University of Sydney, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.
University of Sydney, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; School of Medical Sciences, University of New South Wales, Sydney, Kensington, NSW, 2052, Australia.
Mol Cell Endocrinol. 2021 Aug 1;533:111338. doi: 10.1016/j.mce.2021.111338. Epub 2021 May 29.
The epidermal growth factor receptor (EGFR) is overexpressed in many types of cancer, including epithelial ovarian cancer (EOC), and its expression has been found to correlate with advanced stage and poor prognosis. The EGFR ligand amphiregulin (AREG) has been investigated as a target for human cancer therapy and is known to have an autocrine role in many cancers. A cytokine array identified AREG as one of several cytokines upregulated by EGF in a phosphatidylinositol 3-kinase (PI3-K) dependent manner in EOC cells. To investigate the functional role of AREG in EOC, its effect on cellular migration and proliferation was assessed in two EOC cells lines, OV167 and SKOV3. AREG increased both migration and proliferation of EOC cell line models through activation of PI3-K signaling, but independent of mitogen activated protein kinase (MAPK) signaling. Through an AREG autocrine loop mediated via PI3-K, upregulation of AREG led to increased levels of both AREG transcript and secreted AREG, while downregulation of endogenous AREG decreased the ability of exogenous AREG to induce cell migration and proliferation. Further, inhibition of endogenous AREG activity or metalloproteinase activity decreased EGF-induced EOC migration and proliferation, indicating a role for soluble endogenous AREG in mediating the functional effects of EGFR in inducing migration and proliferation in EOC.
表皮生长因子受体（EGFR）在多种癌症中过度表达，包括上皮性卵巢癌（EOC），其表达与晚期和预后不良相关。表皮生长因子配体 Amphiregulin（AREG）已被研究作为人类癌症治疗的靶点，并且已知在许多癌症中具有自分泌作用。细胞因子阵列鉴定出 AREG 是 EGF 在 EOC 细胞中以磷脂酰肌醇 3-激酶（PI3-K）依赖性方式上调的几种细胞因子之一。为了研究 AREG 在 EOC 中的功能作用，评估了其对两种 EOC 细胞系 OV167 和 SKOV3 的细胞迁移和增殖的影响。AREG 通过激活 PI3-K 信号通路增加了 EOC 细胞系模型的迁移和增殖，但不依赖于丝裂原活化蛋白激酶（MAPK）信号通路。通过 PI3-K 介导的 AREG 自分泌环，AREG 的上调导致 AREG 转录本和分泌的 AREG 水平均增加，而内源性 AREG 的下调降低了外源性 AREG 诱导细胞迁移和增殖的能力。此外，抑制内源性 AREG 活性或金属蛋白酶活性可降低 EGF 诱导的 EOC 迁移和增殖，表明可溶性内源性 AREG 在介导 EGFR 诱导的迁移和增殖中的功能作用。
