Cancer Treatment Research Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Int J Mol Med. 2018 Aug;42(2):998-1007. doi: 10.3892/ijmm.2018.3680. Epub 2018 May 16.
In gastric cancer, >15% of cases are associated with the amplification of human epidermal growth factor receptor 2 (HER2), which leads to poor clinical outcomes. Lapatinib, a potent ATP‑competitive inhibitor, is a small, orally active molecule, which inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1. The activation of receptor tyrosine kinases can contribute to lapatinib resistance in HER2‑positive gastric cancer. The aim of the present study was to explore the effects of miR‑494 and FGFR2 in regulation of cancer‑initiating cell phenotypes and therapeutic efficiency of lapatinib in HER2‑positive gastric cancer. Western blot analysis was used to identify that the expression of fibroblast growth factor receptor 2 (FGFR2), a receptor tyrosine kinase, was upregulated in gastric cancer tissues. Formation of cancer initiating cells (CICs) and resistance to lapatinib were determined using sphere growth assay and MTT assay, respectively. The overexpression of FGFR2 promoted the generation of cancer‑initiating cells (CICs) and resistance to lapatinib in HER2‑positive gastric cancer YCC1 cells. In addition, it was observed that overexpression of microRNA (miR)‑494 downregulated the protein expression of FGFR2, inhibited the formation of CICs and reversed lapatinib resistance in YCC1‑F cells (HER2‑positive, FGFR2 overexpressing and lapatinib‑resistant gastric cancer cells). Therefore, it was concluded that miR‑494 inhibited the CIC phenotype and reversed resistance to lapatinib by inhibiting FGFR2 in HER2‑positive gastric cancer.
在胃癌中，超过 15%的病例与人类表皮生长因子受体 2（HER2）的扩增有关，这导致了不良的临床结局。拉帕替尼是一种有效的 ATP 竞争性抑制剂，是一种小分子、口服活性药物，可抑制 HER2 和表皮生长因子受体 1 的酪氨酸激酶。受体酪氨酸激酶的激活可能导致 HER2 阳性胃癌对拉帕替尼产生耐药性。本研究旨在探讨 miR-494 和 FGFR2 对调节 HER2 阳性胃癌中肿瘤起始细胞表型和拉帕替尼治疗效果的影响。Western blot 分析用于鉴定成纤维细胞生长因子受体 2（FGFR2），一种受体酪氨酸激酶，在胃癌组织中表达上调。使用球体生长测定法和 MTT 测定法分别确定癌症起始细胞（CICs）的形成和对拉帕替尼的耐药性。FGFR2 的过表达促进了 HER2 阳性胃癌 YCC1 细胞中 CICs 的生成和对拉帕替尼的耐药性。此外，还观察到 microRNA（miR）-494 的过表达下调了 FGFR2 的蛋白表达，抑制了 CICs 的形成，并逆转了 YCC1-F 细胞（HER2 阳性、FGFR2 过表达和拉帕替尼耐药的胃癌细胞）对拉帕替尼的耐药性。因此，结论是 miR-494 通过抑制 HER2 阳性胃癌中的 FGFR2 抑制 CIC 表型并逆转对拉帕替尼的耐药性。
