Weng Wen-Hui, Leung Wai-Hung, Pang Yeu Jye, Kuo Li-Wei, Hsu Hsi-Hsien
Department of Chemical Engineering and Biotechnology, Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 10608, Taiwan, R.O.C.
Division of Colorectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei 10491, Taiwan, R.O.C.
Oncol Lett. 2018 Nov;16(5):6188-6194. doi: 10.3892/ol.2018.9408. Epub 2018 Sep 5.
It is known that colorectal cancer (CRC) cells containing mutations of the genes KRAS and BRAF are predominate mechanisms causing resistance to epidermal growth factor receptor (EGFR) inhibitors, and commonly exhibit a lower expression of microRNA-378 (miR-378) when compared with the wild type. In the present study, the aim was to determine the possible mechanism which associates miR-378 with the mitogen-activated protein kinase pathway, and to determine the efficiency of eicosapentaenoic acid ethyl ester (EPA) in its ability to restore sensitivity towards cetuximab, an EGFR inhibitor. The results demonstrated that a combined treatment of 40 µM EPA with 0.2 µM cetuximab can significantly suppress the cell growth in KRAS-mutant and control wild-type cells. Furthermore, the higher phosphorylated protein level of extracellular-signal-regulated kinase 1/2 was notable in KRAS EPA-treated cells (P=0.006-0.047) and resulted in significantly increased cell death; however, inconsistent results were indicated in EPA-treated BRAF-mutant cells, compared with the original cells (without treatment). KRAS-mutant and wild-type Caco-2 cells treated with EPA exhibited increased cetuximab response rates, but these response rates were reduced in the BRAF-mutant cells. In conclusion, upregulation of miR-378 induced by EPA may result in the significant restoration of sensitivity to cetuximab in the KRAS-mutant cells. The present data will contribute to a notable potential therapeutic solution for future clinical CRC treatments.
已知含有KRAS和BRAF基因突变的结直肠癌（CRC）细胞是导致对表皮生长因子受体（EGFR）抑制剂耐药的主要机制，与野生型相比，通常表现出较低的微小RNA-378（miR-378）表达。在本研究中，目的是确定miR-378与丝裂原活化蛋白激酶途径相关的可能机制，并确定二十碳五烯酸乙酯（EPA）恢复对EGFR抑制剂西妥昔单抗敏感性的能力。结果表明，40μM EPA与0.2μM西妥昔单抗联合处理可显著抑制KRAS突变细胞和对照野生型细胞的生长。此外，在KRAS EPA处理的细胞中，细胞外信号调节激酶1/2的磷酸化蛋白水平较高（P=0.006-0.047），并导致细胞死亡显著增加；然而，与原始细胞（未处理）相比，EPA处理的BRAF突变细胞结果不一致。用EPA处理的KRAS突变型和野生型Caco-2细胞表现出西妥昔单抗反应率增加，但BRAF突变细胞中的这些反应率降低。总之，EPA诱导的miR-378上调可能导致KRAS突变细胞对西妥昔单抗敏感性的显著恢复。本数据将为未来临床CRC治疗提供一个显著的潜在治疗方案。
