Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross‐talk in hepatocellular carcinoma

Zhao, Hong; Li, Xiao Xing; Yang, Yang; Zhang, Yanjie; Wang, Hui Yun; Zheng, Xi

doi:10.1002/hep.29715

Cited by 79 publications

(88 citation statements)

References 46 publications

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“…International Publisher Furthermore, both higher serum androgen concentrations and the presence of AR gene variants containing shorter CAG repeats (leading to higher AR activity) have been linked to increased risk of hepatocarcinogenesis, especially of HBV-mediated HCC [7,10]. In addition, androgen/AR signals promote cancer cell stemness through direct activation of Nanog homeobox (NANOG) transcription in HCC [10].…”

Section: Ivyspringmentioning

confidence: 99%

“…The androgen receptor (AR) is a member of the nuclear steroid receptor superfamily [6,7], and is a transcription factor activated by ligand-dependent and ligand-independent mechanisms [8]. In response to stimulation by androgens, AR translocates into the nucleus, where it binds to androgen response elements (AREs), and regulates expression of genes related to cell growth and survival; it is in this role that AR serves an important regulator of pathogenesis in hepatocarcinogenesis [4].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Ivyspringmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Nevertheless, sex hormones and their receptors including AR showed influence on lung cancer in a mouse model, and AR expression together with Ki67 expression are associated with the survival outcome of non‐small‐cell lung cancer . As for liver cancer, AR is overexpressed in about 37% of hepatocellular carcinoma tumors, and AR overexpression stimulates oncogenic growth . In addition, it is reported that androgen promotes the growth of hepatocellular cancer cells by upregulating the transcription factor activity of ETS‐1 .…”

Section: Ar and Other Cancersmentioning

confidence: 99%

“…149 As for liver cancer, AR is overexpressed in about 37% of hepatocellular carcinoma tumors, and AR overexpression stimulates oncogenic growth. 150 In addition, it is reported that androgen promotes the growth of hepatocellular cancer cells by upregulating the transcription factor activity of ETS-1. 151 Presently, enzalutamide is being studied at phase I/II clinical trial for advanced hepatocellular carcinoma (NCT02528643 and NCT02642913).…”

Section: Ar and Bladder Cancer Kidney Cancer Lung Cancer And LIVmentioning

confidence: 99%

A magic drug target: Androgen receptor

Zhou

Pang

et al. 2018

Medicinal Research Reviews

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Androgen receptor (AR) is closely associated with a group of hormone‐related diseases including the cancers of prostate, breast, ovary, pancreas, etc and anabolic deficiencies such as muscle atrophy and osteoporosis. Depending on the specific type and stage of the diseases, AR ligands including not only antagonists but also agonists and modulators are considered as potential therapeutics, which makes AR an extremely interesting drug target. Here, we at first review the current understandings on the structural characteristics of AR, and then address why and how AR is investigated as a drug target for the relevant diseases and summarize the representative antagonists and agonists targeting five prospective small molecule binding sites at AR, including ligand‐binding pocket, activation function‐2 site, binding function‐3 site, DNA‐binding domain, and N‐terminal domain, providing recent insights from a target and drug development view. Further comprehensive studies on AR and AR ligands would bring fruitful information and push the therapy of AR relevant diseases forward.

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“…The animal protocol was approved by the Animal Ethics Committee of Sun Yat-Sen University Cancer Center. Subcutaneous xenograft models were established, and drug treatments were carried out as previously described (21)(22)(23)(24)(25). Four-week-old female BALB/c nude mice were used in this study.…”

Section: In Vivo Studies and Ihcmentioning

confidence: 99%

Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

Jiang

et al. 2018

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers. The 5-year survival rate is very low. Unfortunately, there are few efficacious therapeutic options. Until recently, Sorafenib has been the only available systemic drug for advanced HCC. However, it has very limited survival benefits, and new therapies are urgently needed. In this study, we investigated the anti-HCC activity of carfilzomib, a second-generation, irreversible proteasome inhibitor, as a single agent and in combination with sorafenib. , we found that carfilzomib has moderate anticancer activity toward liver cancer cells, but strongly enhances the ability of sorafenib to suppress HCC cell growth, proliferation, migration, invasion, and survival. Remarkably, the drug combination exhibits even more potent antitumor activity when tested in animal tumor models. Mechanistically, the combined treatment activates caspase-dependent and endoplasmic reticulum stress/CHOP-mediated apoptotic pathways, and suppresses epithelial-mesenchymal transition. In conclusion, our results demonstrate that the combination of carfilzomib and sorafenib has synergistic antitumor activities against HCC, providing a potential therapeutic strategy to improve the mortality and morbidity of HCC patients.

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Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross‐talk in hepatocellular carcinoma

Cited by 79 publications

References 46 publications

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

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

A magic drug target: Androgen receptor

Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

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