Xiong Siyuan, Klausen Christian, Cheng Jung-Chien, Leung Peter C K
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Cell Signal. 2017 Jun;34:92-101. doi: 10.1016/j.cellsig.2017.03.010. Epub 2017 Mar 21.
Endometrial cancer is the most common, and second most lethal, gynecological malignancy, and its rates of incidence and death are growing. This is likely attributable to increased numbers of high-risk type II endometrial cancers which account for ~30% of cases but ~75% of deaths due to their aggressive and metastatic behaviour. Histopathological and in vitro functional studies suggest that aberrant TGFβ1 signaling may contribute to endometrial cancer development and the acquisition of invasive/metastatic characteristics. However, little is known about the cellular and molecular mechanisms of TGFβ1 in high-risk endometrial cancers. In the present study, we examined the roles and mechanisms of TGFβ1 on cell adhesion and motility in type II endometrial cancer cell lines, KLE and HEC-1B. We show that treatment with TGFβ1 increases cell adhesion to vitronectin and transwell cell migration. We also demonstrate that TGFβ1 treatment increases integrin β3 and αv mRNA and protein levels via SMAD-independent MEK-ERK1/2 signaling. Importantly, siRNA depletion or antibody-mediated blocking of integrin αvβ3 reversed the effects of TGFβ1 on cell adhesion and migration. Our results suggest that TGFβ1-MEK-ERK1/2-integrin αvβ3 signaling could contribute to the invasive behaviour of high-risk endometrial cancer by promoting cell adhesion and migration.
子宫内膜癌是最常见且致死率第二高的妇科恶性肿瘤，其发病率和死亡率正在上升。这可能归因于高危II型子宫内膜癌数量的增加，这类癌症约占病例的30%，但因其侵袭性和转移性导致约75%的死亡。组织病理学和体外功能研究表明，异常的TGFβ1信号传导可能促进子宫内膜癌的发展以及侵袭/转移特征的获得。然而，关于TGFβ1在高危子宫内膜癌中的细胞和分子机制知之甚少。在本研究中，我们研究了TGFβ1在II型子宫内膜癌细胞系KLE和HEC-1B中对细胞黏附和迁移的作用及机制。我们发现，用TGFβ1处理可增加细胞对玻连蛋白的黏附以及Transwell细胞迁移。我们还证明，TGFβ1处理通过不依赖SMAD的MEK-ERK1/2信号传导增加整合素β3和αv的mRNA及蛋白水平。重要的是，整合素αvβ3的siRNA敲低或抗体介导的阻断可逆转TGFβ1对细胞黏附和迁移的影响。我们的结果表明，TGFβ1-MEK-ERK1/2-整合素αvβ3信号传导可能通过促进细胞黏附和迁移导致高危子宫内膜癌的侵袭行为。
