YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression.
YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression.
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作者：
He C;Lv X;Hua G;Lele SM;Remmenga S;Dong J;Davis JS;Wang C
卵巢癌发生和发展的机制尚不清楚。在此，我们报告了yes相关蛋白（YAP）， Hippo肿瘤抑制通路的主要效应物，与ERBB信号通路相互作用，调节卵巢癌的发生和进展。免疫组织化学研究表明，YAP表达与患者临床预后不良相关。YAP的过表达或组成性激活导致人卵巢表面上皮细胞的转化和肿瘤发生，促进体内和体外癌细胞的生长。YAP诱导EGF受体（EGFR, ERBB3）的表达和EGF样配体（HBEGF， NRG1和NRG2）的产生。反过来，HBEGF或NRG1激活YAP并刺激癌细胞生长。敲低ERBB3或HBEGF可消除YAP对细胞生长和转化的影响，而敲低YAP可消除NRG1-和HBEGF刺激的细胞增殖。总之，我们的研究证明了HBEGF&NRGs/ERBBs/YAP/HBEGF&NRGs自分泌环的存在，控制卵巢细胞肿瘤的发生和癌症的进展。
Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces expression of EGF receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, while knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF&NRGs/ERBBs/YAP/HBEGF&NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression.