Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma.
Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma.
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整合素α2β1 抑制 MST1 激酶磷酸化并激活肝细胞癌中 Yes 相关蛋白致癌信号传导
DOI：
10.18632/oncotarget.12760
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发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Luk JM
中科院分区：
文献类型：
--
作者：
Wong KF;Liu AM;Hong W;Xu Z;Luk JM
Hippo通路调节下游靶yes相关蛋白（YAP）以维持器官稳态，这在许多类型的癌症中通常是失活的。然而，在肝细胞癌（HCC）中，细胞粘附如何失调激活YAP癌基因的Hippo通路仍不清楚。我们的研究结果表明，α2β1整合素（而不是其他β1整合素）在HCC细胞中表达，与胶原细胞外基质结合后，可以抑制MST1激酶磷酸化并激活YAP的促癌活性。敲低整合素α2基因（ITGA2）可抑制YAP靶基因的体外表达。α2β1与胶原结合抑制哺乳动物不育20样激酶1 （MST1）和大肿瘤抑制同源物1 （LATS1）的Hippo信号，同时激活yap介导的结缔组织生长因子（CTGF）基因表达。体外激酶实验表明，MST1是整合素α2的直接下游靶点，S1180残基是关键磷酸化位点。利用228例HCC肿瘤的基因表达数据集进行临床相关性分析发现，ITGA2的表达与肿瘤进展显著相关，与YAP靶向基因（AXL受体酪氨酸激酶、CTGF、cyclin D1、glypican 3、胰岛素样生长因子1受体、SRY-box 4）的共表达与HCC患者的生存率相关。综上所述，α2β1整合素通过细胞粘附激活，影响实体肿瘤的Hippo通路，调节MST1-YAP信号级联。靶向整合素α2有望治疗yap阳性HCC。
The Hippo pathway regulates the down-stream target Yes-associated protein (YAP) to maintain organ homeostasis, which is commonly inactivated in many types of cancers. However, how cell adhesion dysregulates the Hippo pathway activating YAP oncogene in hepatocellular carcinoma (HCC) remains unclear. Our findings demonstrate that α2β1 integrin (but not other β1 integrins) expressed in HCC cells, after binding to collagen extracellular matrix, could inhibit MST1 kinase phosphorylation and activate YAP pro-oncogenic activities. Knockdown of integrin α2 gene (ITGA2) suppressed YAP targeted gene expression in vitro. α2β1 and collagen binding resulted in suppressing Hippo signaling of mammalian sterile 20-like kinase 1 (MST1) and Large tumor suppressor homolog 1 (LATS1) with concomitant activation of YAP-mediated connective tissue growth factor (CTGF) gene expression. In vitro kinase assay showed that MST1 is an immediate downstream target of integrin α2 with S1180 residue as the critical phosphorylation site. Clinical correlational analysis using a gene expression dataset of 228 HCC tumors revealed that ITGA2 expression was significantly associated with tumor progression, and co-expression with YAP targeted genes (AXL receptor tyrosine kinase, CTGF, cyclin D1, glypican 3, insulin like growth factor 1 receptor, and SRY-box 4) correlated with survivals of HCC patients. In conclusion, α2β1 integrin activation through cellular adhesion impacts the Hippo pathway in solid tumors and modulates MST1-YAP signaling cascade. Targeting integrin α2 holds promises for treating YAP-positive HCC.