Therapeutic Targeting of miR-21 Restores SASH1 and Sensitizes HBV-HCC to Sorafenib

TL;DR

Blocking miR-21 helps restore a tumor suppressor and makes HBV-related liver cancer more responsive to sorafenib treatment.

Contribution

Identifies miR-21 as a novel therapeutic target to overcome sorafenib resistance in HBV-associated HCC.

Findings

miR-21 suppresses SASH1, a tumor suppressor, in HBV-positive HCC.

Inhibiting miR-21 restores SASH1 and increases sorafenib sensitivity in HBV-HCC models.

Combining miR-21 inhibition with sorafenib significantly reduces tumor growth in mouse models.

Abstract

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) frequently develops resistance to sorafenib, limiting treatment efficacy. We showed that miR-21 is highly expressed in HBV-positive HCC and directly suppresses the tumor suppressor SASH1. Loss of SASH1 enhances HBx-driven oncogenic signaling and reduces sorafenib-induced apoptosis. miR-21 inhibition restores the SASH1 expression and significantly improves sorafenib response in in vitro and in vivo models. These findings suggested that targeting miR-21 may represent a promising strategy to overcome sorafenib resistance in HBV-associated HCC.

Background: Sorafenib resistance remains a major barrier to effective therapy in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Introduction: Here, we identified a previously undefined mechanism by which miR-21 promotes sorafenib resistance by suppressing the tumor suppressor SASH1 and enhancing HBx-driven PI3K/AKT/mTOR signaling. Methods: miR-21 expression was markedly elevated in HBV-HCC tissues, HBV-integrated HCC cell lines, and hypoxic conditions. Bioinformatic analyses and luciferase reporter assays confirmed SASH1 as a direct miR-21 target. Results: Mechanistically, SASH1 was functionally associated with HBx-related oncogenic signaling and influenced apoptotic responses. miR-21 inhibition reduced HBV-HCC cell proliferation, increased apoptosis, and restored sorafenib sensitivity in vitro. In an orthotopic HBV-HCC mouse model, the combined administration of miR-21 inhibitor and sorafenib elicited markedly greater tumor suppression and restoration of the SASH1 expression than either monotherapy did. Discussion: Therefore, these findings suggested that the miR-21/SASH1 pathway contributed to therapeutic resistance in HBV-associated HCC and highlighted that miR-21 targeting could be an efficient strategy to improve sorafenib response. Conclusions: The miR-21/SASH1 axis play a critical role in sorafenib resistance in HBV-associated HCC, and targeting miR-21 may provide a promising therapeutic strategy to enhance treatment efficacy.

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