Kindlin-2 induced by TGF-β signaling promotes pancreatic ductal adenocarcinoma progression through downregulation of transcriptional factor HOXB9
Kindlin-2 induced by TGF-β signaling promotes pancreatic ductal adenocarcinoma progression through downregulation of transcriptional factor HOXB9
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TGF-β信号诱导的Kindlin-2通过下调转录因子HOXB9促进胰腺导管腺癌进展
DOI：
10.1016/j.canlet.2015.02.039
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发表时间：
2015-05-28
期刊：
影响因子：
9.7
通讯作者：
Zhang, Hongquan
中科院分区：
文献类型：
--
作者：
Zhan, Jun;Song, Jiagui;Zhang, Hongquan
胰腺导管腺癌（PDAC）是癌症相关死亡的第四大原因，没有有效的治疗方法。侵袭和转移是PDAC的主要特征。然而，PDAC侵袭和转移的机制尚不清楚。在这份报告中，我们发现Kindlin-2是转化生长因子β（TGF-β）信号转导的靶蛋白，并在PDAC细胞中被TGF-β 1上调。TGF-β 1上调的Kindlin-2促进PDAC细胞生长、迁移和侵袭，而Kindlin-2上调转化生长因子受体I（T β RI），这是TGF-β信号传导的关键组分。因此，Kindlin-2和TGF-β信号传导构成正反馈回路。在机制上，Kindlin-2通过下调HOXB 9和E-钙粘蛋白促进PDAC进展。对于临床相关性，Kindlin-2的表达增强预测PDAC患者的总体生存率较差。Kindlin-2、TGF-β、VIZI和HOXB 9的基因表达水平都与Oncomine数据集中PDAC患者的总生存期相关。总之，我们的研究结果表明，TGF-β 1诱导的Kindlin-2表达通过下调HOXB 9和E-cadherin促进PDAC进展。(C)2015爱思唯尔爱尔兰有限公司版权所有。
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.