenchymal interactions. PLoS One,2009.4(8):p. e6718.
[113]. Oak, S.R., et al., A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis. PLoS One,2011.6(6):p. e21253.
[114]. Pandit, K.V., J. Milosevic and N. Kaminski, MicroRNAs in idiopathic pulmonary fibrosis. Transl Res,2011.157(4):p.191-9.
[115]. Yang, I.V., Epigenomics of idiopathic pulmonary fibrosis. Epigenomics,2012. 4(2):p.195-203.
[116]. Yang, I.V. and D.A. Schwartz, Epigenetic control of gene expression in the lung. Am J Respir Crit Care Med,2011.183(10):p.1295-301.
[117]. Jordana, M., et al., Heterogeneous proliferative characteristics of human adult lung fibroblast lines and clonally derived fibroblasts from control and fibrotic tissue. Am Rev Respir Dis,1988.137(3):p.579-84.
[118]. Raghu, G., et al., Differential proliferation of fibroblasts cultured from normal and fibrotic human lungs. Am Rev Respir Dis,1988.138(3):p.703-8.
[119]. Hanahan, D. and R.A. Weinberg, The hallmarks of cancer. Cell,2000.100(1):p. 57-70.
[120]. McAnulty, R.J., et al., Indomethacin suppresses the anti-proliferative effects of transforming growth factor-beta isoforms on fibroblast cell cultures. Biochem J,1997. 321 (Pt 3):p.639-43.
[121]. Moore, B.B., et al., Bleomycin-induced E prostanoid receptor changes alter fibroblast responses to prostaglandin E2. J Immunol,2005.174(9):p.5644-9.
[122]. Vancheri, C., et al., Different expression of TNF-alpha receptors and prostaglandin E(2)Production in normal and fibrotic lung fibroblasts:potential implications for the evolution of the inflammatory process. Am J Respir Cell Mol Biol, 2000.22(5):p.628-34.
[123]. Horowitz, J.C., et al., Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-betal in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem, 2004.279(2):p.1359-67.
[124]. Tian, B., et al., beta 1 integrin regulates fibroblast viability during collagen matrix contraction through a phosphatidylinositol 3-kinase/Akt/protein kinase B signaling pathway. J Biol Chem,2002.277(27):p.24667-75.
[125]. Tang, J.M., et al., Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer,2006. 51(2):p.181-91.
[126]. Johnson, L.N. and M. Koval, Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication. Antioxid Redox Signal,2009.11(2):p. 355-67.
[127]. Cesen-Cummings, K., et al., Frequent reduction of gap junctional intercellular communication and connexin43 expression in human and mouse lung carcinoma cells. Carcinogenesis,1998.19(1):p.61-7.
[128]. Avanzo, J.L., et al., Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43. Carcinogenesis,2004.25(10):p. 1973-82.
[129]. Trovato-Salinaro, A., et al., Altered intercellular communication in lung fibroblast cultures from patients with idiopathic pulmonary fibrosis. Respir Res,2006.7: p.122.
[130]. Mori, R., et al., Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J Cell Sci,2006.119(Pt 24):p.5193-203.
[131]. Hinz, B., et al., The myofibroblast:one function, multiple origins. Am J Pathol, 2007.170(6):p.1807-16.
[132]. Willis, B.C., R.M. DuBois and Z. Borok, Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc,2006.3(4):p.377-82.
[133]. Kim, K.K., et al., Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A,2006.103(35):p.13180-5.
[134]. De Wever, O., et al., Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol, 2008.130(3):p.481-94.
[135]. Phillips, R.J., et al., Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest,2004.114(3):p.438-46.
[136]. Mehrad, B., et al., Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun,2007.353(1):p.104-8.
[137]. Rojas, M., et al., Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol,2005.33(2):p.145-52.
[138]. Direkze, N.C., et al., Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res,2004.64(23):p.8492-5.
[139]. Quan, T.E., S.E. Cowper and R. Bucala, The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep,2006.8(2):p.145-50.
[140]. Phan, S.H., The myofibroblast in pulmonary fibrosis. Chest,2002.122(6 Suppl): p.286S-289S.
[141]. Nicholson, A.G., et al., The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2002.166(2):p.173-7.
[142]. Enomoto, N., et al., Quantitative analysis of fibroblastic foci in usual interstitial pneumonia. Chest,2006.130(1):p.22-9.
[143]. Cool, C.D., et al., Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum. Am J Respir Crit Care Med,2006.174(6):p.654-8.
[144]. Micke, P. and A. Ostman, Tumour-stroma interaction:cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer,2004.45 Suppl 2:p. S163-75.
[145]. Masaki, T., et al., Laminin-5 gamma2 chain expression as a possible determinant of tumor aggressiveness in T1 colorectal carcinomas. Dig Dis Sci,2003. 48(2):p.272-8.
[146]. Garrido, C., et al., HSP27 and HSP70:potentially oncogenic apoptosis inhibitors. Cell Cycle,2003.2(6):p.579-84.
[147]. Pelosi, G., et al., Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer. Br J Cancer,2003.88(4):p.537-47.
[148]. Chilosi, M., et al., Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosis. Respir Res,2006.7:p.95.
[149]. Nusse, R. and H.E. Varmus, Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982.31(1):p.99-109.
[150]. Bienz, M. and H. Clevers, Linking colorectal cancer to Wnt signaling. Cell, 2000.103(2):p.311-20.
[151]. Rhee, C.S., et al., Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene,2002.21(43):p. 6598-605.
[152]. Weeraratna, A.T., et al., Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell,2002.1(3):p.279-88.
[153]. Lu, D., et al., Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A,2004.101(9):p.3118-23.
[154]. Mazieres, J., et al., Wnt signaling in lung cancer. Cancer Lett,2005.222(1):p. 1-10.
[155]. Surendran, K., S.P. McCaul and T.C. Simon, A role for Wnt-4 in renal fibrosis. Am J Physiol Renal Physiol,2002.282(3):p. F431-41.
[156]. Chilosi, M., et al., Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol,2003.162(5):p.1495-502.
[157]. Bowley, E., D.B. O'Gorman and B.S. Gan, Beta-catenin signaling in fibroproliferative disease. J Surg Res,2007.138(1):p.141-50.
[158]. Caraci, F., et al., TGF-betal targets the GSK-3beta/beta-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts. Pharmacol Res,2008.57(4):p.274-82.
[159]. Imamura, T., A. Hikita and Y. Inoue, The roles of TGF-beta signaling in carcinogenesis and breast cancer metastasis. Breast Cancer,2012.19(2):p.118-24.
[160]. Hagimoto, N., et al., TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J Immunol,2002.168(12):p.6470-8.
[161]. Kim, K.K., et al., Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A,2006.103(35):p.13180-5.
[162]. Yu, H., et al., Transgelin is a direct target of TGF-beta/Smad3-dependent epithelial cell migration in lung fibrosis. FASEB J,2008.22(6):p.1778-89.
[163]. Scotton, C.J. and R.C. Chambers, Molecular targets in pulmonary fibrosis:the myofibroblast in focus. Chest,2007.132(4):p.1311-21.
[164]. Sanchez-Elsner, T., et al., Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem,2001.276(42):p.38527-35.
[165]. Derynck, R., R.J. Akhurst and A. Balmain, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet,2001.29(2):p.117-29.
[166]. Coker, R.K., et al., Localisation of transforming growth factor betal and beta3 mRNA transcripts in normal and fibrotic human lung. Thorax,2001.56(7):p.549-56.
[167]. Coker, R.K., et al., Transforming growth factors-beta 1,-beta 2, and -beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis. Am J Pathol,1997.150(3):p.981-91.
[168]. Wang, Q., et al., Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters. Thorax,1999.54(9):p.805-12.
[169]. Bonniaud, P., et al., Progressive transforming growth factor betal-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med,2005.171(8):p.889-98.
[170]. Zhao, J., et al., Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol,2002.282(3):p. L585-93.
[171]. Shi-wen, X., et al., Endothelin is a downstream mediator of profibrotic responses to transforming growth factor beta in human lung fibroblasts. Arthritis Rheum, 2007.56(12):p.4189-94.
[172]. Bagnato, A., F. Spinella and L. Rosano, The endothelin axis in cancer:the promise and the challenges of molecularly targeted therapy. Can J Physiol Pharmacol, 2008.86(8):p.473-84.