Sohlh2 inhibited the angiogenesis of hepatocellular carcinoma through the HIF-1α/VEGFA pathway.

[PURPOSE] To investigate the role of Sohlh2 in hepatocellular carcinoma (HCC) and its potential mechanisms.

[METHODS] This study focused on Hep3B and HepG2 cells and employed lentiviral transfection to create Sohlh2 overexpression and knockdown models. Through CCK8, flow cytometry, angiogenesis and immunofluorescence experiments, the effects of Sohlh2 on tumor cell proliferation, cell cycle progression, apoptosis, and angiogenesis were investigated. Additionally, its regulatory role in the HIF-1α/VEGFA pathway was explored. The experiments were repeated after introducing the Sohlh2 agonist CoCl and antagonist LW6. Additionally, a Hep3B tumor-bearing mouse model was established to evaluate the effect of Sohlh2 on liver cancer growth.

[RESULT] Experimental results indicated that Sohlh2 was highly expressed in normal human hepatocytes but was downregulated in HCC cells. Overexpression of Sohlh2 inhibited HCC cell proliferation by blocking the transition from the G0/G1 phase to the S phase, promoted apoptosis, suppressed the expression of HIF-1α and CD31, and consequently inhibited tumor angiogenesis. Conversely, downregulation produced the opposite effects. In vivo and in vitro mechanistic studies indicated that HIF-1α agonists reversed the anti-proliferative, pro-apoptotic, and anti-angiogenic effects induced by Sohlh2 overexpression in HCC. Conversely, the antagonist LW6 significantly mitigated the effects of Sohlh2 knockdown.

[CONCLUSION] Our research suggested that that Sohlh2 exerted a tumor-suppressing gene function in hepatocellular carcinoma by inhibiting the HIF-1α/VEGFA signaling pathway. These findings provided a potential molecular target for the development of anti-angiogenic therapies in HCC.