Abstract
Esophageal cancer (EC) is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry (IHC) and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin-1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC.
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Cao, H.H., Zhang, S.Y., Shen, J.H., Wu, Z.Y., Wu, J.Y., Wang, S.H., Li, E.M., and Xu, L.Y. (2015). A three-protein signature and clinical outcome in esophageal squamous cell carcinoma. Oncotarget 6, 5435–5448.
Dowling, J.J., Gibbs, E., Russell, M., Goldman, D., Minarcik, J., Golden, J.A., and Feldman, E.L. (2008). Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circul Res 102, 423–431.
Ge, Y.S., Liu, D., Jia, W.D., Li, J.S., Ma, J.L., Yu, J.H., and Xu, G.L. (2015). Kindlin-2: a novel prognostic biomarker for patients with hepatocellular carcinoma. Pathol Res Pract 211, 198–202.
Guo, B., Gao, J., Zhan, J., and Zhang, H. (2015). Kindlin-2 interacts with and stabilizes EGFR and is required for EGF-induced breast cancer cell migration. Cancer Lett 361, 271–281.
Kong, J., Du, J., Wang, Y., Yang, M., Gao, J., Wei, X., Fang, W., Zhan, J., and Zhang, H. (2016). Focal adhesion molecule Kindlin-1 mediates activation of TGF-β signaling by interacting with TGF-βRI, SARA and Smad3 in colorectal cancer cells. Oncotarget 7, 76224–76237.
Kuang, J.J., Jiang, Z.M., Chen, Y.X., Ye, W.P., Yang, Q., Wang, H.Z., and Xie, D.R. (2016). Smoking exposure and survival of patients with esophagus cancer: a systematic review and meta-analysis. Gastroenterol Res Pract 2016, 1–10.
Ma, H.X., Shu, Q.H., Pan, J.J., Liu, D., Xu, G.L., Li, J.S., Ma, J.L., Jia, W.D., Yv, J.H., and Ge, Y.S. (2015). Expression of Kindlin-1 in human hepatocellular carcinoma and its prognostic significance. Tumor Biol 36, 4235–4241.
Mahawithitwong, P., Ohuchida, K., Ikenaga, N., Fujita, H., Zhao, M., Kozono, S., Shindo, K., Ohtsuka, T., Aishima, S., Mizumoto, K., and Tanaka, M. (2013). Kindlin-1 expression is involved in migration and invasion of pancreatic cancer. Int J Oncol 42, 1360–1366.
Mizutani, H., Masuda, K., Nakamura, N., Takenaka, H., Tsuruta, D., and Katoh, N. (2012). Cutaneous and laryngeal squamous cell carcinoma in mixed epidermolysis bullosa, kindler syndrome. Case Rep Dermatol 4, 133–138.
Plow, E.F., Das, M., Bialkowska, K., and Sossey-Alaoui, K. (2016). Of kindlins and cancer. Discoveries (Craiova) 4, e59.
Rognoni, E., Widmaier, M., Jakobson, M., Ruppert, R., Ussar, S., Katsougkri, D., Böttcher, R.T., Lai-Cheong, J.E., Rifkin, D.B., McGrath, J.A., and Fässler, R. (2014). Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation. Nat Med 20, 350–359.
Shafaee, A., Dastyar, D.Z., Islamian, J.P., and Hatamian, M. (2015). Inhibition of tumor energy pathways for targeted esophagus cancer therapy. Metabolism 64, 1193–1198.
Shen, Z., Ye, Y., Kauttu, T., Seppänen, H., Vainionpää, S., Wang, S., Mustonen, H., and Puolakkainen, P. (2013). The novel focal adhesion gene kindlin-2 promotes the invasion of gastric cancer cells mediated by tumor-associated macrophages. Oncol Rep 29, 791–797.
Siegel, R.L., Miller, K.D., and Jemal, A. (2016). Cancer statistics, 2016. CA Cancer J Clin 66, 7–30.
Sin, S., Bonin, F., Petit, V., Meseure, D., Lallemand, F., Bièche, I., Bellahcène, A., Castronovo, V., de Wever, O., Gespach, C., Lidereau, R., and Driouch, K. (2011). Role of the focal adhesion protein Kindlin-1 in breast cancer growth and lung metastasis. J Natl Cancer Inst 103, 1323–1337.
Weinstein, E.J., Bourner, M., Head, R., Zakeri, H., Bauer, C., and Mazzarella, R. (2003). URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas. Biochim Biophys Acta 1637, 207–216.
Xu, Y., and Lu, S. (2013). Metformin inhibits esophagus cancer proliferation through upregulation of USP7. Cell Physiol Biochem 32, 1178–1186.
Yang, J., Pan, T., Yang, H., Wang, T., Liu, W., Liu, B., and Qian, W. (2016). Kindlin-2 promotes invasiveness of prostate cancer cells via NF-κB-dependent upregulation of matrix metalloproteinases. Gene 576, 571–576.
Yu, Y., Wu, J., Guan, L., Qi, L., Tang, Y., Ma, B., Zhan, J., Wang, Y., Fang, W., and Zhang, H. (2013). Kindlin 2 promotes breast cancer invasion via epigenetic silencing of the microRNA200 gene family. Int J Cancer 133, 1368–1379.
Yu, Y., Wu, J., Wang, Y., Zhao, T., Ma, B., Liu, Y., Fang, W., Zhu, W.G., and Zhang, H. (2012). Kindlin 2 forms a transcriptional complex with β-catenin and TCF4 to enhance Wnt signalling. EMBO Rep 13, 750–758.
Zhan, J., Song, J., Wang, P., Chi, X., Wang, Y., Guo, Y., Fang, W., and Zhang, H. (2015). Kindlin-2 induced by TGF-β signaling promotes pancreatic ductal adenocarcinoma progression through downregulation of transcriptional factor HOXB9. Cancer Lett 361, 75–85.
Zhan, J., Yang, M., Chi, X.C., Zhang, J., Pei, X.L., Ren, C.X., Guo, Y.Q., Liu, W., and Zhang, H.Q. (2014). Kindlin-2 expression in adult tissues correlates with their embryonic origins. Sci China Life Sci 57, 690–697.
Zhan, J., Zhu, X., Guo, Y., Wang, Y., Wang, Y., Qiang, G., Niu, M., Hu, J., Du, J., Li, Z., Cui, J., Ma, B., Fang, W., and Zhang, H. (2012). Opposite role of Kindlin-1 and Kindlin-2 in lung cancers. PLoS ONE 7, e50313.
Zhang, G., Gu, Y., Begum, R., Chen, H., Gao, X., McGrath, J.A., Parsons, M., and Song, B. (2016). Kindlin-1 regulates keratinocyte electrotaxis. J Invest Dermatol 136, 2229–2239.
Zhang, H.F., Alshareef, A., Wu, C., Li, S., Jiao, J.W., Cao, H.H., Lai, R., Xu, L.Y., and Li, E.M. (2015). Loss of miR-200b promotes invasion via activating the Kindlin-2/integrin β1/AKT pathway in esophageal squamous cell carcinoma: an E-cadherin-independent mechanism. Oncotarget 6, 28949–28960.
Zhang, H.F., Zhang, K., Liao, L.D., Li, L.Y., Du, Z.P., Wu, B.L., Wu, J.Y., Xu, X.E., Zeng, F.M., Chen, B., Cao, H.H., Zhu, M.X., Dai, L.H., Long, L., Wu, Z.Y., Lai, R., Xu, L.Y., and Li, E.M. (2014). miR-200b suppresses invasiveness and modulates the cytoskeletal and adhesive machinery in esophageal squamous cell carcinoma cells via targeting Kindlin-2. Carcinogenesis 35, 292–301.
Zhao, T., Guan, L., Yu, Y., Pei, X., Zhan, J., Han, L., Tang, Y., Li, F., Fang, W., and Zhang, H. (2013). Kindlin-2 promotes genome instability in breast cancer cells. Cancer Lett 330, 208–216.
Acknowledgements
This work was supported by the Ministry of Science and Technology of China (2016YFC1302103, 2015CB553906, 2013CB910501), the National Natural Science Foundation of China (81230051, 81472734, 31170711, 81321003, 81301802, 30830048), Beijing Natural Science Foundation (7120002), the 111 Project of the Ministry of Education, Peking University (BMU20120314, BMU20130364), and a Leading Academic Discipline Project of Beijing Education Bureau to Hongquan Zhang.
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Wang, P., Zhan, J., Song, J. et al. Differential expression of Kindlin-1 and Kindlin-2 correlates with esophageal cancer progression and epidemiology. Sci. China Life Sci. 60, 1214–1222 (2017). https://doi.org/10.1007/s11427-016-9044-5
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DOI: https://doi.org/10.1007/s11427-016-9044-5