Androgen Receptor (AR)-TLR4 Crosstalk Mediates Gender Disparities in Hepatocellular Carcinoma Incidence and Progression

Abstract

Background: Androgen receptor (AR) has a role in regulating malignancies and gender disparities in hepatocellular carcinoma (HCC). Recently, TLR4 activation is demonstrated to be required for HCC progression; however, whether and how TLR4 interacts with AR is largely unknown. Methods: The tumorigenesis was detected in female and male mice induced by DEN/CCL4, then TLR4 and AR signals were detected in liver tissues by qPCR and FACS. The proliferation, colony formation and migration of HCC cell treated with TLR4 agonist LPS, or/and androgen DHT were evaluated in vitro. Furthermore, the expression of TLR4 and AR was detected by IHC in tissue microarray of HCC, and correlation of AR and TLR4 was defined. Results: Male mice are more susceptible to develop HCC than female mice. Meanwhile, we found baseline TLR4 levels were higher in male mice than in female mice. AR expression in male mice was increased by treatment with DEN/CCL4. And, AR was constitutively expressed in human HCC cell lines. Dihydrotestosterone (DHT) stimulated TLR4 expression in both HepG2 and HepG2 2.15 cells, which could be blocked by silencing AR. On the other hand, treatment with LPS stimulated AR expression, but it was blocked by treatment with TLR4 antagonist and in cells deficient for TLR4. DHT treatment exacerbated TLR4-induced cellular proliferation, colony formation, migration, and invasion of HepG2 cells. The positive relationship between AR and TLR4 was confirmed in human HCC samples. Conclusions: DHT-AR-TLR4 signaling enhances the development of HCC cells and facilitates their migration and invasion, demonstrating a mechanism underlying gender disparity in HCC.

ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-κB signaling pathway

“…Furthermore, abnormal expression of ERCC6L was associated with shorter OS compared with low ERCC6L expression in patients, indicating that ERCC6L expression is markedly significant for the prognosis of HCC patients. Epidemiological studies of HCC have showed that it was notably more prevalent in male than in female, with a male-to-female ratio ranging from 2:1 to 8: 1 [27]. We also found that ERCC6L expression was higher in man than that of women.…”

Determining novel candidate anti-hepatocellular carcinoma drugs using interaction networks and molecular docking between drug targets and natural compounds of SiNiSan

“…AR is an androgen receptor involved in the growth and progression of hepatocellular carcinoma, it can inhibit the expression of CD90 in circulating tumor cells by up-regulating histone 3H2A ( Han et al, 2020 ). Targeting the AR transduction pathway may be the key to inhibiting the progression of advanced HCC ( Han et al, 2020 ; Ma et al, 2014a ; Ma et al, 2014b ). ESR1 is an estrogen receptor that causes abnormal serum methylation and can be used as a biomarker for the diagnosis of HCC.…”

The Similarities and Differences between the Effects of Testosterone and DHEA on the Innate and Adaptive Immune Response

“…In addition, orchectomy increases TLR4 expression [ 57 ]. In addition, the increased TLR4 expression correlates with increased AR expression in a hepatocarcinoma cell model where silencing AR with siRNA decreases the DHT-dependent increase in TLR4 [ 58 ]. In addition, testosterone increases TLR6 expression associated with the epigenetic modification caused by TLR6 promoter methylation and decreases TLR8 expression in the liver of Plasmodium chabaudi -infected mice, contributing to the persistence of infection [ 59 ].…”