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Jin Y, Shama A, Tang H, Zhao T, Zhang X, Yang F, Chen D. Exploring the Mechanism of Luteolin in Protecting Chickens from Ammonia Poisoning Based on Proteomic Technology. Metabolites 2025; 15:326. [PMID: 40422902 DOI: 10.3390/metabo15050326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 05/09/2025] [Accepted: 05/12/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND Ammonia (NH3), a harmful gas, reduces livestock productivity, threatens their health, and causes economic losses. Luteolin (Lut), an anti-inflammatory flavonoid, may counteract these effects. METHODS Our study explored luteolin's protective mechanisms on chicken splenic lymphocytes under ammonia stress using a simulation model and four-dimensional fast data-independent acquisition (4D-FastDIA) proteomics. We identified 316 proteins, with 69 related to ammonia's negative effects and 247 to Lut's protection. Thirty differentially expressed proteins (DEPs) were common to both groups, with 27 showing counter-regulation with Lut. RESULTS Gene Ontology (GO) analysis showed DEPs enriched in molecular responses to interferons and the negative regulation of immune responses, mainly located extracellularly. Molecular function analysis revealed DEPs in antigen binding and synthase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis linked DEPs to pathways like estrogen signaling, NOD-like receptor signaling, cytokine-cytokine receptor interaction, and JAK-STAT signaling. The quantitative real-time polymerase chain reaction (qRT-PCR) results indicated that the mRNA levels of Interferon Alpha and Beta Receptor subunit 2 (IFNAR2) and Signal Transducer and Activator of Transcription 1 (STAT1) were trending downward. This observation was in strong agreement with the downregulation noted in the proteomics analysis. CONCLUSIONS Lut's protective role against ammonia's adverse effects on chicken splenic lymphocytes is linked to the modulation of key signaling pathways, offering insights for further research on treating ammonia exposure with Lut.
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Affiliation(s)
- Yu Jin
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Azi Shama
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Haojinming Tang
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Ting Zhao
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Xinyu Zhang
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Falong Yang
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Dechun Chen
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory of Animal Medicine in Sichuan Province, Southwest Minzu University, Chengdu 610041, China
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Davidson RK, Corry K, Orlofsky A, Li P, Russell CE, Zhang A, Moraes de Lima Perini M, Priddy CN, Nguyen AV, Li J. Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development. PLoS One 2024; 19:e0315078. [PMID: 39689092 PMCID: PMC11651548 DOI: 10.1371/journal.pone.0315078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 11/20/2024] [Indexed: 12/19/2024] Open
Abstract
Studies with genetically modified mice have implicated the transcriptional regulator STAT3 as a key modulator of bone development. STAT3-OKO knockout mouse lines were generated in two genetic backgrounds, pure C57BL/6 (STAT3-OKO-BL) and mixed C57BL/6, CD1 (STAT3-OKO-M). Both lines exhibited defective postnatal bone development resulting in reduced body weight and shortened femurs that displayed low bone mineral density as well as cortical widening and thinning in the diaphyseal region. Remarkably, each of these defects displayed sexual dimorphism that was dependent on genetic background: the phenotype was entirely male-specific in STAT3-OKO-M but not in STAT3-OKO-BL, in which defects were similar in both sexes. However, both lines exhibited a male-specific bone defect in mineralization, and also in bone mechanical properties related to bone quality, such as yield stress and ultimate stress. On the other hand, bone mechanical properties such as ultimate force, that may reflect density and macrostructure rather than bone quality, showed male-specific defects only in STAT3-OKO-M. These findings suggest that STAT3 may regulate multiple sex-dependent mechanisms in bone development that control either mineralization or bone accrual, and that the sex-dependence of at least some of these mechanisms is affected by genetic background. Finally, we used CRISPR/Cas9 to generate STAT3-deficient preosteoblastic cells from immortalized wild-type bone marrow stem cells and showed that the defective osteoblastic differentiation of STAT3-ablated cells was associated with reduced gene expression of Wnt3a and Wnt5a, consistent with other studies that identify Wnt signaling pathways as potential effector mechanisms for STAT3-mediated regulation of bone development.
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Affiliation(s)
- Rebecca K. Davidson
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, United States of America
| | - Kylie Corry
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, United States of America
| | - Amos Orlofsky
- Department of Biological Sciences and Geology, the City University of New York-Queensborough Community College, Bayside, New York, United States of America
| | - Ping Li
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Caleb E. Russell
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, United States of America
| | - Amy Zhang
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, United States of America
| | | | - Carlie N. Priddy
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, United States of America
| | - Andrew V. Nguyen
- Department of Biological Sciences and Geology, the City University of New York-Queensborough Community College, Bayside, New York, United States of America
| | - Jiliang Li
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, United States of America
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Colloca GA, Venturino A. Effect of Subgroups on Study Outcomes in Unresectable Hepatocellular Carcinoma Undergoing Upfront Systemic Treatment: A Meta-analysis. Am J Clin Oncol 2024; 47:585-590. [PMID: 38979979 DOI: 10.1097/coc.0000000000001133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
OBJECTIVES Immunotherapy improved the outcome of patients with unresectable hepatocellular carcinoma, but not all studies are in agreement, nor is it clear whether certain subgroups have really benefited. This study aims to perform an updated meta-analysis of trials comparing upfront immunotherapy-based regimens versus tyrosin-kinase inhibitors, and some exploratory analyses. METHODS After a systematic review, randomized trials of immunotherapy-based regimens versus tyrosin-kinase inhibitors were selected. A meta-analysis assessed the relationship between treatment arm and overall survival. Based on the resulting heterogeneity, a further investigation of 11 variables by meta-regression and an exploration of subgroups were planned. RESULTS Eight studies were selected. From the meta-analysis, the overall survival improvement for the immunotherapy-based arms was consistent (HR: 0.77, CI: 0.68-0.88), although heterogeneity between studies was significant ( Q =16.37; P =0.0373; I2 =51.1%). After meta-regression, the effect of the experimental arm was more pronounced in the elderly and lost among patients with HCV-related liver disease. Subgroups suggested a favorable effect of immunotherapy in patients with HBV-related hepatocellular carcinoma, extrahepatic dissemination, and elevated alpha-fetoprotein. CONCLUSION The study results confirm the significant overall survival improvement after immunotherapy-based regimens but suggest different effects on the outcome depending on age, etiology of liver disease, and tumor burden.
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Boye A, Osei SA, Brah AS. Therapeutic prospects of sex hormone receptor signaling in hormone-responsive cancers. Biomed Pharmacother 2024; 180:117473. [PMID: 39326105 DOI: 10.1016/j.biopha.2024.117473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/11/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Globally, hormone-responsive cancers afflict millions of people contributing to cancer-related morbidity and mortality. While hormone-responsive cancers overburden patients, their close families, and even health budgets at the local levels, knowledge of these cancers particularly their biology and possible avenues for therapy remains poorly exploited. Herewith, this review highlights the role of sex hormones (estrogens and androgens) in the pathophysiology of hormone-responsive cancers and the exploration of therapeutic targets. Major scientific databases including but not limited to Scopus, PubMed, Science Direct, Web of Science core collections, and Google Scholar were perused using a string of search terms: Hormone-responsive cancers, androgens and cancers, estrogens and cancer, androgen receptor signalling, estrogen receptor signalling, etc.
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Affiliation(s)
- Alex Boye
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
| | - Silas Acheampong Osei
- Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Augustine Suurinobah Brah
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
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Xiao Z, Yang F, Liu Z, Chen X, Ma S, Li H. An overview of risk assessment and monitoring of malignant transformation in cirrhotic nodules. Therap Adv Gastroenterol 2024; 17:17562848241293019. [PMID: 39493259 PMCID: PMC11528798 DOI: 10.1177/17562848241293019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/04/2024] [Indexed: 11/05/2024] Open
Abstract
Cirrhotic liver nodules can progress to hepatocellular carcinoma (HCC) through a multi-step carcinogenesis model, with dysplastic nodules being particularly high risk. Currently, monitoring the progression of non-HCC cirrhotic nodules is primarily through dynamic observation, but there is a lack of sensitive, efficient, and convenient methods. Dynamic monitoring and risk evaluation of malignant transformation are essential for timely treatment and improved patient survival rates. Routine liver biopsies are impractical for monitoring, and imaging techniques like ultrasound, computed tomography, and magnetic resonance imaging are not suitable for all patients or for accurately assessing subcentimeter nodules. Identifying serum biomarkers with high sensitivity, specificity, and stability, and developing a multi-index evaluation model, may provide a more convenient and efficient approach to monitoring pathological changes in cirrhotic nodules.
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Affiliation(s)
- Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Zheng Liu
- Department of Combination of Traditional Chinese Medicine and Western Medicine, Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19 Renmin Road, Zhengzhou 450000, China
| | - Heng Li
- Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore
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Naing C, Ni H, Aung HH. Tamoxifen for adults with hepatocellular carcinoma. Cochrane Database Syst Rev 2024; 8:CD014869. [PMID: 39132750 PMCID: PMC11318082 DOI: 10.1002/14651858.cd014869.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
RATIONALE Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Tamoxifen has been evaluated in randomised clinical trials in people with hepatocellular cancer. The reported results have been inconsistent. OBJECTIVES To evaluate the benefits and harms of tamoxifen or tamoxifen plus any other anticancer drugs compared with no intervention, placebo, any type of standard care, or alternative treatment in adults with hepatocellular carcinoma, irrespective of sex, administered dose, type of formulation, and duration of treatment. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and major trials registries, and handsearched reference lists up to 26 March 2024. ELIGIBILITY CRITERIA Parallel-group randomised clinical trials including adults (aged 18 years and above) diagnosed with advanced or unresectable hepatocellular carcinoma. Had we found cross-over trials, we would have included only the first trial phase. We did not consider data from quasi-randomised trials for analysis. OUTCOMES Our critical outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our important outcomes were disease progression, and adverse events considered non-serious. RISK OF BIAS We assessed risk of bias using the RoB 2 tool. SYNTHESIS METHODS We used standard Cochrane methods and Review Manager. We meta-analysed the outcome data at the longest follow-up. We presented the results of dichotomous outcomes as risk ratios (RR) and continuous data as mean difference (MD), with 95% confidence intervals (CI) using the random-effects model. We summarised the certainty of evidence using GRADE. INCLUDED STUDIES We included 10 trials that randomised 1715 participants with advanced, unresectable, or terminal stage hepatocellular carcinoma. Six were single-centre trials conducted in Hong Kong, Italy, and Spain, while three were conducted as multicentre trials in single countries (France, Italy, and Spain), and one trial was conducted in nine countries in the Asia-Pacific region (Australia, Hong Kong, Indonesia, Malaysia, Myanmar, New Zealand, Singapore, South Korea, and Thailand). The experimental intervention was tamoxifen in all trials. The control interventions were no intervention (three trials), placebo (six trials), and symptomatic treatment (one trial). Co-interventions were best supportive care (three trials) and standard care (one trial). The remaining six trials did not provide this information. The number of participants in the trials ranged from 22 to 496 (median 99), mean age was 63.7 (standard deviation 4.18) years, and mean proportion of men was 74.7% (standard deviation 42%). Follow-up was three months to five years. SYNTHESIS OF RESULTS Ten trials evaluated oral tamoxifen at five different dosages (ranging from 20 mg per day to 120 mg per day). All trials investigated one or more of our outcomes. We performed meta-analyses when at least two trials assessed similar types of tamoxifen versus similar control interventions. Eight trials evaluated all-cause mortality at varied follow-up points. Tamoxifen versus the control interventions (i.e. no treatment, placebo, and symptomatic treatment) results in little to no difference in mortality between one and five years (RR 0.99, 95% CI 0.92 to 1.06; 8 trials, 1364 participants; low-certainty evidence). In total, 488/682 (71.5%) participants died in the tamoxifen groups versus 487/682 (71.4%) in the control groups. The separate analysis results for one, between two and three, and five years were comparable to the analysis result for all follow-up periods taken together. The evidence is very uncertain about the effect of tamoxifen versus no treatment on serious adverse events at one-year follow-up (RR 0.44, 95% CI 0.19 to 1.06; 1 trial, 36 participants; very low-certainty evidence). A total of 5/20 (25.0%) participants in the tamoxifen group versus 9/16 (56.3%) participants in the control group experienced serious adverse events. One trial measured health-related quality of life at baseline and at nine months' follow-up, using the Spitzer Quality of Life Index. The evidence is very uncertain about the effect of tamoxifen versus no treatment on health-related quality of life (MD 0.03, 95% CI -0.45 to 0.51; 1 trial, 420 participants; very low-certainty evidence). A second trial found no appreciable difference in global health-related quality of life scores. No further data were provided. Tamoxifen versus control interventions (i.e. no treatment, placebo, or symptomatic treatment) results in little to no difference in disease progression between one and five years' follow-up (RR 1.02, 95% CI 0.91 to 1.14; 4 trials, 720 participants; low-certainty evidence). A total of 191/358 (53.3%) participants in the tamoxifen group versus 198/362 (54.7%) participants in the control group had progression of hepatocellular carcinoma. Tamoxifen versus control interventions (i.e. no treatment or placebo) may have little to no effect on adverse events considered non-serious during treatment, but the evidence is very uncertain (RR 1.17, 95% CI 0.45 to 3.06; 4 trials, 462 participants; very low-certainty evidence). A total of 10/265 (3.8%) participants in the tamoxifen group versus 6/197 (3.0%) participants in the control group had adverse events considered non-serious. We identified no trials with participants diagnosed with early stages of hepatocellular carcinoma. We identified no ongoing trials. AUTHORS' CONCLUSIONS Based on the low- and very low-certainty evidence, the effects of tamoxifen on all-cause mortality, disease progression, serious adverse events, health-related quality of life, and adverse events considered non-serious in adults with advanced, unresectable, or terminal stage hepatocellular carcinoma when compared with no intervention, placebo, or symptomatic treatment could not be established. Our findings are mostly based on trials at high risk of bias with insufficient power (fewer than 100 participants), and a lack of trial data on clinically important outcomes. Therefore, firm conclusions cannot be drawn. Trials comparing tamoxifen administered with any other anticancer drug versus standard care, usual care, or alternative treatment as control interventions were lacking. Evidence on the benefits and harms of tamoxifen in participants at the early stages of hepatocellular carcinoma was also lacking. FUNDING This Cochrane review had no dedicated funding. REGISTRATION Protocol available via DOI: 10.1002/14651858.CD014869.
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Affiliation(s)
- Cho Naing
- Division of Tropical Health and Medicine, James Cook University, Queensland, Australia
| | - Han Ni
- Department of Medicine, Newcastle University Medicine Malaysia, Johor, Malaysia
| | - Htar Htar Aung
- School of Medicine, IMU University, Kuala Lumpur, Malaysia
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Zhu A, Song S, Pei L, Huang Y. Supportive care of female hormones in brain health: what and how? Front Pharmacol 2024; 15:1403969. [PMID: 39114348 PMCID: PMC11303335 DOI: 10.3389/fphar.2024.1403969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/03/2024] [Indexed: 08/10/2024] Open
Abstract
Female hormones, functioning as neuroactive steroids, are utilized beyond menopausal hormone therapy. The rapid onset of allopregnanolone analogs, such as brexanolone and zuranolone, in treating depression, and the effectiveness of megestrol acetate in addressing appetite and weight gain, prompted the Food and Drug Administration to authorize the use of progesterone for treating postpartum depression and cancer-related cachexia. Progesterone has also been found to alleviate neuropathic pain in animal studies. These off-label applications offer a promising option for patients with advanced cancer who often experience various mood disorders such as depression, persistent pain, social isolation, and physical complications like cachexia. These patients have shown low tolerance to opioids and mood-regulating medications. However, the potential risks and uncertainties associated with hormone therapy treatment modalities can be daunting for both patients and medical professionals. This review aims to offer a comprehensive understanding of the non-reproductive functions and mechanisms of female hormones in brain health.
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Affiliation(s)
| | | | - Lijian Pei
- Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuguang Huang
- Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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Alfano C, Filetti M, Farina L, Petti M. MIRROR: miRNA regulation-level differential network to study sex and ethnic disparities in cancer. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2024; 2024:1-4. [PMID: 40040045 DOI: 10.1109/embc53108.2024.10782801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Cancer disparities are adverse differences in cancer measures that exist among certain population groups. Given that the role they play not only in the disease prognosis but also in therapy response, there is an urgent need to understand what causes them. Most studies investigate these disparities by analyzing transcriptomic data and in particular miRNAs for their regulatory role, but only focusing on expression levels. To face this challenge we propose MIRROR, a new method which analyzes a differential co-expression network of miRNAs between patients' cohorts, to study the role they play at the target genes' level. Doing so, we can study the altered molecular mechanism that are linked to cancer disparities. The application of MIRROR to two different cases of cancer disparities has demonstrated its efficacy in identifying molecular players involved in the considered disparity, presenting itself as a viable option to approach this challenge.
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Naing C, Ni H, Aung HH, Htet NH, Nikolova D. Gene therapy for people with hepatocellular carcinoma. Cochrane Database Syst Rev 2024; 6:CD013731. [PMID: 38837373 PMCID: PMC11152182 DOI: 10.1002/14651858.cd013731.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Abstract
BACKGROUND Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Gene therapy, which uses genes to treat or prevent diseases, holds potential for treatment, especially for tumours. Trials on the effects of gene therapy in people with hepatocellular carcinoma have been published or are ongoing. OBJECTIVES To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation. SEARCH METHODS We identified randomised clinical trials through electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We searched five online clinical trial registries to identify unpublished or ongoing trials. We checked reference lists of the retrieved studies for further trials. The date of last search was 20 January 2023. SELECTION CRITERIA We aimed to include randomised clinical trials assessing any type of gene therapy in people diagnosed with hepatocellular carcinoma, irrespective of year, language of publication, format, or outcomes reported. DATA COLLECTION AND ANALYSIS We followed Cochrane methodology and used Review Manager to prepare the review. The primary outcomes were all-cause mortality/overall survival (whatever data were provided), serious adverse events during treatment, and health-related quality of life. The secondary outcomes were proportion of people with disease progression, adverse events considered non-serious, and proportion of people without improvement in liver function tests. We assessed risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We presented the results of time-to-event outcomes as hazard ratios (HR), dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI). Our primary analyses were based on intention-to-treat and outcome data at the longest follow-up. MAIN RESULTS We included six randomised clinical trials with 364 participants. The participants had unresectable (i.e. advanced inoperable) hepatocellular carcinoma. We found no trials assessing the effects of gene therapy in people with operable hepatocellular carcinoma. Four trials were conducted in China, one in several countries (from North America, Asia, and Europe), and one in Egypt. The number of participants in the six trials ranged from 10 to 129 (median 47), median age was 55.2 years, and the mean proportion of males was 72.7%. The follow-up duration ranged from six months to five years. As the trials compared different types of gene therapy and had different controls, we could not perform meta-analyses. Five of the six trials administered co-interventions equally to the experimental and control groups. All trials assessed one or more outcomes of interest in this review. The certainty of evidence was very low in five of the six comparisons and low in the double-dose gene therapy comparison. Below, we reported the results of the primary outcomes only. Pexastimogene devacirepvec (Pexa-Vec) plus best supportive care versus best supportive care alone There is uncertainty about whether there may be little to no difference between the effect of Pexa-Vec plus best supportive care compared with best supportive care alone on overall survival (HR 1.19, 95% CI 0.78 to 1.82; 1 trial (censored observation at 20-month follow-up), 129 participants; very low-certainty evidence) and on serious adverse events (RR 1.42, 95% CI 0.60 to 3.33; 1 trial at 20 months after treatment, 129 participants; very low-certainty evidence). The trial reported quality of life narratively as "assessment of quality of life and time to symptomatic progression was confounded by the high patient dropout rate." Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0.20 to 0.76; 1 trial, 45 participants; very low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation alone There is uncertainty about whether double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation may benefit all-cause mortality at five-year follow-up (RR 0.40, 95% CI 0.22 to 0.73; 1 trial, 86 participants; low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Recombinant human adenovirus-p53 with hydroxycamptothecin (rAd-p53/HCT) versus hydroxycamptothecin alone There is uncertainty about whether there may be little to no difference between the effect of rAd-p53/HCT versus hydroxycamptothecin alone on the overall survival at 12-month follow-up (RR 3.06, 95% CI 0.16 to 60.47; 1 trial, 48 participants; very low-certainty evidence). The trial did not report serious adverse events or quality of life. rAd-p53/5-Fu (5-fluorouracil) plus transarterial chemoembolisation versus transarterial chemoembolisation alone The trial included 46 participants. We had insufficient data to assess overall survival. The trial did not report serious adverse events or quality of life. E1B-deleted (dl1520) adenovirus versus percutaneous ethanol injection The trial included 10 participants. It did not report data on overall survival, serious adverse events, or health-related quality of life. One trial did not provide any information on sponsorship; one trial received a national research grant, one trial by the Pedersen foundation, and three were industry-funded trials. We found five ongoing randomised clinical trials. AUTHORS' CONCLUSIONS The evidence is very uncertain about the effects of gene therapy on the studied outcomes because of high risk of bias and imprecision of outcome results. The trials were underpowered and lacked trial data on clinically important outcomes. There was only one trial per comparison, and we could not perform meta-analyses. Therefore, we do not know if gene therapy may reduce, increase, or have little to no effect on all-cause mortality or overall survival, or serious adverse events in adults with unresectable hepatocellular carcinoma. The impact of gene therapy on adverse events needs to be investigated further. Evidence on the effect of gene therapy on health-related quality of life is lacking.
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Affiliation(s)
- Cho Naing
- Division of Tropical Health and Medicine, James Cook University, Queensland, Australia
| | - Han Ni
- Department of Medicine, Newcastle University Medicine Malaysia, Johor, Malaysia
| | - Htar Htar Aung
- School of Medicine, IMU University, Kuala Lumpur, Malaysia
| | | | - Dimitrinka Nikolova
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital ─ Rigshospitalet, Copenhagen, Denmark
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Cirillo F, Spinelli A, Talia M, Scordamaglia D, Santolla MF, Grande F, Rizzuti B, Maggiolini M, Gérard C, Lappano R. Estetrol/GPER/SERPINB2 transduction signaling inhibits the motility of triple-negative breast cancer cells. J Transl Med 2024; 22:450. [PMID: 38741146 PMCID: PMC11089683 DOI: 10.1186/s12967-024-05269-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/01/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. Due to its favorable safety profile, E4 was recently approved as estrogenic component of a new combined oral contraceptive. E4 is a selective ligand of estrogen receptor (ER)α and ERβ, but its binding to the G Protein-Coupled Estrogen Receptor (GPER) has not been described to date. Therefore, we aimed to explore E4 action in GPER-positive Triple-Negative Breast Cancer (TNBC) cells. METHODS The potential interaction between E4 and GPER was investigated by molecular modeling and binding assays. The whole transcriptomic modulation triggered by E4 in TNBC cells via GPER was explored through high-throughput RNA sequencing analyses. Gene and protein expression evaluations as well as migration and invasion assays allowed us to explore the involvement of the GPER-mediated induction of the plasminogen activator inhibitor type 2 (SERPINB2) in the biological responses triggered by E4 in TNBC cells. Furthermore, bioinformatics analysis was aimed at recognizing the biological significance of SERPINB2 in ER-negative breast cancer patients. RESULTS After the molecular characterization of the E4 binding capacity to GPER, RNA-seq analysis revealed that the plasminogen activator inhibitor type 2 (SERPINB2) is one of the most up-regulated genes by E4 in a GPER-dependent manner. Worthy, we demonstrated that the GPER-mediated increase of SERPINB2 is engaged in the anti-migratory and anti-invasive effects elicited by E4 in TNBC cells. In accordance with these findings, a correlation between SERPINB2 levels and a good clinical outcome was found in ER-negative breast cancer patients. CONCLUSIONS Overall, our results provide new insights into the mechanisms through which E4 can halt migratory and invasive features of TNBC cells.
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Affiliation(s)
- Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy
| | - Asia Spinelli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy
| | - Marianna Talia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy
| | - Domenica Scordamaglia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy
| | - Maria Francesca Santolla
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy
| | - Fedora Grande
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy
| | - Bruno Rizzuti
- Department of Physics, CNR-NANOTEC, SS Rende (CS), University of Calabria, Rende, CS, 87036, Italy
- Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Zaragoza, 50018, Spain
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy
| | - Céline Gérard
- Mithra Pharmaceutical, Rue Saint-Georges 5, Liège, 4000, Belgium.
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy.
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11
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Toniutto P, Shalaby S, Mameli L, Morisco F, Gambato M, Cossiga V, Guarino M, Marra F, Brunetto MR, Burra P, Villa E. Role of sex in liver tumor occurrence and clinical outcomes: A comprehensive review. Hepatology 2024; 79:1141-1157. [PMID: 37013373 DOI: 10.1097/hep.0000000000000277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 12/06/2022] [Indexed: 04/05/2023]
Abstract
Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.
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Affiliation(s)
- Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Azienda Sanitaria Universitaria Integrata, Department of Medical Area, University of Udine, Udine, Italy
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Laura Mameli
- Liver and Pancreas Transplant Center, Azienda Ospedaliera Brotzu Piazzale Ricchi 1, Cagliari, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Valentina Cossiga
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Erica Villa
- Gastroenterology Department, University of Modena and Reggio Emilia, Modena, Italy
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12
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Chen L, Liu D, Tan Y. Research progress in cuproptosis in liver cancer. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2023; 48:1368-1376. [PMID: 38044648 PMCID: PMC10929866 DOI: 10.11817/j.issn.1672-7347.2023.230083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Indexed: 12/05/2023]
Abstract
Copper, like iron, is an essential trace metal element for human cells. The role of iron overload and ferroptosis has been gradually clarified in tumors, but the role of copper overload and cuproptosis is still being explored. Cuproptosis is a novel mode of cell death, secondary to impaired mitochondrial function induced by copper overload, and characterized by copper-dependent and programmed. The excessive copper leads to protein toxicity stress by binding to sulfhydryl proteins in the tricarboxylic acid (TCA) cycle of mitochondria, disrupting cellular homeostasis and triggering cuproptosis. Copper accumulation has carcinogenic effects on normal cells, dual effects on tumor cells. Liver cancer is one of the most common malignant tumors in China and even globally, with hepatocellular carcinoma (HCC) being the most common histological subtype. Copper exhibits dualism in HCC, as it both contributes to the growth and invasion of HCC cells, and exerts anticancer effects by inducing cuproptosis. Also, cuproptosis-related genes can be the evaluation of immunotherapy effect and the construction of prognostic models. Clarifying the role of copper death in liver cancer can help explore new methods for liver cancer screening, treatment, and prognosis evaluation.
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Affiliation(s)
- Leijie Chen
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, China.
| | - Deliang Liu
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yuyong Tan
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, China.
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13
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Hall KA, Filardo EJ. The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer. Cells 2023; 12:2460. [PMID: 37887304 PMCID: PMC10605794 DOI: 10.3390/cells12202460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/28/2023] Open
Abstract
Estrogens have been implicated in the pathogenesis of various cancers, with increasing concern regarding the overall rising incidence of disease and exposure to environmental estrogens. Estrogens, both endogenous and environmental, manifest their actions through intracellular and plasma membrane receptors, named ERα, ERβ, and GPER. Collectively, they act to promote a broad transcriptional response that is mediated through multiple regulatory enhancers, including estrogen response elements (EREs), serum response elements (SREs), and cyclic AMP response elements (CREs). Yet, the design and rational assignment of antiestrogen therapy for breast cancer has strictly relied upon an endogenous estrogen-ER binary rubric that does not account for environmental estrogens or GPER. New endocrine therapies have focused on the development of drugs that degrade ER via ER complex destabilization or direct enzymatic ubiquitination. However, these new approaches do not broadly treat all cancer-involved receptors, including GPER. The latter is concerning since GPER is directly associated with tumor size, distant metastases, cancer stem cell activity, and endocrine resistance, indicating the importance of targeting this receptor to achieve a more complete therapeutic response. This review focuses on the critical importance and value of GPER-targeted therapeutics as part of a more holistic approach to the treatment of estrogen-driven malignancies.
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14
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Tarhuni M, Fotso MN, Gonzalez NA, Sanivarapu RR, Osman U, Latha Kumar A, Sadagopan A, Mahmoud A, Begg M, Hamid P. Estrogen's Tissue-Specific Regulation of the SLC26A6 Anion Transporter Reveal a Phenotype of Kidney Stone Disease in Estrogen-Deficient Females: A Systematic Review. Cureus 2023; 15:e45839. [PMID: 37881392 PMCID: PMC10597593 DOI: 10.7759/cureus.45839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/24/2023] [Indexed: 10/27/2023] Open
Abstract
Kidney stone formation is an intricate process that involves a disruption in the interplay of the multiple organs and systems involved in regulating the concentration of specific ions in the body. Women who have gone through menopause are susceptible to kidney stone disease. This systematic review aims to investigate the potential influence of estrogen on kidney function and oxalate homeostasis, notably through the anion transporter SLC26A6 (also known as putative anion transporter 1 or PAT1) in females. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist, a systematic search of online databases included Pubmed, ScienceDirect Journals, and Ingenta Connect Journals. Predetermined criteria to include and exclude papers, gathering articles published between 2012 and 2022, were determined. After a thorough analysis, eight articles (three cohorts, one case-control, one in vivo, one in vitro, and two cross-sectional studies) were identified for the final quality assessment review. The eight selected and quality-assessed articles provided evidence of a directly proportional connection between estrogen and kidney function. A correlation between serum estrogen levels and the development of kidney stone disease was confirmed. Administration of β-estradiol was shown to effectively inhibit the function of the anion transporter PAT1 in a tissue-specific manner. In the case of the kidney, estrogen was observed to down-regulate PAT1, which led to a reduction in oxalate transporting activity and, consequently, a decrease in kidney stone formation. Consensus suggests that serum estrogen levels and optimal kidney functioning are interrelated. Furthermore, analysis of the quality-assessed articles and a comprehensive literature review revealed estrogen's tissue-specific regulation of the PAT1 anion transporter aids in maintaining kidney function and anion homeostasis. Additional research is needed to solidify estrogen's role in kidney stone disease to determine its therapeutic value in clinical practice.
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Affiliation(s)
- Mawada Tarhuni
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Monique N Fotso
- Obstetrics and Gynecology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Natalie A Gonzalez
- Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Raghavendra R Sanivarapu
- Pulmonary and Critical Care Medicine, Texas Tech University Health Sciences Center, Odessa, USA
- Pulmonary and Critical Care Medicine, Nassau University Medical Center, East Meadow, USA
| | - Usama Osman
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
- Geriatrics, Michigan State University College of Human Medicine, East Lansing, USA
| | - Abishek Latha Kumar
- Internal Medicine and Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aishwarya Sadagopan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Anas Mahmoud
- Internal Medicine, St. Joseph's University Medical Center, Paterson, USA
| | - Maha Begg
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Pousette Hamid
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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15
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Omar MA, Omran MM, Farid K, Tabll AA, Shahein YE, Emran TM, Petrovic A, Lucic NR, Smolic R, Kovac T, Smolic M. Biomarkers for Hepatocellular Carcinoma: From Origin to Clinical Diagnosis. Biomedicines 2023; 11:1852. [PMID: 37509493 PMCID: PMC10377276 DOI: 10.3390/biomedicines11071852] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/15/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) and HCC-related deaths has increased over the last few decades. There are several risk factors of HCC such as viral hepatitis (B, C), cirrhosis, tobacco and alcohol use, aflatoxin-contaminated food, pesticides, diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), and metabolic and genetic diseases. Diagnosis of HCC is based on different methods such as imaging ultrasonography (US), multiphasic enhanced computed tomography (CT), magnetic resonance imaging (MRI), and several diagnostic biomarkers. In this review, we examine the epidemiology of HCC worldwide and in Egypt as well as risk factors associated with the development of HCC and, finally, provide the updated diagnostic biomarkers for the diagnosis of HCC, particularly in the early stages of HCC. Several biomarkers are considered to diagnose HCC, including downregulated or upregulated protein markers secreted during HCC development, circulating nucleic acids or cells, metabolites, and the promising, recently identified biomarkers based on quantitative proteomics through the isobaric tags for relative and absolute quantitation (iTRAQ). In addition, a diagnostic model used to improve the sensitivity of combined biomarkers for the diagnosis of early HCC is discussed.
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Affiliation(s)
- Mona A. Omar
- Chemistry Department, Faculty of Science, Damietta University, New Damietta 34517, Egypt;
| | - Mohamed M. Omran
- Chemistry Department, Faculty of Science, Helwan University, Cairo 11795, Egypt;
| | - Khaled Farid
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35524, Egypt;
| | - Ashraf A. Tabll
- Microbial Biotechnology Department, National Research Centre, Cairo 12622, Egypt
- Immunology Department, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Yasser E. Shahein
- Molecular Biology Department, National Research Centre, Cairo 12622, Egypt
| | - Tarek M. Emran
- Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, New Damietta 34517, Egypt;
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Nikola R. Lucic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Tanja Kovac
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (A.P.); (N.R.L.); (R.S.); (T.K.)
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16
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Pi S, Liu A, Zhu B, Zhu Y, Yuan J, Zhang Z, Gao C, Fu J, Liu Y, Liang X, Xia B, Chen Y. Body composition and risk of liver cancer: a population-based prospective cohort study on gender difference. Front Nutr 2023; 10:1102722. [PMID: 37275645 PMCID: PMC10234331 DOI: 10.3389/fnut.2023.1102722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 04/17/2023] [Indexed: 06/07/2023] Open
Abstract
Background Obesity is a common and highly convincing risk factor for many cancers, including liver cancer. Sex disparities in the body composition and regulatory mechanisms involved in energy homeostasis may contribute to the difference in the incidence of cancer. However, evidence on the gender-specific association between body composition and liver cancer incidence is limited. We performed this study to investigate the linear and non-linear associations of body composition with liver cancer risk by gender. Materials and methods This prospective analysis included 4,75,659 participants free of cancer, based on the UK Biobank. We used Cox proportional hazard models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for potential confounders. Restricted cubic spline was performed to investigate the potential non-linear associations. Results During a median follow-up, 275 cases (174 male patients and 101 female patients) of liver cancer were identified. Male patients in the highest body fat percentage group are more likely to develop liver cancer (HR = 1.89, 95% CI: 1.17-3.03) compared with those in the lowest group. The one-unit increase of whole-body fat mass, arm fat mass, and trunk fat mass was associated with 1.03-, 1.14-, and 1.05-fold increased risk of liver cancer in male subjects, respectively. U-shaped associations of body composition with liver cancer risk were observed in the female subjects. Both high and low levels of whole-body fat-free mass, particularly in the arm and trunk, were associated with an increased risk of liver cancer. Conclusion This study found a gender-specific association between body composition and liver cancer risk and provided evidence for individualized weight management for the prevention of liver cancer.
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Affiliation(s)
- Sainan Pi
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Anran Liu
- Department of Clinical Nutrition, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Beibei Zhu
- Endoscopy Center, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
| | - Yunxiao Zhu
- Health Management Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Zheming Zhang
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Chang Gao
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jinxian Fu
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yao Liu
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Xujing Liang
- Department of Infectious Diseases, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
| | - Bin Xia
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Youpeng Chen
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
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17
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Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, Sánchez-Pérez Y, Pérez-Carreón JI, Camacho J. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol 2023; 29:2571-2599. [PMID: 37213397 PMCID: PMC10198058 DOI: 10.3748/wjg.v29.i17.2571] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
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Affiliation(s)
- Fernanda Villarruel-Melquiades
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - María Eugenia Mendoza-Garrido
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - Claudia M García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Julio Isael Pérez-Carreón
- Instituto Nacional de Medicina Genómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
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18
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Tang YL, Zhu L, Tao Y, Lu W, Cheng H. Role of targeting TLR4 signaling axis in liver-related diseases. Pathol Res Pract 2023; 244:154410. [PMID: 36917917 DOI: 10.1016/j.prp.2023.154410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/05/2023] [Accepted: 03/06/2023] [Indexed: 03/09/2023]
Abstract
Toll-like receptor 4 (TLR4) plays an important role as a key signal-receiving transmembrane protein molecule in the liver, and substances that target the liver exert therapeutic effects via TLR4-related signaling pathways. This article provides a comprehensive review of targeting the TLR4 signaling axis to play an important role in the liver based on endogenous substances. Articles were divided into 5 major types of liver disease, acute liver injury, viral hepatitis, alcoholic and non-alcoholic liver disease, cirrhosis, and liver cancer, to elucidate how various endogenous substances affect the liver via the TLR4 pathway and the important role of the pathway itself in liver-related diseases to discover the potential therapeutic implications of the TLR4-related pathway in the liver. The results indicate that activation of the TLR4-related signaling axis primarily plays a role in promoting disease progression in liver-related diseases, and the TLR4/MyD88/NF-κB axis plays the most dominant role. Therefore, exploring the full effects of drugs targeting the TLR4-related signaling axis in the liver and the new use of old drugs may be a new research direction.
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Affiliation(s)
- Ying-Le Tang
- Medical College, Yangzhou University, Yangzhou, China
| | - Lin Zhu
- Medical College, Yangzhou University, Yangzhou, China
| | - Yan Tao
- Medical College, Yangzhou University, Yangzhou, China
| | - Wen Lu
- Medical College, Yangzhou University, Yangzhou, China
| | - Hong Cheng
- Yangzhou University Medical College, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Institute of Translational Medicine, Yangzhou University, Jiangsu, Yangzhou, China.
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19
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Zhang L, Wu J, Wu Q, Zhang X, Lin S, Ran W, Zhu L, Tang C, Wang X. Sex steroid axes in determining male predominance in hepatocellular carcinoma. Cancer Lett 2023; 555:216037. [PMID: 36563929 DOI: 10.1016/j.canlet.2022.216037] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. The mechanisms for male propensity in HCC incidence, prognosis and treatment responses are complicated and remain inconclusive. Sex-biased molecular signatures in carcinogenesis, viral infections and immune responses have been studied predominantly within the context of sex hormones effects. This review integrates current knowledge on the mechanisms through which the hormones regulate HCC development in sexually dimorphic fashion. Firstly, the androgen/androgen receptor (AR) accelerate cell proliferation and virus infection, especially during the initial stage of HCC, while estrogen/estrogen receptor (ER) function in an opposite way to induce cell apoptosis and immune responses. Interestingly, the controversial effects of AR in late stage of HCC metastasis are summarized and the reasons are attributed to inconsistent cancer grading or experimental models between the studies. In addition, the new insights into these intricate cellular and molecular mechanisms underlying sexual dimorphism are fully discussed. A detailed understanding of sex hormones-associated regulation to male predominance in HCC may help to develop personalized therapeutic strategies in high-risk populations.
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Affiliation(s)
- Lei Zhang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - JinFeng Wu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - QiuMei Wu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - XiangJuan Zhang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - ShuaiCai Lin
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - WanLi Ran
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Li Zhu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - ChengYan Tang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xing Wang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
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20
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Milionis C, Ilias I, Koukkou E. Liver function in transgender persons: Challenges in the COVID-19 era. World J Clin Cases 2023; 11:299-307. [PMID: 36686345 PMCID: PMC9850971 DOI: 10.12998/wjcc.v11.i2.299] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/23/2022] [Accepted: 12/27/2022] [Indexed: 01/12/2023] Open
Abstract
Transgender persons constitute a non-negligible percentage of the general population. Physical gender-transitioning in trans persons is mainly achieved with hormonal cross-sex therapy and sex reassignment surgeries that aim to align bodily appearance with gender identity. Hormonal treatment acts via suppressing the secretion of the endogenous sex hormones and replacing them with the hormones of the desired sex. The administration of testosterone is the typical masculinizing treatment in trans men, whilst trans women are routinely treated with estradiol agents in combination with anti-androgens or gonadotrophin-releasing hormone agonists if testes are present. Exogenous androgenic steroids, estradiol agents, and anti-androgens have been implicated in a series of hepatotoxic effects. Thus, liver integrity is a major concern with the long-term administration of cross-sex therapy. Hepatic tissue is susceptible to coronavirus disease 19 (COVID-19) through various pathophysiological mechanisms. Special consideration should be paid to minimize the risk of hepatic damage from the potential cumulative effect of COVID-19 and gender-affirming treatment in transgender patients. Appropriate care is significant, with continuous laboratory monitoring, clinical observation and, if needed, specific treatment, especially in severe cases of infection and in persons with additional liver pathologies. The pandemic can be an opportunity to provide equal access to care for all and increase the resilience of the transgender population.
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Affiliation(s)
- Charalampos Milionis
- Department of Endocrinology, Diabetes and Metabolism, Elena Venizelou Hospital, Athens GR-11521, Greece
| | - Ioannis Ilias
- Department of Endocrinology, Diabetes and Metabolism, Elena Venizelou Hospital, Athens GR-11521, Greece
| | - Eftychia Koukkou
- Department of Endocrinology, Diabetes and Metabolism, Elena Venizelou Hospital, Athens GR-11521, Greece
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21
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Ji F, Zhang J, Liu N, Gu Y, Zhang Y, Huang P, Zhang N, Lin S, Pan R, Meng Z, Feng XH, Roessler S, Zheng X, Ji J. Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression. Gut 2022; 71:2313-2324. [PMID: 34996827 DOI: 10.1136/gutjnl-2021-326050] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
OBJECTS The incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis. DESIGN Two HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models. RESULTS A global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis. CONCLUSIONS The liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.
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Affiliation(s)
- Fubo Ji
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianjuan Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Niya Liu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuanzhuo Gu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yan Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Peipei Huang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Nachuan Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shengda Lin
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ran Pan
- Department of Pathology and Pathophysiology, Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhuoxian Meng
- Department of Pathology and Pathophysiology, Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xin-Hua Feng
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.,Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China
| | - Stephanie Roessler
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Xin Zheng
- Taoharmony Biotech L.L.C, Hangzhou, Zhejiang, China
| | - Junfang Ji
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China .,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
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22
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Investigation of Anti-Liver Cancer Activity of the Herbal Drug FDY003 Using Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5765233. [PMID: 36118098 PMCID: PMC9481369 DOI: 10.1155/2022/5765233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 08/10/2022] [Indexed: 11/18/2022]
Abstract
Globally, liver cancer (LC) is the sixth-most frequently occurring and the second-most fatal malignancy, responsible for 0.83 million deaths annually. Although the application of herbal drugs in cancer therapies has increased, their anti-LC activity and relevant mechanisms have not been fully studied from a systems perspective. To address these issues, we conducted a system-perspective network pharmacological investigation into the activity and mechanisms underlying the action of the herbal drug. FDY003 reduced the viability of human LC treatment. FDY003 reduced the viability of human LC cells and elevated their chemosensitivity. There were a total of 16 potential bioactive chemical components in FDY003 and they had 91 corresponding targets responsible for the pathological processes in LC. These FDY003 targets were functionally involved in regulating the survival, proliferation, apoptosis, and cell cycle of LC cells. Additionally, we found that FDY003 may target key signaling cascades connected to diverse LC pathological mechanisms, namely, PI3K-Akt, focal adhesion, IL-17, FoxO, MAPK, and TNF pathways. Overall, this study contributed to integrative mechanistic insights into the anti-LC potential of FDY003.
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23
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Xu L, Yuan Y, Che Z, Tan X, Wu B, Wang C, Xu C, Xiao J. The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones. Front Immunol 2022; 13:939631. [PMID: 35860276 PMCID: PMC9289199 DOI: 10.3389/fimmu.2022.939631] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/13/2022] [Indexed: 12/18/2022] Open
Abstract
Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the "sexual dimorphism" is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.
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Affiliation(s)
- Linlin Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuan Yuan
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhaodi Che
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaozhi Tan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Cunchuan Wang
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Chengfang Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jia Xiao
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
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24
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Zhang Y, Cheng J, Zhong C, Xia Q, Li Y, Chen P, Fan X, Mao Q, Lin H, Hong D. ESR1 Regulates the Obesity- and Metabolism-Differential Gene MMAA to Inhibit the Occurrence and Development of Hepatocellular Carcinoma. Front Oncol 2022; 12:899969. [PMID: 35795061 PMCID: PMC9252523 DOI: 10.3389/fonc.2022.899969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 05/18/2022] [Indexed: 11/29/2022] Open
Abstract
Obesity is often regarded as a factor that promotes tumorigenesis, but the role of obesity in promoting hepatocellular carcinoma (HCC) is still controversial. We compared the trend change of 14 obesity-related genes in the formation and development of HCC in normal, adjacent, and HCC tissues. Mendelian randomization (MR) analysis was used to verify the relationship between obesity and HCC occurrence. Metabolism of cobalamin-associated A (MMAA) was discovered as an obesity- and metabolism-differential gene, and its function in HCC was tested in vitro and in vivo. Finally, we explored how obese female patients with an originally high expression of female estrogen receptor (ESR1) directly upregulated MMAA to interfere with the progression of HCC. Fourteen obesity-related genes were downregulated in adjacent and tumoral tissues compared with normal liver tissues, which indicated that obesity may be inversely related to the occurrence of HCC and was consistent with the results of MR analysis. We also discovered that MMAA is a metabolic gene closely related to the occurrence and development of HCC by mining the TCGA database, and it functioned an anti-tumor-promoting role in HCC by damaging the mitochondrial function and preserving the redox balance. We further verified that obese females with a high expression of ESR1 can regulate MMAA to protect HCC from progression. This study elucidates that obesity might be a protective factor for female HCC patients, as they originally highly expressed ESR1, which could upregulate MMAA to suppress tumor growth and participate in metabolic reprogramming.
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Affiliation(s)
- Yiyin Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiaxi Cheng
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Cheng Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qiming Xia
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Peng Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- State Key Laboratory of Modern Optical Instrumentations, Centre for Optical and Electromagnetic Research, College of Optical Science and Engineering, International Research Center for Advanced Photonics, Zhejiang University, Hangzhou, China
| | - Qijiang Mao
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Engineering Research Center of Cognitive Healthcare, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Defei Hong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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25
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Lee T. Hormone replacement therapy and risk of hepatocellular carcinoma. ADVANCES IN DIGESTIVE MEDICINE 2022. [DOI: 10.1002/aid2.13333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Teng‐Yu Lee
- Division of Gastroenterology and Hepatology Taichung Veterans General Hospital Taichung Taiwan
- School of Medicine Chung Shan Medical University Taichung Taiwan
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26
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Li G, He Y, Liu H, Liu D, Chen L, Luo Y, Chen L, Qi L, Wang Y, Wang Y, Wang Y, Zhan L, Zhang N, Zhu X, Song T, Guo H. DNAJC24 is a potential therapeutic target in hepatocellular carcinoma through affecting ammonia metabolism. Cell Death Dis 2022; 13:490. [PMID: 35606363 PMCID: PMC9127113 DOI: 10.1038/s41419-022-04953-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/04/2022] [Accepted: 05/13/2022] [Indexed: 12/14/2022]
Abstract
Evolutionarily conserved heat shock proteins are involved in the heat shock response of cells in response to changes in the external environment. In normal tissues, heat shock proteins can help cells survive in a rapidly changing environment. Likewise, in malignant tumors heat shock proteins may help tumor cells cope with external stresses as well as the stress of treatment. In this way they become accomplices of malignant tumors. Here we demonstrated for the first time that high expression of DNAJC24 (a heat shock protein) shortens survival in patients with HCC by immunohistochemical staining of 167 paired hepatocellular carcinomas and paraneoplastic tissues as well as data from public databases. In vitro experiments demonstrated that stimuli such as hypoxia, starvation and heat could upregulate DNAJC24 expression in HCC cells through transcriptional regulation of HSF2, and high expression of DNAJC24 in HCC cells could promote the proliferation and motility of HCC cells. In addition, we also verified that targeting DNAJC24 under normal culture conditions can affect the proliferation and autophagy of HCC cells by interfering with ammonia metabolism, thereby inhibiting the malignant progression of HCC. Overall, we suggested that DNAJC24 may become a new target for the treatment of HCC.
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Affiliation(s)
- Guangtao Li
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Yuchao He
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Hui Liu
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Dongming Liu
- grid.411918.40000 0004 1798 6427Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Lu Chen
- grid.411918.40000 0004 1798 6427Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Yi Luo
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Liwei Chen
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Lisha Qi
- grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China
| | - Yun Wang
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Yingying Wang
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Yu Wang
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Linlin Zhan
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Ning Zhang
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Xiaolin Zhu
- grid.411918.40000 0004 1798 6427Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Tianqiang Song
- grid.411918.40000 0004 1798 6427Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Hua Guo
- grid.411918.40000 0004 1798 6427Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China ,grid.411918.40000 0004 1798 6427National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
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27
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Meng X, Liu X. Therapeutic Value of Estrogen Receptor α in Hepatocellular Carcinoma Based on Molecular Mechanisms. J Clin Transl Hepatol 2022; 10:140-146. [PMID: 35233383 PMCID: PMC8845150 DOI: 10.14218/jcth.2021.00224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 12/04/2022] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is significantly lower in women than men, implying that estrogen receptors (ERs) may play an important role in this sex dimorphism. Recently, considerable progress has been made in expanding our understanding of the mechanisms of ERs in HCC. As one of the most important ERs, ERα functions as a tumor suppressor in the progression of HCC through various pathways, such as STAT3 signaling pathways, lipid metabolism-related signaling pathways, and non-coding RNAs. However, the function of ERα was reduced with the changes of some molecules in the liver, which may develop further into HCC and make it difficult to achieve an effective hormone treatment effect. Intriguingly, there are signs that individualized hormone therapy according to the activity of ERα will overcome this challenge. Based on these observations, it is particularly imperative to reassess and extend the function of ERα. In this review, we mainly elucidated molecular mechanisms associated with ERα in HCC and investigated the individualized hormone therapy based on these mechanisms, with the aim of providing new insights for HCC treatment.
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Affiliation(s)
- Xiangzhe Meng
- Second Clinical College, Jining Medical University, Jining, Shandong, China
| | - Xue Liu
- Department of Pathology, College of Basic Medicine, Jining Medical University, Jining, Shandong, China
- Correspondence to: Xue Liu, Department of Pathology, College of Basic Medicine, Jining Medical University, 133 Hehua Road, Jining, Shandong 272067, China. ORCID: https://orcid.org/0000-0001-7817-8392. Tel: +86-15053798589, E-mail:
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28
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Cokan KB, Hancock JM, Spindelböck W, Režen T, Juvan P, Rozman D. Matching mouse models to specific human liver disease states by comparative functional genomics of mouse and human datasets. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2022; 1865:194785. [PMID: 34971790 DOI: 10.1016/j.bbagrm.2021.194785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 12/07/2021] [Accepted: 12/14/2021] [Indexed: 06/14/2023]
Abstract
Omics has broadened our view of transcriptional and gene regulatory networks of multifactorial diseases, such as metabolism associated liver disease and its advanced stages including hepatocellular carcinoma. Identifying liver disease biomarkers and potential treatment targets makes use of experimental models, e.g. genetically engineered mice, which show molecular features of human pathologies but are experimentally tractable. We compared gene expression profiling data from human to our studies on transgenic mice with hepatocyte deletion of Cyp51 from cholesterol synthesis with the aim of identifying the human liver disease state best matched by the Cyp51 knockout model. Gene Expression Omnibus was used to identify relevant human datasets. We identified enriched and deregulated genes, pathways and transcription factors of mouse and human disease samples. Analysis showed a closer match of the Cyp51 knockout to the female patient samples. Importantly, CYP51 was depleted in both mouse and female human data. Among the enriched genes were the oxysterol-binding protein-related protein 3 (OSBPL3), which was enriched in all datasets, and the collagen gene COL1A2, which was enriched in both the mouse and one human dataset. KEGG and Reactome analyses revealed the most enriched pathway to be ECM-receptor interaction. Numerous transcription factors were differentially expressed in mice of both sexes and in the human female dataset, while depleted HNF4α and RXRα:PPARα-isoform1 were a hallmark in all cases. Our analysis exposed novel potential biomarkers, which may provide new avenues towards more personalized approaches and different targets in females and males. The analysis was only possible because of availability of open data resources and tools and broadly consistent annotation.
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Affiliation(s)
- Kaja Blagotinšek Cokan
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - John M Hancock
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Walter Spindelböck
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Peter Juvan
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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29
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Association between long working hours and liver enzymes: evidence from the Korea National Health and Nutrition Examination Survey, 2007–2017. Ann Occup Environ Med 2022; 34:e9. [PMID: 35801225 PMCID: PMC9209099 DOI: 10.35371/aoem.2022.34.e9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 11/20/2022] Open
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30
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Berkel C, Cacan E. Estrogen- and estrogen receptor (ER)-mediated cisplatin chemoresistance in cancer. Life Sci 2021; 286:120029. [PMID: 34634322 DOI: 10.1016/j.lfs.2021.120029] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/28/2021] [Accepted: 10/02/2021] [Indexed: 12/21/2022]
Abstract
Cisplatin is a platinum-based chemotherapeutic drug used in the standard treatment of various solid cancers including testicular, bladder, head and neck, cervical and ovarian cancer. Although successful clinical responses are observed in patients following initial cisplatin treatment, resistance to cisplatin ultimately develops in most patients, leading to therapeutic failure. Multiple molecular mechanisms contributing to cisplatin resistance in cancer cells have been identified to date. In this review, we discuss the effect of estrogen, estrogen receptors (ERs) and estrogen-related receptors (ERRs) on cisplatin resistance in various cancer types. We highlight that estrogen treatment or increased expression of ERs or ERRs are generally associated with higher cisplatin resistance in cancer in vitro, mostly due to decreased caspase activity, increased anti-apoptotic protein levels such as BCL-2, higher drug efflux and higher levels of antioxidant enzymes. Targeted inhibition of ERs or estrogen production in combination with cisplatin treatment thus can be a useful strategy to overcome chemoresistance in certain cancer types. Estrogen levels and ER status can also be considered to identify cancer patients with a high potential of therapy response against cisplatin. A better mechanistic understanding of the involvement of estrogen, ERs and ERRs in the development of cisplatin resistance is needed to improve the management of cancer treatment.
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Affiliation(s)
- Caglar Berkel
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, Tokat 60250, Turkey.
| | - Ercan Cacan
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, Tokat 60250, Turkey.
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31
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Tang N, Dou X, You X, Li Y, Li X, Liu G. Androgen Receptors Act as a Tumor Suppressor Gene to Suppress Hepatocellular Carcinoma Cells Progression via miR-122-5p/RABL6 Signaling. Front Oncol 2021; 11:756779. [PMID: 34745992 PMCID: PMC8564478 DOI: 10.3389/fonc.2021.756779] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/30/2021] [Indexed: 01/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor with a high degree of malignancy and a poor prognosis. Androgen receptor (AR) has been reported to play important roles in the regulation of the progression of HCC, but the underlying mechanisms of how AR regulates HCC initiation, progression, metastasis, and chemotherapy resistance still need further study. Our study found that AR could act as a tumor suppression gene to suppress HCC cells invasion and migration capacities via miR-122-5p/RABL6 signaling, and the mechanism study further confirmed that miR-122-5p could suppress the expression of RABL6 to influence HCC cells progression by directly targeting the 3'UTR of the mRNA of RABL6. The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the clinical data gotten from online databases based on TCGA samples also confirmed the linkage of AR/miR-122-5p/RABL6 signaling to the HCC progression. Together, these findings suggest that AR could suppress HCC invasion and migration capacities via miR-122-5p/RABL6 signaling, and targeting this newly explored signaling may help us find new therapeutic targets for better treatment of HCC.
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Affiliation(s)
- Neng Tang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaolin Dou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xing You
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yixiong Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Guodong Liu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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32
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Kang S, Jo H, Kim MR. Safety Assessment of Endocrine Disruption by Menopausal Health Functional Ingredients. Healthcare (Basel) 2021; 9:healthcare9101376. [PMID: 34683056 PMCID: PMC8544397 DOI: 10.3390/healthcare9101376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/06/2021] [Accepted: 10/09/2021] [Indexed: 12/23/2022] Open
Abstract
During menopause, women experience various symptoms including hot flashes, mood changes, insomnia, and sweating. Hormone replacement therapy (HRT) has been used as the main treatment for menopausal symptoms; however, other options are required for women with medical contraindications or without preference for HRT. Functional health foods are easily available options for relieving menopausal symptoms. There are growing concerns regarding menopausal functional health foods because the majority of them include phytoestrogens which have the effect of endocrine disruption. Phytoestrogens may cause not only hormonal imbalance or disruption of the normal biological function of the organ systems, but also uterine cancer or breast cancer if absorbed and accumulated in the body for a long period of time, depending on the estrogen receptor binding capacity. Therefore, we aimed to determine the effects and safety of menopausal functional health ingredients and medicines on the human body as endocrine disruptors under review in the literature and the OECD guidelines.
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Affiliation(s)
- Soyeon Kang
- St. Vincent’s Hospital, Division of Gynecologic Endocrinology, Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Hagyeong Jo
- Seoul St. Mary’s Hospital, Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Mee-Ran Kim
- Seoul St. Mary’s Hospital, Division of Gynecologic Endocrinology, Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- Correspondence: ; Tel.: +82-2-2258-6170
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Huang S, Wang W, Cheng Y, Lin J, Wang M. Clinicopathological and Prognostic Significance of Klotho and Estrogen Receptors Expression in Human Hepatocellular Carcinoma. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2021; 32:828-836. [PMID: 34787087 PMCID: PMC8975321 DOI: 10.5152/tjg.2021.19986] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 09/21/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is male-predominant cancer, but the underlying mechanism remains unclear. This study aimed to investigate the expression of the age-suppressing gene klotho and estrogen receptors (ERs) in HCC patients and analyze their association with clinicopathological variables and their effects on prognosis. METHODS The expression patterns of klotho, ERα, and ERβ were determined by tissue microarray and immunohistochemical technique, and their correlations with clinicopathological characteristics were investigated using univariate and multivariate analysis. RESULTS Klotho expression was significantly lower in HCC than in the adjacent noncancerous tissues (52.7% (49/93) vs. 90.8% (79/87), P = .000), and its protein level in HCC tissue was negatively correlated with clinical staging, histological grade, and stage of the primary tumor (T) (P < .05). Whereas the expression of nuclear ERα and ERβ was higher in HCC than their corresponding non-neoplastic tissues (55.9% (52/93) vs. 35.6% (31/87), P = .006; 59.1% (55/93) vs. 43.7% (38/87), P = .038), and the level of nuclear ERα and ERβ in HCC tissue was inversely correlated with T stage, tumor size, and clinical staging (P < .05). Correlation analysis showed the expression level of klotho, which is positively correlated with that of nuclear ERα (r = 0.243, P = .019). Patients with klotho-positive tumors had longer survival than those with klotho-negative tumors (P = .002). Cox proportional hazards model analysis demonstrated that positive expression of klotho was an important factor indicating good prognosis (P = .003). CONCLUSION Klotho, partially regulated by ERα-mediated estrogen pathway, acts as a tumor suppressor and might be a novel biomarker candidate for predicting progression and prognosis in HCC patients.
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Affiliation(s)
- Shu Huang
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Wei Wang
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Yajun Cheng
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Jie Lin
- Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China
- Department of Gastroenterology, The Fourth Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Min Wang
- Digestive Endoscopy Department, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
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Chiu CJ, Li ML, Chang CM, Wu CH, Tan MP. Disability trajectories prior to death for ten leading causes of death among middle-aged and older adults in Taiwan. BMC Geriatr 2021; 21:420. [PMID: 34246236 PMCID: PMC8272348 DOI: 10.1186/s12877-021-02300-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 05/26/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Prolonged life expectancy is associated with increased prevalence of chronic diseases. The aim of this study was to determine the different disability trajectories for the top ten leading causes of death in Taiwan . METHODS A total of 2,431 participants aged 50-96 in 1996 from the Taiwan longitudinal study on aging (TLSA) who died from 1996 to 2016 were analyzed. Integration of Cause of Death Data and TLSA helped sort out participants who had died from the ten leading causes of death. The level of physical disability was evaluated with the Activities of Daily Living Scale (ADLs), ranging from 0 to 6 points, in 1996, 1999, 2003, 2007, and 2011. A multilevel model was used to investigate the levels and rates of change in disability development before death. RESULTS The outcome of the research showed that the earliest group to experience physical limitation was individuals living with diabetes. The groups with the highest ADL scores were participants with diabetes, cerebrovascular disease, and hypertension-related diseases. Most groups reach ADL scores ≥ 1 (mild-level) during 4-6 years before death except chronic hepatitis and cirrhosis and injury. CONCLUSIONS People who had died from the ten leading causes of death experienced different disability trajectories before death. The trajectory of the participants who had died from diabetes showed a unique pattern with the earliest occurrence and more severe deterioration in terms of development of disabilities. Disability trajectories provide a prediction of survival status for middle-aged and older adults associated with the ten leading causes of death.
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Affiliation(s)
- Ching-Ju Chiu
- Institute of Gerontology, College of Medicine, National Cheng Kung University, No. 1 University Road, 701, Tainan, Taiwan.
| | - Meng-Ling Li
- Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Chia-Ming Chang
- Division of Geriatrics and Gerontology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan City, Taiwan
| | - Chih-Hsing Wu
- Institute of Gerontology, College of Medicine, National Cheng Kung University, No. 1 University Road, 701, Tainan, Taiwan
- Department of Family medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Maw Pin Tan
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Fashe M, Yi M, Sueyoshi T, Negishi M. Sex-specific expression mechanism of hepatic estrogen inactivating enzyme and transporters in diabetic women. Biochem Pharmacol 2021; 190:114662. [PMID: 34157297 DOI: 10.1016/j.bcp.2021.114662] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/21/2022]
Abstract
Circulating estrogens levels significantly decrease in menopause and levels off in postmenopausal women. Accordingly, the liver represses levels of enzymes and membrane transporters, thereby decreasing capability of inactivating and excreting estrogens. Women increasingly develop type 2 diabetes during or after menopause. Estrogens are known to promote liver diseases in these women. Here, we have found that the estrogen inactivating sulfotransferase (SULT1E1) and an ATP-binding cassette subfamily G member 2 (ABCG2), a gene encoding breast cancer resistance protein that exports sulfated estrogens, increased their expression levels in diabetic women but not men. For the sulfotransferase gene, phosphorylated nuclear receptors ERα and RORα, at Ser212 and Ser100, respectively, bind their response elements to activate the SULT1E1 promoter in women. This coordinated increase in estrogen inactivation and excretion, and the phosphorylated nuclear receptor-mediated gene activation could be a defense mechanism against toxicities of estrogens through inactivation and excretion in the livers of women.
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Affiliation(s)
- Muluneh Fashe
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
| | - MyeongJin Yi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Tatsuya Sueyoshi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Masahiko Negishi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
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Estrogen exposure causes the progressive growth of SK-Hep1-derived tumor in ovariectomized mice. Toxicol Res 2021; 38:1-7. [PMID: 35070935 PMCID: PMC8748573 DOI: 10.1007/s43188-021-00100-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/29/2021] [Accepted: 05/15/2021] [Indexed: 01/03/2023] Open
Abstract
Liver cancer, one of the leading death causes, has different incidence and mortality rates in men and women. The influencing factor is considered to estrogen. However, the role of estrogen in liver cancer remains controversial. In this study, we investigated the effects of estrogen on tumor progression. Total RNA sequencing was analyzed in SK-Hep1-derived tumor tissues, and 15 genes were expressed only in female mice. Among the differentially expressed genes, matrix metalloprotease 7 (MMP7), germ cell associated 1 (GSG1), and chromosome 6 open reading frame 15 (C6orf15) were associated with significantly different overall survival rates based on their expression level in liver cancer patients. Interestingly, exogenous estrogen aggravated SK-Hep1-derived tumor growth in ovariectomized (OVX) mice. When OVX mice were treated with exogenous estrogen, SK-Hep1-derived tumor tissues exhibited high MMP7 expression levels and low GSG1 and C6orf15 expression levels. These expression patterns were consistent with those of liver cancer patients with low overall survival rates. These results suggest that these genes are expected to be prognostic biomarkers of liver cancer. In conclusion, our results suggest that continuous estrogen exposure may promote tumor growth in OVX mice.
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37
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Naing C, Ni H, Aung HH, Mak JW. Tamoxifen for hepatocellular carcinoma. Hippokratia 2021. [DOI: 10.1002/14651858.cd014869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Cho Naing
- International Medical University; Kuala Lumpur Malaysia
- Division of Tropical Health and Medicine; James Cook University; Townsville Australia
| | - Han Ni
- Department of Medicine; Newcastle University Medicine Malaysia; Johor Malaysia
| | | | - Joon Wah Mak
- Institute for Research, Development and Innovation (IRDI); International Medical University; Kuala Lumpur Malaysia
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38
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O’Brien MH, Pitot HC, Chung SH, Lambert PF, Drinkwater NR, Bilger A. Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression. Cancers (Basel) 2021; 13:2355. [PMID: 34068249 PMCID: PMC8153146 DOI: 10.3390/cancers13102355] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.
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Affiliation(s)
- Mara H. O’Brien
- Department of Craniofacial Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA;
| | - Henry C. Pitot
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
| | - Sang-Hyuk Chung
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA;
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
| | - Norman R. Drinkwater
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
| | - Andrea Bilger
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
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Wu J, Nagy LE, Liangpunsakul S, Wang L. Non-coding RNA crosstalk with nuclear receptors in liver disease. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166083. [PMID: 33497819 PMCID: PMC7987766 DOI: 10.1016/j.bbadis.2021.166083] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/28/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023]
Abstract
The dysregulation of nuclear receptors (NRs) underlies the pathogenesis of a variety of liver disorders. Non-coding RNAs (ncRNAs) are defined as RNA molecules transcribed from DNA but not translated into proteins. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two types of ncRNAs that have been extensively studied for regulating gene expression during diverse cellular processes. NRs as therapeutic targets in liver disease have been exemplified by the successful application of their pharmacological ligands in clinics. MiRNA-based reagents or drugs are emerging as flagship products in clinical trials. Advancing our understanding of the crosstalk between NRs and ncRNAs is critical to the development of diagnostic and therapeutic strategies. This review summarizes recent findings on the reciprocal regulation between NRs and ncRNAs (mainly on miRNAs and lncRNAs) and their implication in liver pathophysiology, which might be informative to the translational medicine of targeting NRs and ncRNAs in liver disease.
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Affiliation(s)
- Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America.
| | - Laura E Nagy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States of America; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Li Wang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, United States of America
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Mahboobifard F, Dargahi L, Jorjani M, Ramezani Tehrani F, Pourgholami MH. The role of ERα36 in cell type-specific functions of estrogen and cancer development. Pharmacol Res 2021; 163:105307. [PMID: 33246174 DOI: 10.1016/j.phrs.2020.105307] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023]
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Bean J, Mohan RD. Hepatocellular carcinoma reduces ATXN7L3 to evade estrogen-dependent growth suppression. EBioMedicine 2020; 63:103179. [PMID: 33340995 PMCID: PMC7750566 DOI: 10.1016/j.ebiom.2020.103179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 12/04/2020] [Indexed: 11/30/2022] Open
Affiliation(s)
- Joe Bean
- School of Biological and Chemical Sciences, Division of Genetics, Developmental and Evolutionary Biology, University of Missouri - Kansas City, MO, USA
| | - Ryan D Mohan
- School of Biological and Chemical Sciences, Division of Genetics, Developmental and Evolutionary Biology, University of Missouri - Kansas City, MO, USA.
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42
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Chang K, Mo L, Wang C, Hsieh C, Hsu H, Tseng Y, Tseng Y. Long‐term effects of hormone replacement therapy on hepatocellular carcinoma risk and overall survival rate in women with chronic hepatitis C: A population‐based cohort study in Taiwan. ADVANCES IN DIGESTIVE MEDICINE 2020. [DOI: 10.1002/aid2.13250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Kuo‐Kuan Chang
- Department of Hepatogastroenterology Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Lein‐Ray Mo
- Department of Hepatogastroenterology Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Chun‐Hsiang Wang
- Department of Hepatogastroenterology Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Chia‐Chi Hsieh
- Departments of Nursing Chang Bing Show Chwan Memorial Hospital Changhua Taiwan
| | - Hua‐Yin Hsu
- Departments of Nursing Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Yi‐Chen Tseng
- Departments of Obstetrics & Gynecology An Nan Hospital, China Medical University Tainan Taiwan
| | - Yuan‐Tsung Tseng
- Committee of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
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43
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Präkanzerosen und Malignome des Gastrointestinaltrakts. COLOPROCTOLOGY 2020. [DOI: 10.1007/s00053-020-00502-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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44
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Mai Q, Sheng D, Chen C, Gou Q, Chen M, Huang X, Yin H, Chen X, Chen Z. Steroid 5 alpha-reductase 3 (SRD5A3) promotes tumor growth and predicts poor survival of human hepatocellular carcinoma (HCC). Aging (Albany NY) 2020; 12:25395-25411. [PMID: 33229626 PMCID: PMC7803539 DOI: 10.18632/aging.104142] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/05/2020] [Indexed: 12/24/2022]
Abstract
Steroid 5 alpha-reductase 3 (SRD5A3) is an important molecule in glycosylation metabolism and steroid hormone formation. It is differentially expressed in human fetal liver, endometrial cancer and prostate cancer; however, its prognostic value and biological function in hepatocellular carcinoma (HCC) remain unclear. Here, bioinformatics analysis was employed to explore the expression and prognostic significance of SRD5A3 in various cancers including HCC. Additionally, clinical specimens of HCC were applied to analyze the expression of SRD5A3. SRD5A3-underexpressed HCC cell lines were established to test the effect of SRD5A3 on cell proliferation in in vitro and in vivo. We found that the elevated expression of SRD5A3 was common in many cancers with poor prognosis. Moreover, public datasets and our specimens revealed that SRD5A3 was also upregulated in HCC tissues and associated with clinical stage and patient’s gender. Kaplan-Meier survival analysis showed that higher SRD5A3 level predicted poor overall survival, progression-free survival, relapse-free survival and disease specific survival in HCC patients. Further experiments showed that the lack of SRD5A3 inhibited the growth of HCC. Collectively, these findings indicate that SRD5A3 functions as an oncogene and might serve as a potential biomarker for prognosis and a therapeutic target for HCC.
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Affiliation(s)
- Qicong Mai
- Department of Interventional Radiology, Cancer Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China
| | - Dafeng Sheng
- PET/CT Center, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou 515041, Guangdong, China
| | - Chengcong Chen
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China
| | - Qing Gou
- Department of Interventional Radiology, Cancer Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China
| | - Meng Chen
- Department of Interventional Radiology, Cancer Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China
| | - Xiaoting Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China
| | - Heng Yin
- Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China
| | - Xiaoming Chen
- Department of Interventional Radiology, Cancer Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China
| | - Zide Chen
- Department of Interventional Radiology, Cancer Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China.,The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, China
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Sun N, Zhong X, Wang S, Zeng K, Sun H, Sun G, Zou R, Liu W, Liu W, Lin L, Song H, Lv C, Wang C, Zhao Y. ATXN7L3 positively regulates SMAD7 transcription in hepatocellular carcinoma with growth inhibitory function. EBioMedicine 2020; 62:103108. [PMID: 33186807 PMCID: PMC7670205 DOI: 10.1016/j.ebiom.2020.103108] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 09/11/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, with unmet need for the pharmacological therapy. The functions of ATXN7L3 in HCC progression are not known. Methods RNA sequence, quantitative real-time PCR, and western blot were performed to detect gene expression. Chromatin immunoprecipitation was performed to detect possible mechanisms. Immunohistochemical stain was performed to examine the protein expression. Colony formation, cell growth curve and xenograft tumor experiments were performed to examine cell growth in vitro and in vivo. Findings ATXN7L3 functions as a coactivator for ERα-mediated transactivation in HCC cells, thereby contributing to enhanced SMAD7 transcription. ATXN7L3 is recruited to the promoter regions of SMAD7 gene, thereby regulating histone H2B ubiquitination level, to enhance the transcription of SMAD7. A series of genes regulated by ATXN7L3 were identified. Moreover, ATXN7L3 participates in suppression of tumor growth. In addition, ATXN7L3 is lower expressed in HCC samples, and the lower expression of ATXN7L3 positively correlates with poor clinical outcome in patients with HCC. Interpretation This study demonstrated that ATXN7L3 is a novel regulator of SMAD7 transcription, subsequently participating in inhibition of tumor growth in HCC, which provides an insight to support a previously unknown role of ATXN7L3 in HCC progression. Fund This work was funded by 973 Program Grant from the Ministry of Science and Technology of China (2013CB945201), National Natural Science Foundation of China (31871286, 81872015, 31701102, 81702800, 81902889), Foundation for Special Professor of Liaoning Province, Natural Science Foundation of Liaoning Province (No.20180530072); China Postdoctoral Science Foundation (2019M651164).
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Affiliation(s)
- Ning Sun
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Xinping Zhong
- Department of General Surgery, the First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province, 110001, China
| | - Shengli Wang
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Kai Zeng
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Hongmiao Sun
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Ge Sun
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Renlong Zou
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Wei Liu
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Wensu Liu
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Lin Lin
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Huijuan Song
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Chi Lv
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China; Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province, 110004, China
| | - Chunyu Wang
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China.
| | - Yue Zhao
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China; Department of Endocrinology and Metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province 110001, China.
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Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes. Endocrinology 2020; 161:bqaa127. [PMID: 32730568 PMCID: PMC7438701 DOI: 10.1210/endocr/bqaa127] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 07/23/2020] [Indexed: 01/08/2023]
Abstract
Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17β-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Diabetes Discovery & Sex-Based Medicine Laboratory, Section of Endocrinology, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
- Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana
| | - Sabra L Klein
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Ellis R Levin
- Department of Medicine and Biochemistry, University of California, Irvine, California
- Long Beach VA Medical Center, Long Beach, California
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Insights into Aflatoxin B1 Toxicity in Cattle: An In Vitro Whole-Transcriptomic Approach. Toxins (Basel) 2020; 12:toxins12070429. [PMID: 32610656 PMCID: PMC7404968 DOI: 10.3390/toxins12070429] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/24/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023] Open
Abstract
Aflatoxins, and particularly aflatoxin B1 (AFB1), are toxic mycotoxins to humans and farm animal species, resulting in acute and chronic toxicities. At present, AFB1 is still considered a global concern with negative impacts on health, the economy, and social life. In farm animals, exposure to AFB1-contaminated feed may cause several untoward effects, liver damage being one of the most devastating ones. In the present study, we assessed in vitro the transcriptional changes caused by AFB1 in a bovine fetal hepatocyte-derived cell line (BFH12). To boost the cellular response to AFB1, cells were pre-treated with the co-planar PCB 3,3′,4,4′,5-pentachlorobiphenyl (PCB126), a known aryl hydrocarbon receptor agonist. Three experimental groups were considered: cells exposed to the vehicle only, to PCB126, and to PCB126 and AFB1. A total of nine RNA-seq libraries (three replicates/group) were constructed and sequenced. The differential expression analysis showed that PCB126 induced only small transcriptional changes. On the contrary, AFB1 deeply affected the cell transcriptome, the majority of significant genes being associated with cancer, cellular damage and apoptosis, inflammation, bioactivation, and detoxification pathways. Investigating mRNA perturbations induced by AFB1 in cattle BFH12 cells will help us to better understand AFB1 toxicodynamics in this susceptible and economically important food-producing species.
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Jiang G, Shi L, Zheng X, Zhang X, Wu K, Liu B, Yan P, Liang X, Yu T, Wang Y, Cai X. Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma. Aging (Albany NY) 2020; 12:11466-11484. [PMID: 32579541 PMCID: PMC7343489 DOI: 10.18632/aging.103231] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/29/2020] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with gender-related differences in onset and course. Androgen receptor (AR), a male hormone receptor, is critical in the initiation and progression of HCC. The role of AR in HCC has been mechanistically characterized and anti-AR therapies have been developed, showing limited efficacy. Immunotherapy targeting immune checkpoint proteins may substantially improve the clinical management of HCC. The mechanism by which AR influences HCC immune state remains unclear. In this study, we demonstrated that AR negatively regulated PD-L1, by acting as a transcriptional repressor of PD-L1. Notably, AR over-expression in HCC cells enhanced CD8+T function in vitro. We then verified the AR/PD-L1 correlation in patients. In animal experiment we found that lower AR expressed tumor achieved better response to PD-L1 inhibitor. Thus, AR suppressed PD-L1 expression, possibly contributing to gender disparity in HCC. Better understanding of the roles of AR during HCC initiation and progression will provide a novel angle to develop potential HCC immunotherapies.
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Affiliation(s)
- Guangyi Jiang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liang Shi
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xueyong Zheng
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xinjie Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ke Wu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Boqiang Liu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Peijian Yan
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tunan Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yifan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Han Q, Yang D, Yin C, Zhang J. Androgen Receptor (AR)-TLR4 Crosstalk Mediates Gender Disparities in Hepatocellular Carcinoma Incidence and Progression. J Cancer 2020; 11:1094-1103. [PMID: 31956356 PMCID: PMC6959060 DOI: 10.7150/jca.30682] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 08/02/2019] [Indexed: 02/06/2023] Open
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.
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Affiliation(s)
- Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Dan Yang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
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50
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Pagano MT, Ortona E, Dupuis ML. A Role for Estrogen Receptor alpha36 in Cancer Progression. Front Endocrinol (Lausanne) 2020; 11:506. [PMID: 32849292 PMCID: PMC7411082 DOI: 10.3389/fendo.2020.00506] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 06/24/2020] [Indexed: 12/22/2022] Open
Abstract
Estrogen receptor α (ERα) functions as a ligand dependent transcription factor that directly binds specific estrogen responsive elements, thus regulating the transcription of estrogen sensitive genes. ERα has also been shown to be associated with the plasma membrane (membrane associated ERα, mERα), concentrated in lipid rafts, plasma membrane microdomains with a distinct lipid composition, where it transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein (MAP) kinase signaling pathway. Two isoforms of ERα have been described: the "traditional" ERα66 (66 kDa) and a lower molecular weight variant: the ERα46 (46 kDa). More recently, a novel ERα variant with a molecular mass of 36 kDa (ERα36) has been discovered. Notably, ERα36 has been found expressed in different human tumor cells, including both ER- positive and ER- negative breast cancer cells. Estrogen signaling at the cell membrane via ERα36 appears as capable of activating multiple pathways of importance for cancer aggressiveness and metastatic potential. The presence of serum autoantibodies reacting with mERα (anti-ERα Abs) in a large percentage of patients with breast cancer has recently been reported by our group. These anti-ERα Abs seem to act as estrogen agonists rapidly triggering MAP kinase pathway activation thus inducing tumor cell proliferation and overcoming cell resistance to anti-estrogen drug tamoxifen. In this review, we describe the involvement of ERα36 in different tumors. We also report the potential pathogenetic activity of anti-ERα Abs and their implication in drug resistance.
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