Histamine H3 Receptor Promotes Cell Survival via Regulating PKA/CREB/CDKN1A Signal Pathway in Hepatocellular Carcinoma

BACKGROUND: The histamine H3 receptor (HRH3) is mainly expressed in areas of the brain involved in the regulation of the release of various neurotransmitters. Recent studies have shown that HRH3 expression is increased in several types of carcinomas. However, the functional roles and underlying molecular mechanism by which HRH3 regulates cell survival in hepatocellular carcinoma (HCC) remain unknown. METHODS: The mRNA and protein expression level of target genes were evaluated by qRT-PCR, Western blot and immunohistochemistry, respectively. Cell viability and cell proliferation activity were assessed by MTS assay and EdU incorporation assay. Cell apoptosis and cell cycle were assessed by flow cytometry analysis. A xenograft mouse model was constructed to investigate the effect of HRH3 on tumor growth in vivo. RESULTS: Our results indicated that HRH3 was significantly upregulated in HCC, which promoted cell survival by accelerating cell proliferation and inhibiting cell apoptosis. Our results also showed that HRH3 in HCC downregulated the expression of cyclin-dependent kinase inhibitor p21 (CDKN1A) to promote G1-S phase transition by inactivating the cAMP/PKA/CREB pathway, which finally contributed to the malignant growth of HCC. CONCLUSION: Our findings indicated that HRH3 functioned in promoting HCC survival by inactivating the cAMP/PKA/CREB pathway to downregulate CDKN1A expression. Thus, HRH3 might serve as a potential therapeutic target in HCC treatment.