ARID4B Promotes the Progression of Hepatocellular Carcinoma Through the PI3K/AKT Pathway

Background: AT-rich interaction domain 4B (ARID4B) is a transcriptional activator that regulates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in prostate cancer. However, the role of ARID4B in hepatocellular carcinoma (HCC) has remained unclear.

Methods: This study included 162 patients who had undergone primary hepatic resection for HCC between 2008 and 2019. Their HCC samples were immunohistochemically stained for ARID4B, and ARID4B score was calculated from the intensity and percentage of staining. We retrospectively investigated the association of ARID4B score with disease-free and overall survival, and primary recurrence patterns of HCC. Furthermore, human HCC cell lines (HuH-1 and HuH-7) were knocked down for ARID4B using small-interfering RNA (siRNA), and the expression of PI3K/AKT proteins, cell proliferation, migration, and invasion ability were assessed.

Results: In multivariate analyses, negative HBs-antigen (p = 0.02), multiple tumors (p < 0.01), microvascular invasion (p = 0.03), and high ARID4B score (p = 0.01) were independent predictors of disease-free survival, while tumor size >5 cm (p = 0.03), microvascular invasion (p < 0.01), and high ARID4B score (p = 0.04) were independent predictors of overall survival. A high ARID4B score was associated with high serum α-fetoprotein (AFP) level (p = 0.04), poor tumor differentiation (p < 0.01), and microvascular invasion (p < 0.01). ARID4B scores were significantly lower in the no recurrence, intrahepatic recurrence, and extrahepatic recurrence groups, in that order. Knockdown of ARID4B using siRNA in human HCC cell lines significantly suppressed the PI3K/AKT pathway, cell proliferation, migration, and invasion.

Conclusions: ARID4B may activate the PI3K/AKT signaling pathway in HCC and may be a prognostic factor after hepatic resection for HCC.