MicroRNA-146a-5p enhances radiosensitivity in hepatocellular carcinoma through replication protein A3-induced activation of the DNA repair pathway

Abstract

Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aimed to evaluate the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to replication protein A3 (RPA3). First, the limma package of R was performed to differentially analyze HCC expression chip, and regulative miRNA of RPA3 was predicted. Expression of miR-146a-5p, RPA3, and DNA damage repair pathway-related factors in tissues and cells was determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle, and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and the DNA repair pathway. The positive rate of ATM, pCHK2, and Rad51 in HCC tissues was higher when compared with that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3.

Reduced expression of microRNA‑139‑5p in hepatocellular carcinoma results in a poor outcome: An exploration the roles of microRNA‑139‑5p in tumorigenesis, advancement and prognosis at the molecular biological level using an integrated meta‑analysis and bioinformatic investigation

“…Previous studies have reported that certain pharmaceutical molecules, including corylin, melatonin and gefitinib in combination with irinotecan, were able to enhance cancer cell sensitivity to chemotherapy by inhibiting RAD51-induced DNA repair in HCC (78)(79)(80). Luo et al (81) observed increased expression of RAD51 in HCC tissues, consistent with the findings of the present study, and revealed that miRNA-146a-5p enhanced the radio-sensitivity of HCC cells via the DNA repair pathway. However, studies have not yet reported an association between miR-139-5p and RAD51 regulation in patients with HCC.…”

miRNA-based biomarkers, therapies, and resistance in Cancer

“…RPA can inhibit DNA repair pathway [190], and then promote tumor cell growth and resist apoptosis in radiotherapy of liver cancer. After radiotherapy, miR-146a-5p expression was raised in HCC cells, while RPA expression was suppressed, and the DNA repair pathway was activated to promote the sensitivity to radiotherapy [191]. Similarly, the decrease of miR-29b level and the increase of phosphatase and tensin homologous protein (PTEN) expression in residual tumor cells happened after radiotherapy for cervical cancer.…”

High-Throughput MicroRNA Profiling of Vitreoretinal Lymphoma: Vitreous and Serum MicroRNA Profiles Distinct from Uveitis

“…Its role in inflammation is less well studied but has been suggested to be a potential biomarker for rheumatoid arthritis [53][54][55]. Furthermore, similar to rheumatoid arthritis patients, miR-146a-5p expression levels are reduced in hepatocellular cell carcinoma [56]. miR-146a is involved in B cell hyperplasia [57], and miR-146a-5p has been reported to be a useful prognostic biomarker for DLBCL [58].…”