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

Abstract

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.

Exploring the role of mast cells in the progression of liver disease

“…At the same time, inhibition of HRH3 inhibited the metastasis of HCC cells, further supporting the functional role of HRH3 in promoting the metastasis of malignant tumors, which indicates that increased HRH3 levels can be a potential prognostic marker for HCC patients ( Yu et al, 2019 ). Besides, HRH3 in HCC inactivates the cAMP/PKA/CREB pathway by down-regulating the expression of cyclin-dependent kinase inhibitor P21 (CDKN1A), promoting the G1-S phase transition, and ultimately promotes the malignant growth of HCC ( Zhang et al, 2020 ).…”

Mast cells in liver disease progression: An update on current studies and implications

“…H3HR expression is elevated in HCC, promoting cell growth and survival through protein kinase/cyclic adenosine monophosphate responsive element-binding/cyclindependent kinase inhibitor p21 signaling. [16] The increase of tryptase-positive and chymase-positive MCs in human HCC [17] and the decrease in tryptase serum level in patients with HCC after hepatic transarterial chemoembolization [18] suggest a role for these as biomarkers. The majority of MCs in HCC are inactive, and resting MC density is elevated in 305 HCC livers using tryptase immunohistochemistry.…”

<p>Inhibition of CSRP2 Promotes Leukemia Cell Proliferation and Correlates with Relapse in Adults with Acute Myeloid Leukemia</p>

“…Several cell cyclerelated genes are regulated by p-CREB and p-AKT. [19][20][21][22] Knockdown of CREB induces cell cycle arrest and significantly reduces tumor cell proliferation. [23][24][25] Our research found that cyclin-dependent kinase inhibitors p21 and p27 were reduced in CSRP2 knockdown cells.…”