MicroRNA-761 promotes the sensitivity of colorectal cancer cells to 5-Fluorouracil through targeting FOXM1

Abstract

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.

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“…Notably, the mechanisms responsible for the tumor-suppressing action on miR-761 upregulation in OS cells were also thoroughly analyzed in this study. miR-761 is downregulated in colorectal [20][21][22] and ovarian 23 cancers. The downregulation of miR-761 is related with the tumor size, tumor grade, and tumor stage in patients with colorectal cancer.…”

“…The downregulation of miR-761 is related with the tumor size, tumor grade, and tumor stage in patients with colorectal cancer. 20,21 Patients with colorectal cancer having low miR-761 expression show worse 5-year overall survival compared to patients with high miR-761 expression. 20 On the contrary, miR-761 is upregulated in non-small cell lung cancer, 24,38 breast cancer 25 and hepatocellular carcinoma.…”

“…For instance, restoring miR-761 expression decreases cell proliferation, cell cycle, colony formation, migration, and invasion in colorectal cancer. [20][21][22] Moreover, it has been reported that upregulation of miR-761 increases the chemosensitivity of colorectal cancer cells to 5-Fluorouracil. 21 Shi and Zhang have reported that restoring miR-761 expression attenuated the proliferation and invasion of ovarian cancer cells.…”

“…[20][21][22] Moreover, it has been reported that upregulation of miR-761 increases the chemosensitivity of colorectal cancer cells to 5-Fluorouracil. 21 Shi and Zhang have reported that restoring miR-761 expression attenuated the proliferation and invasion of ovarian cancer cells. 23 On the contrary, miR-761 plays oncogenic roles in non-small cell lung cancer by promoting cell growth and metastasis in vitro.…”

“…Recently, miR-761 has been reported to be downregulated in many types of human cancer, and has been revealed to play important roles in the genesis and progression of cancer. [20][21][22][23][24][25] However, the biological roles of miR-761 in OS and its underlying mechanism remains largely unknown. In the present study, we detected miR-761 expression in OS and investigated the regulatory effects of miR-761 overexpression on OS progression.…”