Cao Shuguang, Lin Limiao, Xia Xuanping, Wu Hao
Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
Oncotarget. 2017 Aug 10;9(1):321-331. doi: 10.18632/oncotarget.20109. eCollection 2018 Jan 2.
Resistance to chemotherapy is a big challenge for treatment of patients with colorectal cancer; however; the mechanism underlying chemoresistance in colorectal cancer cell has not been elucidated. MicroRNAs (miRNAs) are new players in the development of drug chemoresistance. In our study, we indicated that overexpression of miR-761 promoted the sensitivity of colorectal cancer cells to 5-Fluorouracil (5-FU). miR-761 expression was downregulated in colorectal cancer cell lines and tissues. miR-761 expression was lower in patients with low grade than in patients with high grade. In additon, we showed that elevated expression of miR-761 suppressed colorectal cancer cell proliferation, cell cycle, colony formation and cell invasion. We identified that FOXM1 was a direct target gene of miR-761 in colorectal cancer cell. FOXM1 expression was upregulated in colorectal cancer tissues compare to the adjacent non-tumor tissues. MiR-761 expression was negatively associated with the expression of FOXM1 in colorectal cancer tissues. Elevated expression of FOXM1 suppressed the sensitivity of miR-761-overexpressing HT29 cells to 5-FU. We also indicated that FOXM1 overexpression promoted cell proliferation, cycle and invasion of miR-761-overexpressing HT29 cells. These data suggested that miR-761 played a tumor suppressor miRNA in colorectal cancer progression and reduced miR-761 expression might be a major mechanism for 5-FU resistance in colorectal cancer cell.
化疗耐药是结直肠癌患者治疗面临的一大挑战；然而，结直肠癌细胞化疗耐药的潜在机制尚未阐明。微小RNA（miRNA）是药物化疗耐药发展中的新因素。在我们的研究中，我们表明miR-761的过表达促进了结直肠癌细胞对5-氟尿嘧啶（5-FU）的敏感性。miR-761在结直肠癌细胞系和组织中的表达下调。低级别患者的miR-761表达低于高级别患者。此外，我们表明miR-761表达升高可抑制结直肠癌细胞增殖、细胞周期、集落形成和细胞侵袭。我们确定FOXM1是结直肠癌细胞中miR-761的直接靶基因。与相邻非肿瘤组织相比，FOXM1在结直肠癌组织中的表达上调。在结直肠癌组织中，miR-761表达与FOXM1表达呈负相关。FOXM1表达升高抑制了miR-761过表达的HT29细胞对5-FU的敏感性。我们还表明，FOXM1过表达促进了miR-761过表达的HT29细胞的增殖、细胞周期进程和侵袭。这些数据表明，miR-761在结直肠癌进展中发挥肿瘤抑制性miRNA的作用，miR-761表达降低可能是结直肠癌细胞对5-FU耐药的主要机制。
