Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

Abstract

Objectives Interleukin‐34 (IL‐34) is associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). However, the role and associated mechanisms of IL‐34 in HBV‐related HCC remain unclear. In this study, the expression, biological function and associated mechanisms of IL‐34 in HBV‐related HCC cells were investigated. Methods IL‐34 expression induced by HBV and HBV X (HBX) gene was measured in hepatoma cells. The role of CCAAT/enhancer‐binding protein α (CEBP/α) in HBX‐induced IL‐34 expression was examined. The signal pathways involved in the expression of CEBP/α and IL‐34 induced by HBX were assessed. The role of IL‐34 in the proliferation and migration of HCC cells, and related mechanisms were explored. Results Dependent on HBX, HBV increased IL‐34 expression in hepatoma cells, and HBX upregulated and interacted with CEBP/α to enhance the activity of IL‐34 promoters. CEBP/α mediated by HBX was associated with the activation of PI3‐K and NF‐κB pathways to promote IL‐34 expression. Via CSF1‐R and CD138, IL‐34 promoted the proliferation and migration of hepatoma cells, and contributed to the activation of ERK and STAT3 pathways and the upregulation of Bcl‐xl and c‐Myc mediated by HBX. Conclusion We demonstrate that IL‐34 contributes to HBX‐mediated functional abnormality of HCC cells and provides a novel insight into the molecular mechanism of carcinogenesis mediated by HBX.

The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis

“…HBV is also a major factor associated with the development of hepatocellular carcinoma (HCC). Expression of the HBx viral particle in HCC-infected cells induced expression of IL-34, which promoted cancer cell proliferation and migration via CSF-1R and syndecan-1 receptors in an ERK- and STAT3-dependent manner 84 .…”

The Role of Bcl-xL Protein in Viral Infections

“…Upregulation of Bcl-xL expression causes a decrease in the apoptotic potential of HCC cells that contributes to their survival, intensified growth, and colony formation [ 44 ]. The study of Kong et al [ 45 ] on HBV-positive HCC has shown that HBV causes an increase in Bcl-xL in an IL-34-dependent manner [ 45 ].…”

A novel prognostic models for identifying the risk of hepatocellular carcinoma based on epithelial-mesenchymal transition-associated genes

“…Besides, we executed a TF-EAGs network to investigate the possible transcription factors of these 96 EAGs. Among these transcription factors (TFs), CEBP, AP1, STAT3 have been reported to mediate oncogenic effects of other substances in HCC, indicating that these TFs might have potential research values in HCC [21][22][23]. Through the analysis of gene sequencing data and clinical prognostic information of HCC patients, a prognostic risk model was constructed by 5 hub prognosisrelated EAGs, including LGALS1, MMP1, P3H1, ITGB5, and SPP1.…”