MicroRNA-122 mimic/microRNA-221 inhibitor combination as a novel therapeutic tool against hepatocellular carcinoma.

Abstract

Therapeutic microRNAs (miRNAs) delivery holds a lot of promise for treating human malignancies. So, this study was carried out to examine the potential of miR-122 mimic and/or miR-221 inhibitor as an innovative therapeutic strategy for HCC in an animal model. Mice were categorized into five groups comprising: (1) a normal control group, (2) an HCC group subjected to diethylnitrosamine (DEN) injection for 12 weeks, (3) a miR-122 mimic-treated HCC group, (4) a miR-221 inhibitor-treated HCC group, and (5) a miR-122 mimic/miR-221 inhibitor-treated HCC group. After 16 weeks, all animals were sacrificed and underwent biochemical, miRNAs and genes expression, histopathological, and immunohistochemical examinations. The miR-122 mimic/miR-221 inhibitor combination dramatically reduced the levels of pro-inflammatory, liver cancer, angiogenesis, and cell proliferation markers when compared to either treatment alone. It also down-regulated the expression of cyclin D1, TGF-β, and β-catenin genes, which are involved in promoting cell cycle progression and cancer cell proliferation. Furthermore, it caused the resolution of nearly all the histological malignant features as well as the reduction of malignant cellular markers, including α-smooth muscle actin, arginase-1, and tropomyosin-1. The co-treatment with miR-122 mimic and miR-221 inhibitor amplifies the benefits of either treatment on HCC through targeting the SENP1 and ARF4 genes, respectively. This combination can inhibit cancer cell proliferation and angiogenesis while inducing tumor apoptosis and necrosis. This study demonstrates the therapeutic potential of reversing a dysregulated miRNAs expression pattern in HCC. As a result, future research should concentrate on turning miRNA understanding into therapeutic applications.