• Androgens
• Breast cancer
• Estrogens
• Hepatocellular carcinoma
• Hormone-responsive cancer
• Prostate cancer

• Humans
• Signal Transduction/drug effects
• Receptors, Estrogen/metabolism
• Animals
• Receptors, Androgen/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Estrogens/metabolism
• Androgens/metabolism
• Antineoplastic Agents, Hormonal/therapeutic use
• Gonadal Steroid Hormones/metabolism
• Neoplasms, Hormone-Dependent/drug therapy
• Neoplasms, Hormone-Dependent/metabolism
• Neoplasms, Hormone-Dependent/pathology
• Female

• Hepatitis B virus (HBV)
• androgens
• dihydrotestosterone
• gender-specific alteration
• steroid profiling

• cancer
• molecular biology
• pathophysiology

• complete response
• liver cancer
• older patient
• stage IV disease
• systemic therapy

• SARS‐CoV‐2
• TMPRSS2
• androgen response element
• antiandrogens
• enzalutamide
• seasonal coronaviruses

• Male
• Female
• Humans
• Androgens/metabolism
• Androgens/pharmacology
• Androgen Antagonists/pharmacology
• Androgen Antagonists/metabolism
• Seasons
• Coronavirus 229E, Human
• Antiviral Agents/pharmacology
• Antiviral Agents/metabolism
• Luciferases
• Benzamides
• Nitriles
• Phenylthiohydantoin

• 360G-Wellcome-220981_Z_20_Z Wellcome Trust

• AR-complement system interaction
• HBV integration risk loci
• HBV mutation diversity
• hepatocyte-immune cell communication
• liver cancer
• single-cell sequencing

• 2022A1515012650 Natural Science Foundation of Guangdong Province
• 92249303 Integrated Project of Major Research Plan of National Natural Science Foundation of China
• 2021A1515110972 Guangdong Basic and Applied Basic Research Foundation
• 23ptpy62 Fundamental Research Funds for the Central Universities - Sun Yat-sen University

• Humans
• Female
• Male
• Animals
• Mice
• SARS-CoV-2/genetics
• SARS-CoV-2/metabolism
• COVID-19/genetics
• Peptidyl-Dipeptidase A/metabolism
• Angiotensin-Converting Enzyme 2/genetics
• Angiotensin-Converting Enzyme 2/metabolism
• Immunologic Factors
• Interferon Regulatory Factors/metabolism

• EBV
• HPV
• benign prostate hyperplasia
• microbiome
• prostate cancer

• Epstein-Barr Virus Infections
• Herpesvirus 4, Human/genetics
• Humans
• Male
• Prostatic Hyperplasia/diagnosis
• Prostatic Hyperplasia/genetics
• Prostatic Neoplasms
• RNA, Ribosomal, 16S/genetics

• Wellcome Trust
• The Wellcome Trust DBT India Alliance
• Science and Engineering Research Board
• Department of Science and Technology, Government of West Bengal

• HCC screening
• hepatocellular carcinoma
• metabolic syndrome
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis

• HBV
• androgen
• cancer
• dimorphism
• epidemiology
• gender
• hepatitis
• hepatocellular carcinoma
• oestrogen
• outcome
• sex
• stigma
• testosterone
• treatment

• HBV
• androgen
• cancer
• dimorphism
• epidemiology
• gender
• hepatitis
• hepatocellular carcinoma
• oestrogen
• outcome
• sex
• stigma
• testosterone
• treatment

• Wellcome Trust
• CC2223 Arthritis Research UK
• R01 AI133673 NIAID NIH HHS

• HBV
• androgen
• cancer
• dimorphism
• epidemiology
• gender
• hepatitis
• hepatocellular carcinoma
• oestrogen
• outcome
• sex
• stigma
• testosterone
• treatment

Hepatocellular Carcinoma (HCC) is a sexually dimorphic cancer, with female sex being independently protective against HCC incidence and progression. The aim of our study was to understand the mechanism of estrogen receptor signaling in driving sex differences in hepatocarcinogenesis.

We integrated 1,268 HCC patient sample profiles from publicly available gene expression data to identify the most differentially expressed genes (DEGs). We mapped DEGs into a physical protein interaction network and performed network topology analysis to identify the most important proteins. Experimental validation was performed in vitro on HCC cell lines, in and in vivo, using HCC mouse model.

We showed that the most central protein, ESR1, is HCC prognostic, as increased ESR1 expression was protective for overall survival, with HR=0.45 (95%CI 0.32-0.64, p=4.4E-06), and was more pronounced in women. Transfection of HCC cell lines with ESR1 and exposure to estradiol affected expression of genes involved in the Wnt/β-catenin signaling pathway. ER-α (protein product of ESR1) agonist treatment in a mouse model of HCC resulted in significantly longer survival and decreased tumor burden (p<0.0001), with inhibition of Wnt/β-Catenin signaling. In vitro experiments confirmed colocalization of β-catenin with ER-α, leading to inhibition of β-catenin-mediated transcription of target genes c-Myc and Cyclin D1.

Combined, the centrality of ESR1 and its inhibition of the Wnt/β-catenin signaling axis provide a biological rationale for protection against HCC incidence and progression in women.

• ESR1
• PPIs
• Wnt/b-catenin
• estrogen
• hepatocellular carcinoma
• high-throughput
• interactome
• network analysis

Sex hormones are steroid hormones synthesized from the gonads of animals and tissues such as the placenta and adrenocortical reticular zone. The physiological functions of sex hormones are complex. Sex hormones are not only pathologically correlated with many diseases of the reproductive system, but are etiological factors in some viral infectious diseases, including disease caused by infections of coronaviruses, herpesviruses, hepatitis viruses, and other kinds of human viruses, which either exhibit a male propensity in clinical practice, or crosstalk with androgen receptor (AR)-related pathways in viral pathogenesis. Due to the global pandemic of coronavirus disease 2019 (COVID-19), the role of androgen/AR in viral infectious disease is highlighted again, majorly representing by the recent advances of AR-responsive gene of transmembrane protease/serine subfamily member 2 (TMPRSS2), which proteolytically activates the receptor-mediated virus entry by many coronaviruses and influenza virus, along with the role of androgen-mediated signaling for the transcription of hepatitis B virus (HBV), and the role of sex hormone responsive genes during Zika virus (ZIKV) pathogenesis, et al. Collectively, we propose to provide a comprehensive overview of the role of male sex hormones during multiple phases in the life cycle of different human viruses, which may be partly responsible for the sex-specific prevalence, severity and mortality of some diseases, therefore, may provide clues to develop more efficient prevention and treatment strategies for high-risk populations.

• androgen receptor
• human viruses
• male predominance
• transmembrane protease/serine subfamily member 2
• virus infection

• Benzamides
• Carcinoma, Hepatocellular/drug therapy
• Double-Blind Method
• Humans
• Liver Neoplasms/drug therapy
• Nitriles
• Phenylthiohydantoin
• Sorafenib

The population of patients with hepatocellular carcinoma (HCC) overlaps to a high degree with those for chronic kidney disease (CKD) and end-stage renal disease (ESRD). The degrees of renal dysfunction vary, from the various stages of CKD to dialysis-dependent ESRD, which often affects the prognosis and treatment choice of patients with HCC. In addition, renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes. This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction. The possible mechanisms of CKD causing HCC involve uremia itself, long-term dialysis status, immunosuppressive agents for postrenal transplant status, and miscellaneous factors such as hormone alterations and dysbiosis. The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome. Finally, we categorized the risk factors that could lead to both HCC and CKD into four categories: Environmental toxins, viral hepatitis, metabolic syndrome, and vasoactive factors. Both CKD and ESRD have been reported to negatively affect HCC prognosis, but more research is warranted to confirm this. Furthermore, ESRD status itself ought not to prevent patients receiving aggressive treatments. This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment, treatment-related adverse renal effects, and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD. Such aggressive treatments include liver resection, simultaneous liver kidney transplantation, radiofrequency ablation, and transarterial chemoembolization. Finally, focusing on patients unable to receive active treatment, this study compiled information on the latest systemic pharmacological therapies, including targeted and immunotherapeutic drugs. Based on available clinical studies and Food and Drug Administration labels, this study details the drug indications, side effects, and dose adjustments for patients with renal dysfunction. It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.

• Hepatocellular carcinoma
• Chronic kidney disease
• End-stage renal disease
• Hemodialysis
• Cancer prognosis
• Cancer therapeutics

• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Humans
• Kidney Failure, Chronic
• Liver Neoplasms/complications
• Liver Neoplasms/therapy
• Prognosis

Hepatitis B virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC). Understanding the unique features for HBV-induced HCC can shed new light on the unmet needs in its early diagnosis and effective therapy. During decades of chronic hepatitis B, hepatocytes undergoing repeated damage and regeneration accumulate genetic changes predisposing to HCC development. In addition to traditional mutations in viral and cellular oncogenes, HBV integration into the cell chromosomes is an alternative genetic change contributing to hepatocarcinogenesis. A striking male dominance in HBV-related HCC further highlights an interaction between androgen sex hormone and viral factors, which contributes to the gender difference via stimulating viral replication and activation of oncogenes preferentially in male patients. Meanwhile, a novel circulating tumor biomarker generated by HBV integration shows great potential for the early diagnosis of HCC. These unique HBV-induced hepatocarcinogenic mechanisms provide new insights for the future development of superior diagnosis and treatment strategies.

Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus–host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV–HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC.

• circulating tumor DNA
• hepatitis B virus (HBV)
• hepatocellular carcinoma (HCC)
• inflammation
• sex hormone
• virus integration

There is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.

Hepatocellular carcinoma (HCC) is the most 5th commonly diagnosed and 2nd most lethal tumor in the world. The obvious gender advantage of HCC indicates that androgen receptor (AR) may play an important role in the tumor occurrence, develop and metastasis of HCC. Here we found that decreased AR could alter miR-325 to increase ACP5 expression in HCC cells, to increase HCC cells migration and invasion capacities. Mechanism dissection revealed that AR could regulate miR-325 expression through transcriptional regulation and miR-325 might directly target the 3'UTR of ACP5-mRNA to suppress its translation. The in vivo orthotopic xenografts mouse model with oemiR-325 also validated in vitro data. Together, these findings suggest that AR may decrease HCC progression through miR-325/ACP5 signaling and targeting the AR/miR-325/ACP5 signaling may help in the development of the novel therapies to better suppress the HCC progression.

• ACP5
• AR
• HCC
• invasion
• miR-325
• migration

• ACLF (acute-on-chronic liver failure)
• estradiol
• hepatitis B
• mortality
• prognosis
• testosterone (androgen)

Fibronectin, a matrix glycoprotein aberrantly expressed in various tumor cells, is a known candidate biomarker for the early diagnosis of hepatocellular carcinoma (HCC). In this study, we investigated whether serum fibronectin levels could predict tumor recurrence in patients with early-stage HCC after curative treatment. A total of 83 patients who showed complete response after initial curative treatment were included. The levels of serum fibronectin at baseline and 4–6 weeks after initial treatment were analyzed with regard to their associations with recurrence. Multivariate logistic regression analyses were performed to construct a prognostic nomogram. Baseline fibronectin levels were not significantly correlated with tumor size, number, stage, and serum α-fetoprotein levels. However, decrease in serum fibronectin levels after treatment was significantly associated with reduced HCC recurrence in multivariate logistic regression (odds ratio, 0.009; p < 0.001). Furthermore, a nomogram consisting of gender and changes in serum fibronectin showed a good discriminatory capability for the prediction of HCC recurrence with an area under the receiver-operating curve of 0.87. In conclusion, changes in serum fibronectin levels may be a surrogate indicator for assessment of treatment response in patients with early HCC after curative treatment.

• Androgen receptor
• Bufalin
• Cell cycle-related kinase
• HBV X protein
• HBV-associated HCC
• HBx transgenic mice

• Notch4
• VE-Cadherin
• androgen receptor
• circRNA7
• hepatocellular carcinoma
• miRNA7-5p
• vasculogenic mimicry

• cohort study
• mass spectrometry
• sex hormones
• hepatocellular carcinoma
• intrahepatic cholangiocarcinoma
• human

• Androgen receptor
• Emodin succinyl ester
• Enhancer of zeste homolog 2
• Hepatocellular carcinoma

• Glycogen synthase kinase 3 (GSK-3)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Hepatocellular carcinoma (HCC)
• Non-alcoholic fatty liver disease (NAFLD)
• Signaling pathways

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.

• KLF5
• androgen receptor
• cell proliferation
• prostate cancer
• tumorigenesis

• AR-V7
• TSPX
• TSPY
• androgen receptor
• cell cycle regulation
• cyclin B-CDK1
• oncogene
• sex chromosomes
• sex differences
• tumor suppressor

• Carcinogenesis/genetics
• Cell Cycle Proteins/genetics
• Chromosomes, Human, Y/genetics
• DNA-Binding Proteins/genetics
• Humans
• Male
• Proto-Oncogene Mas
• Testis/metabolism

• I01 BX000865 BLRD VA
• I01 BX004446 BLRD VA
• IK6 BX004854 BLRD VA

Liver cancer is one of the major causes of cancer death worldwide, with significantly higher incidence and mortality among the male patients. Although sex hormones and their receptors could contribute to such sex differences, the story is incomplete. Genes on the male-specific region of the Y chromosome could play a role(s) in this cancer. TSPY is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY) that is ectopically expressed in a subset of male hepatocellular carcinomas (HCCs). Although various studies showed that TSPY expression is associated with poor prognosis in the patients and its overexpression promotes cell proliferation of various cancer cell lines, it remains unclear how TSPY contributes to the clinical outcomes of the HCC patients. Identifying the downstream genes and pathways of TSPY actions would provide novel insights on its contribution(s) to male predominance in this deadly cancer.

To determine the effects of TSPY on HCC, a TSPY transgene was introduced to the HCC cell line, HuH-7, and studied with RNA-Seq transcriptome analysis. The results showed that TSPY upregulates various genes associated with cell-cycle and cell-viability, and suppresses cell-death related genes. To correlate the experimental observations with those of clinical specimens, transcriptomes of male HCCs with high TSPY expression were analyzed with reference to those with silent TSPY expression from the Cancer Genome Atlas (TCGA). The comparative analysis identified 49 genes, which showed parallel expression patterns between HuH-7 cells overexpressing TSPY and clinical specimens with high TSPY expression. Among these 49 genes, 16 likely downstream genes could be associated with survival rates in HCC patients. The major upregulated targets were cell-cycle related genes and growth factor receptor genes, including CDC25B and HMMR, whose expression levels are negatively correlated with the patient survival rates. In contrast, PPARGC1A, SLC25A25 and SOCS2 were downregulated with TSPY expression, and possess favorable prognoses for HCC patients.

We demonstrate that TSPY could exacerbate the oncogenesis of HCC by differentially upregulate the expression of pro-oncogenic genes and downregulate those of anti-oncogenic genes in male HCC patients, thereby contributing to the male predominance in this deadly cancer.

The online version of this article (10.1186/s13578-019-0287-x) contains supplementary material, which is available to authorized users.

• Datamining
• Hepatocellular carcinoma
• Male predominance
• TCGA dataset
• TSPY
• Transcriptome analysis
• Y-chromosome

• Hepatitis B virus
• Hepatitis C virus
• Hepatocellular carcinoma
• Liver disease
• Sexual dimorphism

• Androgen receptor
• CSC
• Drug sensitivity
• Liver cancer
• microRNAs

• HBV
• cccDNA
• hepatocarcinogenesis
• post-translational modifications
• replication
• transcription

To study sex disparity in susceptibility to hepatocellular carcinoma (HCC), we created a transgenic mouse model that expressed the full hepatitis B virus (HBV) genome with the W4P mutation.

Transgenic mice were generated by transferring the pHY92-1.1x-HBV-full genome plasmid (genotype A2) into C57Bl/6N mice. We compared serum levels of hepatitis B surface antigen (HBsAg), interleukin (IL)-6, and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST), as well as liver histopathological features in male and female transgenic (W4P TG) mice and in nontransgenic littermates of 10 mo of age.

W4P TG males exhibited more pronounced hepatomegaly, significantly increased granule generation in liver tissue, elevated HBsAg expression in the liver and serum, and higher serum ALT and IL-6 levels compared to W4P TG females or littermate control groups.

Together, our data indicate that the W4P mutation in preS1 may contribute to sex disparity in susceptibility to HCC by causing increased HBV virion replication and enhanced IL-6-mediated inflammation in male individuals. Additionally, our transgenic mouse model that expresses full HBV genome with the W4P mutation in preS1 could be effectively used for the studies of the progression of liver diseases, including HCC.

• Hepatitis B virus
• W4P mutation of preS1
• Transgenic mice
• Hepatocellular carcinoma

• Alanine Transaminase/blood
• Animals
• Aspartate Aminotransferases/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Disease Susceptibility/blood
• Disease Susceptibility/virology
• Female
• Genome, Viral/genetics
• Hepatitis B Surface Antigens/blood
• Hepatitis B Surface Antigens/genetics
• Hepatitis B virus/genetics
• Hepatitis B virus/isolation & purification
• Hepatitis B, Chronic/blood
• Hepatitis B, Chronic/pathology
• Hepatitis B, Chronic/virology
• Humans
• Interleukin-6/blood
• Liver/enzymology
• Liver/pathology
• Liver/virology
• Liver Neoplasms/blood
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation
• Protein Precursors/blood
• Protein Precursors/genetics
• Sex Factors
• Viral Load

• gender disparity
• hepatocarcinoma
• heptitis B virus

Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC. Here, we discuss the recent data on AR and HCC, and the combination of sorafenib and inhibitors of AR for advanced-HCC patients. Androgen-dependent and androgen-independent AR activation exist in human hepatocarcinogenesis. AR could directly control hepatocarcinogenesis and regulate the innate immune system to influence HCC progression. Combination of sorafenib with AR inhibitors might represent a potential treatment for patients with advanced HCC.

• androgen receptor
• hepatocellular carcinoma
• sorafenib

• androgen receptor
• fatty acid
• liver cancer

• Hepatitis B
• Liver
• Pregnancy
• Transmission

• Animals
• Cell Line
• DEAD Box Protein 58
• Disease Models, Animal
• Hepatitis B/immunology
• Hepatitis B/virology
• Hepatitis B virus/physiology
• Hepatocytes/immunology
• Hepatocytes/virology
• Host-Pathogen Interactions
• Humans
• Intracellular Signaling Peptides and Proteins
• Mice
• MicroRNAs
• Receptors, Immunologic
• Signal Transduction

• androgen
• androgen receptor
• estrogen
• estrogen receptor α
• hepatitis B virus