The clinicopathological significance of miR-149 and PARP-2 in hepatocellular carcinoma and their roles in chemo/radiotherapy

Abstract

Hepatocellular carcinomas (HCC) are commonly diagnosed at an advanced stage with unresectable tumors. Although numerous non-surgical approaches have been developed to treat HCC, the prognosis of patients with HCC is still poor. This study investigated the expression of miR-149 and PARP-2 in HCC tumor tissues and their roles in sensitizing chemo/radiotherapy. The expression of miR-149 was measured by real-time PCR, and PARP-2 protein was measured by immunohistochemistry and Western blot. The xenograft HCC mouse model was established by inoculating Hep G2 cells. Increased PARP-1 and decreased miR-149 expression was observed in HCC tissues compared to peritumoral tissues. Positive PARP-2 and low miR-149 expression correlated with larger tumor mass size (P < 0.001), capsular and vascular invasion (P < 0.001), lymph node metastasis (P = 0.02), high histological grade (P < 0.001), TNM (P < 0.001), and BCLC grade (P = 0.001). The Kaplan-Meier survival analysis showed a negative correlation between high PARP-2 expression or low miR-149 expression in HCC tissues with the survival of patients. High PARP-2 and low miR-149 correlated with a low 5-year survival rate and are poor prognosis factors. Overexpression of miR-149 or inhibition of PARP-2 expression could inhibit tumor growth but was more effective in sensitizing chemotherapy and radiotherapy in xenograft HCC animal models. Increased PARP-2 expression and loss of miR-149 expression are involved in the pathogenesis of HCC and are poor prognosis factors in patients with HCC. Although both miR-149 overexpression and PARP-2 inhibitor exert some antitumoral effect, PARP-2 inhibitor is a chemo/radio sensor and can be used to enhance chemotherapy and radiotherapy in patients with HCC.

Identifying Differentially Expressed MicroRNAs Between Cirrhotic and Non-Cirrhotic Hepatocellular Carcinoma and Exploring Their Functions Using Bioinformatic Analysis

“…Hence, we may infer that hsa-mir-149 plays completely different roles across different tumor types. Intriguingly, hsa-mir-149 was considered an anti-oncogene for HCC in previous studies [36]; this finding contradicts our results. After reviewing the miRNA databases, we found that hsa-mir-149 contains two segments, named hsa-miR-149-5p (also named hsa-miR-149) and hsa-miR-149-3p (also named hsa-miR-149*).…”

“…The gene serves as an anti-oncogene in colorectal cancer [35], HCC [36], laryngeal squamous cell carcinoma [37], and renal cell carcinoma [38]. In contrast, the gene functioned as an oncogene gene in T-cell acute lymphoblastic leukemia [39] and prostate cancer [40].…”

Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

“…[63] A meta-analysis showed that the miR-149 gene rs2292832 polymorphism contributes to the risk of hepatocellular carcinoma [64]. The overexpression of miR-149 or the inhibition of PARP-2 expression can inhibit tumor growth, which is more effective in the sensitization of animals with HCC xenografts to chemotherapy and radiotherapy[65]. MiR-149 suppresses HCC cell invasion and metastasis via the suppression of Mg2+/Mn2+-dependent , 1F ( PPM1F ), which mediates the formation of stress fibers in vivo [66].…”

miR-149 suppresses human non-small cell lung cancer growth and metastasis by inhibiting the FOXM1/cyclin�D1/MMP2 axis

“…Recently, microRNA-149 (miR-149) was identified as a tumor inhibitor in human cancers. In hepatocellular carcinoma, low expression of miR-149 was found to be correlated with larger tumor mass size, capsular and vascular invasion, lymph node metastasis, high histological grade, advanced tumor-node-metastasis (TNM) stage and poor prognosis (7). In vitro, miR-149 inhibited cell proliferation, migration and invasion by targeting PPM1F (8).…”