Abstract
Resistance to radiotherapy is the main reason causing treatment failure in locally advanced rectal cancer. MicroRNAs (miRNAs) have been well demonstrated to regulate cancer development and progression. However, how miRNAs regulate radiotherapy resistance in colorectal cancer remains unknown. Herein, we established two human colorectal cancer cell lines resistant to radiotherapy, named HCT116-R and RKO-R, using the strategy of fractionated irradiation. The radioresistant phenotypical changes of the two cell lines were validated by cell viability assay, colony formation assay and apoptosis assay. The miRNA expression profilings of HCT116-R and RKO-R were determined using RNA-seq analyses, and further confirmed by quantitative real-time PCR. Multiple miRNAs, including miR-423-5p, miR-7-5p, miR-522-3p, miR-3184-3p, and miR-3529-3p, were identified with altered expression in both of the radiotherapy-resistant cells, compared to the parental cells. The downregulation of miR-423-5p was further validated in the rectal cancer tissues from radiotherapy-resistant patients. Silencing of miR-423-5p in parental HCT116 and RKO cells decreased the sensitivity to radiation treatment, and inhibited the radiation-induced apoptosis. In consistence, overexpression of miR-423-5p in HCT116-R and RKO-R cells partially rescued their sensitivity to radiotherapy, and promoted the radiation-induced apoptosis. Bcl-xL (Bcl-2-like protein 1) was predicted to be a potential target gene for miR-423-5p, and miR-423-5p/Bcl-xL axis could be a critical mediator of radiosensitivity in colorectal cancer cells. The current finding not only revealed a novel role of miR-423-5p in regulating the radiosensitivity in colorectal cancer, but also suggested miR-423-5p as a molecular candidate for combination therapy with radiation to treat colorectal cancer.
Highlights
Despite tremendous advances in cancer screening and adjuvant treatment, existing research has recognized approximately 135,430 new cases and 50,260 deaths with colorectal cancer (CRC) in the United States in 2017 [1, 2]
Human CRC cell lines HCT116 and RKO were purchased from the American Type Culture Collection (ATCC), and were maintained in DMEM, supplemented with 10% FBS and 1% antibiotics under 5% CO2 and a 95% air atmosphere at 37°C
The radiosensitivity of the four colorectal cancer cell lines were determined by CCK-8 assay
Summary
Despite tremendous advances in cancer screening and adjuvant treatment, existing research has recognized approximately 135,430 new cases and 50,260 deaths with colorectal cancer (CRC) in the United States in 2017 [1, 2]. Due to MIR-423-5p Regulates Colorectal Cancer Radioresistance the limited radiotherapeutic efficiency often caused by the occurrence of resistance to radiation, merely estimated 20% of rectal cancer patients develop pathological complete regression before surgery, while the others present with partial remission or no response, which are more likely to result in poor prognosis [5,6,7]. MiR-191 modulates radiation resistance of prostate cancer through interaction with Retinoid X receptor alpha, RXRA [18]. It remains to be elucidated the altered miRNA expression patterns and their role in inducing resistance to radiotherapy in colorectal cancer cells
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