Dunfield Lesley Deanne, Nachtigal Mark William
Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada, B3H 1X5.
Oncogene. 2003 Jul 24;22(30):4745-51. doi: 10.1038/sj.onc.1206617.
The majority of ovarian cancers (OCs) arise from the ovarian surface epithelium (OSE). Proliferation of the OSE can be regulated by a number of autocrine and paracrine factors, including transforming growth factor beta (TGFbeta). Defects in the TGFbeta signaling pathway have been implicated in a number of cancers, including ovarian. We previously found that the TGFbeta signaling pathway is intact and functional in primary human OC cells, and that these cells stop growing in response to TGFbeta. Ovarian cancer cells in vivo are exposed to TGFbeta, yet continue to proliferate, therefore, mechanisms must exist to inhibit TGFbeta signaling contributing to uncontrolled cellular proliferation. Numerous signaling pathways converge with the TGFbeta pathway to modulate its effects, including signaling induced by epidermal growth factor (EGF). We hypothesized that EGF can modulate TGFbeta signaling and contribute to uncontrolled cellular proliferation of OC cells. Our results show that EGF abrogates the antiproliferative effect of TGFbeta. EGF does not modulate TGFbeta signaling by inhibiting receptor-activated Smad (R-Smad) phosphorylation or nuclear translocation. Rather, EGF decreases TGFbeta-induced mRNA expression of the cell cycle regulator, p15(INK4B), contributing to decreased sensitivity of OC cells to the antiproliferative effect of TGFbeta.
大多数卵巢癌（OC）起源于卵巢表面上皮（OSE）。OSE的增殖可受多种自分泌和旁分泌因子调控，包括转化生长因子β（TGFβ）。TGFβ信号通路缺陷与包括卵巢癌在内的多种癌症有关。我们之前发现，TGFβ信号通路在原代人OC细胞中是完整且有功能的，并且这些细胞会对TGFβ作出反应而停止生长。然而，体内的卵巢癌细胞暴露于TGFβ时仍会继续增殖，因此，必然存在抑制TGFβ信号传导从而导致细胞不受控制地增殖的机制。许多信号通路与TGFβ通路汇聚以调节其作用，包括表皮生长因子（EGF）诱导的信号传导。我们假设EGF可调节TGFβ信号传导并导致OC细胞不受控制地增殖。我们的结果表明，EGF消除了TGFβ的抗增殖作用。EGF并非通过抑制受体激活型Smad（R-Smad）磷酸化或核转位来调节TGFβ信号传导。相反，EGF降低了TGFβ诱导的细胞周期调节因子p15（INK4B）的mRNA表达，导致OC细胞对TGFβ抗增殖作用的敏感性降低。
