Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths with no effective therapeutics. Invasion and metastasis are the major characteristics of PDAC. However, mechanisms underlying PDAC invasion and metastasis are elusive. In this report, we found that Kindlin-2 is a target protein of transforming growth factor beta (TGF-beta) signaling and is upregulated by TGF-beta 1 in PDAC cells. TGF-beta 1-upregulated Kindlin-2 promotes PDAC cell growth, migration and invasion, whereas Kindlin-2 upregulates transforming growth factor receptor I (T beta RI), a key component of TGF-beta signaling. Thereby Kindlin-2 and TGF-beta signaling constitute a positive feedback loop. Mechanistically, Kindlin-2 promotes PDAC progression by downregulation of HOXB9 and E-cadherin. For clinical relevance, enhanced expression of Kindlin-2 predicts a poor overall survival for PDAC patients. Gene expression levels of Kindlin-2, TGF-beta, VIZI and HOXB9 are all correlated with the overall survival of PDAC patients in an Oncomine dataset. Taken together, our findings demonstrated that TGF-beta 1-induced Kindlin-2 expression promotes PDAC progression by downregulation of HOXB9 and E-cadherin. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
基金：
Ministry of Science and Technology of ChinaMinistry of Science and Technology, China [2015CB553906, 2013CB910501, 2013ZX09401004-006]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81230051, 81472734, 31170711, 81321003, 30830048, 81301802]; 111 Project of the Ministry of EducationMinistry of Education, China - 111 Project; Beijing Natural Science FoundationBeijing Natural Science Foundation [7120002]; Peking UniversityPeking University [BMU20120314, BMU20130364, BMU20130373, BMU20110254]; Leading Academic Discipline Project of Beijing Education Bureau
医学