Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang 110001, Liaoning, China.
Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang 110001, Liaoning, China
Biosci Rep. 2019 Mar 22;39(3). doi: 10.1042/BSR20190249. Print 2019 Mar 29.
Resistance to chemotherapy is one of main obstacles in the treatment of colorectal cancer (CRC). However, the mechanisms are still unclear, and the treatment options are still limited. miR-543 has been indicated to act as an oncogene in some cancers, but its function in regulating chemoresistance has not been considered in CRC cells. This study investigated whether the down-regulation of miR-543 expression enhanced 5-fluorouracil (5-FU)-induced apoptosis in HCT8/FU colon cancer cells. In our study, qRT-PCR revealed that miR-543 expression was up-regulated in the HCT8/FU colon cancer cell line compared with that of HCT8 colon cancer cell line. An miR-543 inhibitor or mimic was transfected, followed by MTT assay to detect 5-FU sensitivity in HCT8 and HCT8/FU cell lines, which showed that IC of 5-FU was positively correlated with miR-543 expression. Further studies showed that miR-543 enhanced drug resistance by down-regulating the expression of phosphatase and tensin homolog (PTEN), which negatively regulates protein kinase B (AKT) activation. Additionally, an elevated expression of PTEN reversed the chemoresistance of miR-543-overexpressing HCT8 cells to 5-FU. These results indicate that miR-543 might be a target to increase the sensitivity of CRC cells to 5-FU through the PTEN/PI3K/AKT pathway.
化疗耐药性是结直肠癌（CRC）治疗中的主要障碍之一。然而，其机制仍不清楚，治疗选择仍然有限。miR-543 已被表明在某些癌症中作为癌基因发挥作用，但在 CRC 细胞中，其调节化疗耐药性的功能尚未得到考虑。本研究探讨了下调 miR-543 表达是否增强了 HCT8/FU 结肠癌细胞中 5-氟尿嘧啶（5-FU）诱导的细胞凋亡。在我们的研究中，qRT-PCR 显示 miR-543 在 HCT8/FU 结肠癌细胞系中的表达上调与 HCT8 结肠癌细胞系相比。转染 miR-543 抑制剂或模拟物后，通过 MTT 测定检测 HCT8 和 HCT8/FU 细胞系对 5-FU 的敏感性，结果表明 5-FU 的 IC 与 miR-543 的表达呈正相关。进一步的研究表明，miR-543 通过下调磷酸酶和张力蛋白同源物（PTEN）的表达来增强药物耐药性，PTEN 负调节蛋白激酶 B（AKT）的激活。此外，PTEN 的高表达逆转了 miR-543 过表达 HCT8 细胞对 5-FU 的化疗耐药性。这些结果表明，miR-543 可能是一个通过 PTEN/PI3K/AKT 途径增加 CRC 细胞对 5-FU 敏感性的靶点。
