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Antelo-Cea DA, Martínez-Rojas L, Cabrerizo-Ibáñez I, Roudi Rashtabady A, Hernández-Alvarez MI. Regulation of Mitochondrial and Peroxisomal Metabolism in Female Obesity and Type 2 Diabetes. Int J Mol Sci 2024; 25:11237. [PMID: 39457018 PMCID: PMC11508381 DOI: 10.3390/ijms252011237] [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: 10/03/2024] [Revised: 10/16/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal-mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases.
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Affiliation(s)
- Damián A. Antelo-Cea
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; (D.A.A.-C.); (L.M.-R.); (I.C.-I.); (A.R.R.)
- IBUB Universitat de Barcelona—Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain
| | - Laura Martínez-Rojas
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; (D.A.A.-C.); (L.M.-R.); (I.C.-I.); (A.R.R.)
| | - Izan Cabrerizo-Ibáñez
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; (D.A.A.-C.); (L.M.-R.); (I.C.-I.); (A.R.R.)
| | - Ayda Roudi Rashtabady
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; (D.A.A.-C.); (L.M.-R.); (I.C.-I.); (A.R.R.)
- IBUB Universitat de Barcelona—Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain
| | - María Isabel Hernández-Alvarez
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; (D.A.A.-C.); (L.M.-R.); (I.C.-I.); (A.R.R.)
- IBUB Universitat de Barcelona—Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Shi Y, Ma J, Li S, Liu C, Liu Y, Chen J, Liu N, Liu S, Huang H. Sex difference in human diseases: mechanistic insights and clinical implications. Signal Transduct Target Ther 2024; 9:238. [PMID: 39256355 PMCID: PMC11387494 DOI: 10.1038/s41392-024-01929-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 06/26/2024] [Accepted: 07/23/2024] [Indexed: 09/12/2024] Open
Abstract
Sex characteristics exhibit significant disparities in various human diseases, including prevalent cardiovascular diseases, cancers, metabolic disorders, autoimmune diseases, and neurodegenerative diseases. Risk profiles and pathological manifestations of these diseases exhibit notable variations between sexes. The underlying reasons for these sex disparities encompass multifactorial elements, such as physiology, genetics, and environment. Recent studies have shown that human body systems demonstrate sex-specific gene expression during critical developmental stages and gene editing processes. These genes, differentially expressed based on different sex, may be regulated by androgen or estrogen-responsive elements, thereby influencing the incidence and presentation of cardiovascular, oncological, metabolic, immune, and neurological diseases across sexes. However, despite the existence of sex differences in patients with human diseases, treatment guidelines predominantly rely on male data due to the underrepresentation of women in clinical trials. At present, there exists a substantial knowledge gap concerning sex-specific mechanisms and clinical treatments for diverse diseases. Therefore, this review aims to elucidate the advances of sex differences on human diseases by examining epidemiological factors, pathogenesis, and innovative progress of clinical treatments in accordance with the distinctive risk characteristics of each disease and provide a new theoretical and practical basis for further optimizing individualized treatment and improving patient prognosis.
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Affiliation(s)
- Yuncong Shi
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Jianshuai Ma
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Sijin Li
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Chao Liu
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Yuning Liu
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Jie Chen
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ningning Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shiming Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Hui Huang
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China.
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
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Barjesteh F, Heidari-Kalvani N, Alipourfard I, Najafi M, Bahreini E. Testosterone, β-estradiol, and hepatocellular carcinoma: stimulation or inhibition? A comparative effect analysis on cell cycle, apoptosis, and Wnt signaling of HepG2 cells. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:6121-6133. [PMID: 38421409 DOI: 10.1007/s00210-024-03019-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/20/2024] [Indexed: 03/02/2024]
Abstract
Unlike breast and prostate cancers, which are specifically affected by estrogens or androgens, hepatocellular carcinoma has been reported to be influenced by both sex hormones. Given the coincidental differences of hepatocellular carcinoma in men and women, we investigated the effects of β-estradiol and testosterone on the cell cycle, apoptosis, and Wnt signaling in a model of hepatocellular carcinoma to understand the sex hormone-related etiology. To determine the effective concentration of both hormones, an MTT assay was performed. The effects of β-estradiol and testosterone on cell proliferation and death were evaluated by specific staining and flow cytometry. In addition, gene expression levels of estimated factors involved in GPC3-Wnt survival signaling were analyzed using quantitative real-time polymerase chain reaction. Both hormones inhibited hepatic cell proliferation through arresting the cell cycle at S/G2 and increased the apoptosis rate in HepG2 cells. Both hormones dose-dependently decreased GPC3, Wnt, and DVL expression levels as activators of the Wnt-signaling pathway. In the case of Wnt-signaling inhibitors, the effects of both hormones on WIF were negligible, but they increased DKK1 levels in a dose-dependent manner. In each of the effects mentioned above, β-estradiol was notably more potent than testosterone. In contrast to the primary hypothesis of the project, in which testosterone was considered a stimulating carcinogenic factor in HCC pathogenesis, testosterone inhibited the occurrence of HCC similarly to β-estradiol. However, this inhibitory effect was weaker than that of β-estradiol and requires further study.
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Affiliation(s)
- Fereshteh Barjesteh
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, 1449614525, Iran
| | - Nafiseh Heidari-Kalvani
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, 1449614525, Iran
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland
| | - Mohammad Najafi
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, 1449614525, Iran
| | - Elham Bahreini
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, 1449614525, Iran.
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Green CD, Brown RDR, Uranbileg B, Weigel C, Saha S, Kurano M, Yatomi Y, Spiegel S. Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma. Mol Metab 2024; 86:101971. [PMID: 38925249 PMCID: PMC11261290 DOI: 10.1016/j.molmet.2024.101971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 06/16/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. METHODS Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. RESULTS Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. CONCLUSIONS This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.
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Affiliation(s)
- Christopher D Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Ryan D R Brown
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Cynthia Weigel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sumit Saha
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; CREST, JST, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; CREST, JST, Japan
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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Zhang Y, Feng J, Mi Y, Fan W, Qin R, Mei Y, Jin G, Mao J, Zhang H. Epigenetic Activation of Cytochrome P450 1A2 Sensitizes Hepatocellular Carcinoma Cells to Sorafenib. Drug Metab Dispos 2024; 52:555-564. [PMID: 38565301 DOI: 10.1124/dmd.124.001665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/08/2024] [Accepted: 03/12/2024] [Indexed: 04/04/2024] Open
Abstract
Cytochrome P450 1A2 (CYP1A2) is a known tumor suppressor in hepatocellular carcinoma (HCC), but its expression is repressed in HCC and the underlying mechanism is unclear. In this study, we investigated the epigenetic mechanisms of CYP1A2 repression and potential therapeutic implications. In HCC tumor tissues, the methylation rates of CYP1A2 CpG island (CGI) and DNA methyltransferase (DNMT) 3A protein levels were significantly higher, and there was a clear negative correlation between DNMT3A and CYP1A2 protein expression. Knockdown of DNMT3A by siRNA significantly increased CYP1A2 expression in HCC cells. Additionally, treating HCC cells with decitabine (DAC) resulted in a dose-dependent upregulation of CYP1A2 expression by reducing the methylation level of CYP1A2 CGI. Furthermore, we observed a decreased enrichment of H3K27Ac in the promoter region of CYP1A2 in HCC tissues. Treatment with the trichostatin A (TSA) restored CYP1A2 expression in HCC cells by increasing H3K27Ac levels in the CYP1A2 promoter region. Importantly, combination treatment of sorafenib with DAC or TSA resulted in a leftward shift of the dose-response curve, lower IC50 values, and reduced colony numbers in HCC cells. Our findings suggest that hypermethylation of the CGI at the promoter, mediated by the high expression of DNMT3A, and hypoacetylation of H3K27 in the CYP1A2 promoter region, leads to CYP1A2 repression in HCC. Epigenetic drugs DAC and TSA increase HCC cell sensitivity to sorafenib by restoring CYP1A2 expression. Our study provides new insights into the epigenetic regulation of CYP1A2 in HCC and highlights the potential of epigenetic drugs as a therapeutic approach for HCC. SIGNIFICANCE STATEMENT: This study marks the first exploration of the epigenetic mechanisms underlying cytochrome P450 (CYP) 1A2 suppression in hepatocellular carcinoma (HCC). Our findings reveal that heightened DNA methyltransferase expression induces hypermethylation of the CpG island at the promoter, coupled with diminished H3K27Ac levels, resulting in the repression of CYP1A2 in HCC. The use of epigenetic drugs such as decitabine and trichostatin A emerges as a novel therapeutic avenue, demonstrating their potential to restore CYP1A2 expression and enhance sorafenib sensitivity in HCC cells.
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Affiliation(s)
- Yi Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Jingyu Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Yang Mi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Wu Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Runwen Qin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Yingwu Mei
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Ge Jin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Jian Mao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
| | - Haifeng Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (Y.Z., J.F., Y.M., R.Q., Y.M., G.J., H.Z.) and Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, China (W.F., J.M.)
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Abboud Y, Ismail M, Khan H, Medina-Morales E, Alsakarneh S, Jaber F, Pyrsopoulos NT. Hepatocellular Carcinoma Incidence and Mortality in the USA by Sex, Age, and Race: A Nationwide Analysis of Two Decades. J Clin Transl Hepatol 2024; 12:172-181. [PMID: 38343612 PMCID: PMC10851066 DOI: 10.14218/jcth.2023.00356] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/27/2023] [Accepted: 12/15/2023] [Indexed: 07/26/2024] Open
Abstract
BACKGROUND AND AIMS While the incidence rates of hepatocellular carcinoma (HCC) are increasing, there are limited comprehensive data on demographic-specific incidence and mortality trends in the USA. We aimed to evaluate recent trends in HCC incidence and mortality among different demographic groups in the USA. METHODS Age-adjusted HCC incidence rates were calculated from the Centers for Disease Control's United States Cancer Statistics database, which combines incidence data on newly diagnosed cancer cases and covers approximately 98% of the population in the USA. Additionally, age-adjusted HCC mortality rates were obtained from the Centers for Disease Control's National Center for Health Statistics database, which offers comprehensive coverage spanning nearly 100% of deaths attributed to HCC in the USA. Rates were stratified by sex, age (older [≥55 years] and younger [<55 years] adults), race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic, Non-Hispanic Asian/Pacific Islander, and Non-Hispanic American Indian/Alaska Native), and tumor stage at diagnosis (early and late). Annual and average annual percentage change (AAPC) were calculated using joinpoint regression. A sex-specific pairwise comparison was conducted. RESULTS Between 2001 and 2020, there were 467,346 patients diagnosed with HCC (26.0% women), with increasing incidence in both sexes without significant difference (p=0.65). In younger adults (78,169 patients), the incidence decreased in men but not in women (AAPC difference=-2.39, p=0.002). This was seen in various racial and ethnic groups, mostly driven by early-stage tumors (AAPC difference=-2.65, p=0.02). There were 329,973 deaths attributed to HCC between 2000 and 2020 (28.4% women). In younger adults (43,093 deaths), mortality decreased in men at a greater rate than in women (AAPC difference=1.61, p=0.007). This was seen in various racial and ethnic groups, most notably in non-Hispanic American Indian/Alaska Natives (AAPC difference=-4.51, p=0.01). CONCLUSIONS Nationwide USA data, covering nearly all HCC cases, show an increasing incidence and mortality over the last two decades. In younger adults, there was a decreasing incidence in men but not in women, due to early-stage tumors. Mortality improved in younger men at a greater rate than in women, especially in Non-Hispanic American Indian/Alaska Natives. Future studies are warranted to identify the risk factors associated with the occurrence and outcomes of HCC in demographic-specific populations, especially younger women.
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Affiliation(s)
- Yazan Abboud
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mohamed Ismail
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Hamza Khan
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Esli Medina-Morales
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Saqr Alsakarneh
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Fouad Jaber
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Nikolaos T. Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ, USA
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Opitz CA, Holfelder P, Prentzell MT, Trump S. The complex biology of aryl hydrocarbon receptor activation in cancer and beyond. Biochem Pharmacol 2023; 216:115798. [PMID: 37696456 PMCID: PMC10570930 DOI: 10.1016/j.bcp.2023.115798] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/13/2023]
Abstract
The aryl hydrocarbon receptor (AHR) signaling pathway is a complex regulatory network that plays a critical role in various biological processes, including cellular metabolism, development, and immune responses. The complexity of AHR signaling arises from multiple factors, including the diverse ligands that activate the receptor, the expression level of AHR itself, and its interaction with the AHR nuclear translocator (ARNT). Additionally, the AHR crosstalks with the AHR repressor (AHRR) or other transcription factors and signaling pathways and it can also mediate non-genomic effects. Finally, posttranslational modifications of the AHR and its interaction partners, epigenetic regulation of AHR and its target genes, as well as AHR-mediated induction of enzymes that degrade AHR-activating ligands may contribute to the context-specificity of AHR activation. Understanding the complexity of AHR signaling is crucial for deciphering its physiological and pathological roles and developing therapeutic strategies targeting this pathway. Ongoing research continues to unravel the intricacies of AHR signaling, shedding light on the regulatory mechanisms controlling its diverse functions.
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Affiliation(s)
- Christiane A Opitz
- German Cancer Research Center (DKFZ), Heidelberg, Division of Metabolic Crosstalk in Cancer and the German Cancer Consortium (DKTK), DKFZ Core Center Heidelberg, 69120 Heidelberg, Germany; Neurology Clinic and National Center for Tumor Diseases, 69120 Heidelberg, Germany.
| | - Pauline Holfelder
- German Cancer Research Center (DKFZ), Heidelberg, Division of Metabolic Crosstalk in Cancer and the German Cancer Consortium (DKTK), DKFZ Core Center Heidelberg, 69120 Heidelberg, Germany; Faculty of Bioscience, Heidelberg University, 69120 Heidelberg, Germany
| | - Mirja Tamara Prentzell
- German Cancer Research Center (DKFZ), Heidelberg, Division of Metabolic Crosstalk in Cancer and the German Cancer Consortium (DKTK), DKFZ Core Center Heidelberg, 69120 Heidelberg, Germany; Faculty of Bioscience, Heidelberg University, 69120 Heidelberg, Germany
| | - Saskia Trump
- Molecular Epidemiology Unit, Berlin Institute of Health at Charité and the German Cancer Consortium (DKTK), Partner Site Berlin, a partnership between DKFZ and Charité -Universitätsmedizin Berlin, 10117 Berlin, Germany
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Yang H, Rothenberger E, Zhao T, Fan W, Kelly A, Attaya A, Fan D, Panigrahy D, Deng J. Regulation of inflammation in cancer by dietary eicosanoids. Pharmacol Ther 2023:108455. [PMID: 37257760 DOI: 10.1016/j.pharmthera.2023.108455] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Cancer is a major burden of disease worldwide and increasing evidence shows that inflammation contributes to cancer development and progression. Eicosanoids are derived from dietary polyunsaturated fatty acids, such as arachidonic acid (AA), and are mainly produced by a series of enzymatic pathways that include cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 epoxygenase (CYP). Eicosanoids consist of at least several hundred individual molecules and play important roles in the inflammatory response and inflammation-related cancers. SCOPE AND APPROACH Dietary sources of AA and biosynthesis of eicosanoids from AA through different metabolic pathways are summarized. The bioactivities of eicosanoids and their potential molecular mechanisms on inflammation and cancer are revealed. Additionally, current challenges and limitations in eicosanoid research on inflammation-related cancer are discussed. KEY FINDINGS AND CONCLUSIONS Dietary AA generates a large variety of eicosanoids, including prostaglandins, thromboxane A2, leukotrienes, cysteinyl leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). Eicosanoids exert different bioactivities and mechanisms involved in the inflammation and related cancer developments. A deeper understanding of eicosanoid biology may be advantageous in cancer treatment and help to define cellular targets for further therapeutic development.
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Affiliation(s)
- Haixia Yang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
| | - Eva Rothenberger
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Tong Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Wendong Fan
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Abigail Kelly
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ahmed Attaya
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Jianjun Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China; State Key Laboratory of Vegetable Biobreeding, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
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9
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Zhao H, Zhang Y, Zhang Y, Chen C, Liu H, Yang Y, Wang H. The role of NLRP3 inflammasome in hepatocellular carcinoma. Front Pharmacol 2023; 14:1150325. [PMID: 37153780 PMCID: PMC10157400 DOI: 10.3389/fphar.2023.1150325] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
Inflammasomes play an important role in innate immunity. As a signal platform, they deal with the excessive pathogenic products and cellular products related to stress and injury. So far, the best studied and most characteristic inflammasome is the NLR-family pyrin domain-containing protein 3(NLRP3) inflammasome, which is composed of NLRP3, apoptosis associated speck like protein (ASC) and pro-caspase-1. The formation of NLRP3 inflammasome complexes results in the activation of caspase-1, the maturation of interleukin (IL)-1β and IL-18, and pyroptosis. Many studies have demonstrated that NLRP3 inflammasome not only participates in tumorigenesis, but also plays a protective role in some cancers. Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Currently, due to the lack of effective treatment methods for HCC, the therapeutic effect of HCC has not been ideal. Therefore, it is particularly urgent to explore the pathogenesis of HCC and find its effective treatment methods. The increasing evidences indicate that NLRP3 inflammasome plays a vital role in HCC, however, the related mechanisms are not fully understood. Hence, we focused on the recent progress about the role of NLRP3 inflammasome in HCC, and analyzed the relevant mechanisms in detail to provide reference for the future in-depth researches.
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Affiliation(s)
- Huijie Zhao
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Yiming Zhang
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Yanting Zhang
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Chaoran Chen
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
- *Correspondence: Honggang Wang, ; Chaoran Chen,
| | - Huiyang Liu
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Yihan Yang
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Honggang Wang
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
- *Correspondence: Honggang Wang, ; Chaoran Chen,
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10
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Marie S, Frost KL, Hau RK, Martinez-Guerrero L, Izu JM, Myers CM, Wright SH, Cherrington NJ. Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients. Acta Pharm Sin B 2023; 13:1-28. [PMID: 36815037 PMCID: PMC9939324 DOI: 10.1016/j.apsb.2022.08.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 07/29/2022] [Accepted: 08/03/2022] [Indexed: 12/18/2022] Open
Abstract
The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters. Non-alcoholic steatohepatitis (NASH) causes disease-specific alterations to the absorption, distribution, metabolism, and excretion (ADME) processes, including a decrease in protein expression of basolateral uptake transporters, an increase in efflux transporters, and modifications to enzyme activity. This can result in increased drug exposure and adverse drug reactions (ADRs). Our goal was to predict drugs that pose increased risks for ADRs in NASH patients. Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease, mainly non-alcoholic fatty liver disease (NAFLD), 54 of which are known substrates of transporters and/or metabolizing enzymes. Since NASH is the progressive form of NAFLD but is most frequently undiagnosed, we identified other drugs at risk based on NASH-specific alterations to ADME processes. Here, we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH, based on their transport and/or metabolism processes. It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients, especially when eliminated through multiple pathways altered by the disease. Therefore, these results may inform clinicians regarding the selection of drugs for use in NASH patients.
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Affiliation(s)
- Solène Marie
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Kayla L. Frost
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Raymond K. Hau
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Lucy Martinez-Guerrero
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Jailyn M. Izu
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Cassandra M. Myers
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Stephen H. Wright
- College of Medicine, Department of Physiology, University of Arizona, Tucson, AZ 85724, USA
| | - Nathan J. Cherrington
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA,Corresponding author. Tel.: +1 520 6260219; fax: +1 520 6266944.
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11
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Zhang H, Xu P, Wang T, Wang S, Li W, Mao J, Wang J, Zhang F, Cheng M. Design, synthesis and biological evaluation of highly potent and selective CYP1B1 inhibitors. NEW J CHEM 2023. [DOI: 10.1039/d2nj05691g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
A series of highly potent and selective CYP1B1 inhibitors based on N-phenyl-[2,4′-bithiazol]-2′-amine were obtained and their structure–activity-relationships were analyzed.
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Affiliation(s)
- Haoyu Zhang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
- Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ping Xu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Ting Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
- Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Shiyu Wang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Weixia Li
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
- Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jianping Mao
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Jian Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
- Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Fengjiao Zhang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Maosheng Cheng
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
- Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China
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12
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Yoo JE, Nahm JH, Kim YJ, Jeon Y, Park YN. The dual role of transforming growth factor-beta signatures in human B viral multistep hepatocarcinogenesis: early and late responsive genes. JOURNAL OF LIVER CANCER 2022; 22:115-124. [PMID: 37383409 PMCID: PMC10035736 DOI: 10.17998/jlc.2022.04.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/07/2022] [Accepted: 04/20/2022] [Indexed: 06/30/2023]
Abstract
Background/Aim Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis. Methods The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry. Results The expression levels of TGF-β signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-β (GADD45B, FBP1, CYP1A2 and CYP3A4) gradually decreased, and that of the late TGF-β signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-β signaling, whereas FBP1 expression was inversely correlated with that of stemness markers. Conclusions The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.
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Affiliation(s)
- Jeong Eun Yoo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Young-Joo Kim
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung, Korea
| | - Youngsic Jeon
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung, Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
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13
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Akhtar S, Hourani S, Therachiyil L, Al-Dhfyan A, Agouni A, Zeidan A, Uddin S, Korashy HM. Epigenetic Regulation of Cancer Stem Cells by the Aryl Hydrocarbon Receptor Pathway. Semin Cancer Biol 2022; 83:177-196. [PMID: 32877761 DOI: 10.1016/j.semcancer.2020.08.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/20/2020] [Accepted: 08/23/2020] [Indexed: 12/14/2022]
Abstract
Compelling evidence has demonstrated that tumor bulk comprises distinctive subset of cells generally referred as cancer stem cells (CSCs) that have been proposed as a strong sustainer and promoter of tumorigenesis and therapeutic resistance. These distinguished properties of CSCs have raised interest in understanding the molecular mechanisms that govern the maintenance of these cells. Numerous experimental and epidemiological studies have demonstrated that exposure to environmental toxins such as the polycyclic aromatic hydrocarbons (PAHs) is strongly involved in cancer initiation and progression. The PAH-induced carcinogenesis is shown to be mediated through the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR)/Cytochrome P4501A pathway, suggesting a possible direct link between AhR and CSCs. Several recent studies have investigated the role of AhR in CSCs self-renewal and maintenance, however the molecular mechanisms and particularly the epigenetic regulations of CSCs by the AhR/CYP1A pathway have not been reviewed before. In this review, we first summarize the crosstalk between AhR and cancer genetics, with a particular emphasis on the mechanisms relevant to CSCs such as Wnt/β-catenin, Notch, NF-κB, and PTEN-PI3K/Akt signaling pathways. The second part of this review discusses the recent advances and studies highlighting the epigenetic mechanisms mediated by the AhR/CYP1A pathway that control CSC gene expression, self-renewal, and chemoresistance in various human cancers. Furthermore, the review also sheds light on the importance of targeting the epigenetic pathways as a novel therapeutic approach against CSCs.
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Affiliation(s)
- Sabah Akhtar
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Shireen Hourani
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Lubna Therachiyil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdullah Al-Dhfyan
- Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Asad Zeidan
- Department of Biomedical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Hesham M Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
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14
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Mo HY, Wei QY, Zhong QH, Zhao XY, Guo D, Han J, Noracharttiyapot W, Visser L, van den Berg A, Xu YM, Lau ATY. Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway. Int J Mol Sci 2022; 23:7853. [PMID: 35887201 PMCID: PMC9324654 DOI: 10.3390/ijms23147853] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/28/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023] Open
Abstract
Cytochrome P450 enzymes (CYP450s) exert mighty catalytic actions in cellular metabolism and detoxication, which play pivotal roles in cell fate determination. Preliminary data shows differential expression levels of CYP27C1, one of the "orphan P450s" in human lung cancer cell lines. Here, we study the functions of CYP27C1 in lung cancer progression and drug endurance, and explore its potential to be a diagnostic and therapeutic target for lung cancer management. Quantitative real-time PCR and immunoblot assays were conducted to estimate the transcription and protein expression level of CYP27C1 in human lung cancer cell lines, which was relatively higher in A549 and H1975 cells, but was lower in H460 cells. Stable CYP27C1-knockdown A549 and H1975 cell lines were established, in which these cells showed enhancement in cell proliferation, colony formation, and migration. In addition, aberrant IGF-1R/Akt/p53 signal transduction was also detected in stable CYP27C1-knockdown human lung cancer cells, which exhibited greater tolerance towards the treatments of anticancer agents (including vinorelbine, picropodophyllin, pacritinib, and SKLB610). This work, for the first time, reveals that CYP27C1 impacts lung cancer cell development by participating in the regulation of the IGF-1R/Akt/p53 signaling pathway, and the level of CYP27C1 plays indispensable roles in dictating the cellular sensitivity towards multiple anticancer agents.
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Affiliation(s)
- Hai-Ying Mo
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | - Qi-Yao Wei
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | - Qiu-Hua Zhong
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | - Xiao-Yun Zhao
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | - Dan Guo
- Department of Pathology, Shantou University Medical College, Shantou 515041, China
| | - Jin Han
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | - Wachiraporn Noracharttiyapot
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | - Lydia Visser
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
| | - Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
| | - Andy T. Y. Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, China
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15
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Matsushima-Nishiwaki R, Yamada N, Hattori Y, Hosokawa Y, Tachi J, Hori T, Kozawa O. SERMs (selective estrogen receptor modulator), acting as estrogen receptor β agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-α-induced migration via specific inhibition of AKT signaling pathway. PLoS One 2022; 17:e0262485. [PMID: 35007301 PMCID: PMC8746762 DOI: 10.1371/journal.pone.0262485] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 12/27/2021] [Indexed: 01/18/2023] Open
Abstract
Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HCC), accumulating evidence indicates gender differences in the development, and that men are at higher morbidity risk than premenopausal women, suggesting that estrogen protects against HCC. However, it remains unclear whether SERM affects the HCC progression. Previously, we have shown that transforming growth factor (TGF)-α promotes the migration of HCC cells via p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and AKT. In the present study, we investigated whether SERM such as tamoxifen, raloxifene and bazedoxifene, affects the HCC cell migration using human HCC-derived HuH7 cells. Raloxifene and bazedoxifene but not tamoxifen, significantly suppressed the TGF-α-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) β agonists, inhibited the TGF-α-induced cell migration whereas PPT, an ERα agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK and c-Jun N-terminal kinase. Raloxifene and bazedoxifene also inhibited the phosphorylation of AKT by TGF-α. Furthermore, PHTPP, an ERβ antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-α-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-α-induced migration of HCC cells through ERβ-mediated inhibition of the AKT signaling pathway.
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Affiliation(s)
| | - Noriko Yamada
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yuria Hattori
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yui Hosokawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Junko Tachi
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takamitsu Hori
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Osamu Kozawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
- * E-mail:
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16
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Huang P, Xu M, Han H, Zhao X, Li MD, Yang Z. Integrative Analysis of Epigenome and Transcriptome Data Reveals Aberrantly Methylated Promoters and Enhancers in Hepatocellular Carcinoma. Front Oncol 2021; 11:769390. [PMID: 34858848 PMCID: PMC8631276 DOI: 10.3389/fonc.2021.769390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/14/2021] [Indexed: 12/15/2022] Open
Abstract
DNA methylation is a key transcription regulator, whose aberration was ubiquitous and important in most cancers including hepatocellular carcinoma (HCC). Whole-genome bisulfite sequencing (WGBS) was conducted for comparison of DNA methylation in tumor and adjacent tissues from 33 HCC patients, accompanying RNA-seq to determine differentially methylated region-associated, differentially expressed genes (DMR-DEGs), which were independently replicated in the TCGA-LIHC cohort and experimentally validated via 5-aza-2-deoxycytidine (5-azadC) demethylation. A total of 9,867,700 CpG sites showed significantly differential methylation in HCC. Integrations of mRNA-seq, histone ChIP-seq, and WGBS data identified 611 high-confidence DMR-DEGs. Enrichment analysis demonstrated activation of multiple molecular pathways related to cell cycle and DNA repair, accompanying repression of several critical metabolism pathways such as tyrosine and monocarboxylic acid metabolism. In TCGA-LIHC, we replicated about 53% of identified DMR-DEGs and highlighted the prognostic significance of combinations of methylation and expression of nine DMR-DEGs, which were more efficient prognostic biomarkers than considering either type of data alone. Finally, we validated 22/23 (95.7%) DMR-DEGs in 5-azadC-treated LO2 and/or HepG2 cells. In conclusion, integration of epigenome and transcriptome data depicted activation of multiple pivotal cell cycle-related pathways and repression of several metabolic pathways triggered by aberrant DNA methylation of promoters and enhancers in HCC.
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Affiliation(s)
- Peng Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengxiang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haijun Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyi Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming D Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China
| | - Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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17
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Kozaczek M, Bottje W, Albataineh D, Hakkak R. Effects of Short- and Long-Term Soy Protein Feeding on Hepatic Cytochrome P450 Expression in Obese Nonalcoholic Fatty Liver Disease Rat Model. Front Nutr 2021; 8:699620. [PMID: 34262928 PMCID: PMC8273275 DOI: 10.3389/fnut.2021.699620] [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: 04/23/2021] [Accepted: 06/03/2021] [Indexed: 12/16/2022] Open
Abstract
Obesity can lead to chronic health complications such as nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by lipid aggregation in the hepatocytes and inflammation of the liver tissue as a consequence that can contribute to the development of cirrhosis and hepatocellular carcinoma (HCC). Previously, we reported that feeding obese Zucker rats with soy protein isolate (SPI) can reduce liver steatosis when compared with a casein (CAS) diet as a control. However, the effects of SPI on cytochrome P450 (CYP) in an obese rat model are less known. In addition, there is a lack of information concerning the consumption of soy protein in adolescents and its effect in reducing the early onset of NAFLD in this group. Our main goal was to understand if the SPI diet had any impact on the hepatic CYP gene expression when compared with the CAS diet. For this purpose, we used the transcriptomic data obtained in a previous study in which liver samples were collected from obese rats after short-term (eight-week) and long-term (16-week) feeding of SPI (n = 8 per group). To analyze this RNAseq data, we used Ingenuity Pathway Analysis (IPA) software. Comparing short- vs long-term feeding revealed an increase in the number of downregulated CYP genes from three at 8 weeks of SPI diet to five at 16 weeks of the same diet (P ≤ 0.05). On the other hand, upregulated CYP gene numbers showed a small increase in the long-term SPI diet compared to the short-term SPI diet, from 14 genes at 8 weeks to 17 genes at 16 weeks (P ≤ 0.05). The observed changes may have an important role in the attenuation of liver steatosis.
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Affiliation(s)
- Melisa Kozaczek
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Poultry Science and The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States.,Arkansas Children's Research Institute, Little Rock, AR, United States
| | - Walter Bottje
- Department of Poultry Science and The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Diyana Albataineh
- Department of Poultry Science and The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Reza Hakkak
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Arkansas Children's Research Institute, Little Rock, AR, United States.,Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, United States
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18
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Cheng B, Tian J, Chen Y. Identification of RNA binding protein interacting with circular RNA and hub candidate network for hepatocellular carcinoma. Aging (Albany NY) 2021; 13:16124-16143. [PMID: 34133325 PMCID: PMC8266373 DOI: 10.18632/aging.203139] [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: 02/25/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
The interaction between RNA binding protein (RBP) and circular RNA (circRNA) is important for the regulation of tumor progression. This study aimed to identify the RBP-circRNA network in hepatocellular carcinoma (HCC). 22 differentially expressed (DE) circRNAs in HCC were screened out from Gene Expression Omnibus (GEO) database and their binding RBPs were predicted by Circular RNA Interactome. Among them, 17 DERBPs, which were commonly dysregulated in HCC from The Clinical Proteomic Tumor Analysis Consortium (CPTAC), The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects, were utilized to construct the RBP-circRNA network. Through survival analysis, we found TARDBP was the only prognostic RBP for HCC in CPTAC, TCGA and ICGC projects. High expression of TARDBP was correlated with high grade, advanced stage and low macrophage infiltration of HCC. Additionally, gene set enrichment analysis showed that dysregulated TARDBP might be involved in some pathways related to the HCC pathogenesis. Therefore, a hub RBP-circRNA network was generated based on TARDBP. RNA immunoprecipitation and RNA pull-down confirmed that hsa_circ_0004913 binds to TARDBP. These findings indicated certain RBP-circRNA regulatory network potentially involved in the pathogenesis of HCC, which provides novel insights into the mechanism study and biomarker identification for HCC.
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Affiliation(s)
- Binglin Cheng
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Jingdong Tian
- School of Biomedical Engineering, Xinhua College of Sun Yat-Sen University, Guangzhou, Guangdong Province 510520, China
| | - Yuhan Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
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19
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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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20
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Kwon YJ, Shin S, Chun YJ. Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes. Arch Pharm Res 2021; 44:63-83. [PMID: 33484438 DOI: 10.1007/s12272-021-01306-w] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022]
Abstract
Human cytochrome P450 enzymes (CYPs) play a critical role in various biological processes and human diseases. CYP1 family members, including CYP1A1, CYP1A2, and CYP1B1, are induced by aryl hydrocarbon receptors (AhRs). The binding of ligands such as polycyclic aromatic hydrocarbons activates the AhRs, which are involved in the metabolism (including oxidation) of various endogenous or exogenous substrates. The ligands that induce CYP1 expression are reported to be carcinogenic xenobiotics. Hence, CYP1 enzymes are correlated with the pathogenesis of cancers. Various endogenous substrates are involved in the metabolism of steroid hormones, eicosanoids, and other biological molecules that mediate the pathogenesis of several human diseases. Additionally, CYP1s metabolize and activate/inactivate therapeutic drugs, especially, anti-cancer agents. As the metabolism of drugs determines their therapeutic efficacy, CYP1s can determine the susceptibility of patients to some drugs. Thus, understanding the role of CYP1s in diseases and establishing novel and efficient therapeutic strategies based on CYP1s have piqued the interest of the scientific community.
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Affiliation(s)
- Yeo-Jung Kwon
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Sangyun Shin
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
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21
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He K, Chen H, Cao T, Lin J. Elucidation of the Mechanisms and Molecular Targets of Shuanglian Decoction for the Treatment of Hepatocellular Carcinoma Based on Network Pharmacology. ACS OMEGA 2021; 6:917-924. [PMID: 33458543 PMCID: PMC7808160 DOI: 10.1021/acsomega.0c05550] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/21/2020] [Indexed: 05/02/2023]
Abstract
Shuanglian decoction (SLD) is traditionally used to treat hepatocellular carcinoma (HCC) in the clinical practice of traditional Chinese medicine. However, its mechanisms of action and molecular targets for the treatment of HCC are not clear. The active compounds of SLD were collected and their targets were identified. HCC-related targets were obtained by analyzing the differentially expressed genes between HCC patients and healthy individuals. Protein-protein interaction (PPI) data were then obtained and PPI networks of SLD putative targets and HCC-related targets were visualized and merged to identify the candidate targets for SLD against HCC. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out. The gene-pathway network was constructed to screen the key target genes. In total, 35 active compounds and 31 targets of SLD were identified. In total, 245 differentially expressed genes with P values <0.005 and |log2 (fold change)| > 1 were identified between HCC patients and control groups, and 68 target genes associated with HCC were finally identified. Twenty-one pathways including cellular senescence, p53 signaling pathway, and cell cycle were significantly enriched. CYP3A4 was the core gene and other several genes including CYP1A2, PPP3CA, PTGS2, CCCNB1, and CDK1 were the key genes in the gene-pathway network of SLD for the treatment of HCC. The results indicated that SLD's effects against HCC may relate to the regulation of an antioxidant function through specific biological processes and related pathways. This study demonstrates the application of network pharmacology in evaluating mechanisms of action and molecular targets of complex herbal formulations.
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Affiliation(s)
- Kun He
- Hepatobiliary
Surgery, Zhongshan People’s Hospital, Zhongshan 528403, China
| | - Hua Chen
- The
Second Tumor Department, Maoming People’s
Hospital, Maoming 525000, China
| | - Tianshou Cao
- Research
Center of Guangdong Medical University, Guangdong Medical University, Dongguan 523808, China
| | - Jiantao Lin
- Research
Center of Guangdong Medical University, Guangdong Medical University, Dongguan 523808, China
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22
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Yu J, Xia X, Dong Y, Gong Z, Li G, Chen GG, Lai PBS. CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling. Am J Cancer Res 2021; 11:2123-2136. [PMID: 33500715 PMCID: PMC7797680 DOI: 10.7150/thno.49368] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 11/27/2020] [Indexed: 02/06/2023] Open
Abstract
Rationale: Hyperactivation of HGF/MET signaling pathway is a critical driver in liver tumorigenesis. Cytochrome P450 1A2 (CYP1A2) was significantly down-regulated in hepatocellular carcinoma (HCC). However, little is explored about its tumor suppressive role in HCC. In this study, we examined the functional mechanisms and clinical implication of CYP1A2 in HCC. Methods: The clinical impact of CYP1A2 was evaluated in HCC patients in Hong Kong cohort. The biological functions of CYP1A2 were investigated in vitro and in vivo. A series of biochemical experiments including Western blot assay, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and Co-immunoprecipitation assay were conducted. Results: CYP1A2 expression was prominently silenced in HCC tumor tissues and the high expression of CYP1A2 was significantly correlated with lower AFP level, less vascular invasion, and better tumor-free survival in local cohort of HCC patients. The overexpression of CYP1A2 inhibited HCC cell viability and clonogenicity, reduced cell migration and invasion abilities in vitro, and suppressed tumorigenicity in vivo, whereas CYP1A2 knockdown exhibited the opposite effects. CYP1A2 significantly hindered HGF/MET signaling and Matrix metalloproteinases (MMPs) expression in HCC cells. Mechanically, CYP1A2 decreased HGF level and diminished HIF-1α expression, both of which are recognized as key regulators of MET activation. As the transcriptional activator of MET, HIF-1α was identified as a binding partner of CYP1A2. Direct binding of CYP1A2 with HIF-1α induced ubiquitin-mediated degradation of HIF-1α, inhibiting HIF-1α-mediated transcriptions. Conclusions: In conclusion, our results have identified CYP1A2 as a novel antagonist of HGF/MET signaling, and CYP1A2 may serve as an independent new biomarker for the prognosis of HCC patients.
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23
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Guo Y, Wu G, Yi J, Yang Q, Jiang W, Lin S, Yang X, Cai X, Mao L. Anti-Hepatocellular Carcinoma Effect and Molecular Mechanism of the Estrogen Signaling Pathway. Front Oncol 2021; 11:763539. [PMID: 35096574 PMCID: PMC8789654 DOI: 10.3389/fonc.2021.763539] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/14/2021] [Indexed: 12/18/2022] Open
Abstract
There are significant gender differences in the incidence and mortality of hepatocellular carcinoma (HCC). Compared with men, the incidence and mortality of HCC in women are relatively low. The estrogen signaling pathway, composed of estrogen and estrogen receptors, has been postulated to have a protective effect on the occurrence and development of HCC. There have been multiple studies that have supported anti-HCC effects of the estrogen signaling pathways, including direct and indirect pathways such as genomic pathways, rapid transduction pathways, non-coding RNA, tumor microenvironment, estrogen metabolites, and inhibition of hepatitis infection and replication. Based on the evidence of an anti-HCC effect of the estrogen signaling pathway, a number of strategies have been investigated to determine the potential therapeutic effect. These have included estrogen replacement therapy, targeting the estrogen receptor, key molecules, inflammatory mediators, and regulatory pathways of the estrogen signaling pathway. In this review, we have systematically summarized the latest developments in the complex functions and molecular mechanisms of the estrogen signaling pathway in liver cancer. Furthermore, we have highlighted the potential targets of treatment strategies based on the estrogen signaling pathway in the treatment of liver cancer and the principal obstacles currently encountered for future investigation.
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Affiliation(s)
- Yusheng Guo
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Guohui Wu
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Junrong Yi
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qin Yang
- Nephrology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wengong Jiang
- Nephrology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Shaoqiang Lin
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaorong Yang
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
| | - Xiangsheng Cai
- Center for Medical Experiments, University of Chinese Academy of Science-Shenzhen Hospital, Shenzhen, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
| | - Liufeng Mao
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
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24
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Yu J, Wang N, Gong Z, Liu L, Yang S, Chen GG, Lai PBS. Cytochrome P450 1A2 overcomes nuclear factor kappa B-mediated sorafenib resistance in hepatocellular carcinoma. Oncogene 2020; 40:492-507. [PMID: 33184472 DOI: 10.1038/s41388-020-01545-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 10/09/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023]
Abstract
Sorafenib resistance has become the main obstacle in the effective treatment of advanced hepatocellular carcinoma (HCC) patients. Activation of nuclear factor kappa B (NF-κB) is a newly identified mechanism that contributes to desensitized sorafenib. Cytochrome P450 1A2 (CYP1A2) functions as a tumor suppressor in HCC and its expression is negatively associated with NF-κB in the liver. This study aimed to study whether CYP1A2 could overcome sorafenib resistance. To investigate whether CYP1A2 and NF-κB p65 played roles in sorafenib desensitization, we established sorafenib-resistant (SR) HCC cells. SR cells decreased the expression of CYP1A2 along with the upregulation of NF-κB p65. CYP1A2 overexpression attenuated SR cell proliferation, increased sorafenib sensitivity, and inhibited the NF-κB pathway, whereas CYP1A2 silence showed opposite effects. Sorafenib, in combination with omeprazole, a CYP1A2 inducer, significantly hindered the growth and invasion of SR cells in vitro as well as decreased the tumor growth in vivo. The combination treatment markedly increased CYP1A2 expression and inhibited the sorafenib-induced NF-κB signaling. In addition, the overexpression of NF-κB p65 stimulated the SR cell growth and desensitized sorafenib in SR cells, where CYP1A2 overexpression reversed the phenomenon. Lastly, the majority of HCC tissue samples displayed decreased CYP1A2 but increased NF-κB p65 protein expression. Collectively, CYP1A2 can sensitize SR cells to sorafenib via inhibiting NF-κB p65 axis. Omeprazole in combination with sorafenib exerts a synergistic effect in alleviating acquired sorafenib resistance.
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Affiliation(s)
- Jianqing Yu
- Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Nuozhou Wang
- Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhongqin Gong
- Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Liping Liu
- Department of Hepatobiliary and Pancreas Surgery, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, 524000, Guangdong, China
| | - Shengli Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - George Gong Chen
- Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. .,Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Prince of Walves Hospital, The Chinese University of Hong Kong, Hong Kong, China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
| | - Paul Bo San Lai
- Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
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25
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Luo Y, Liu JY. Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer. Front Pharmacol 2020; 11:580897. [PMID: 33192522 PMCID: PMC7658919 DOI: 10.3389/fphar.2020.580897] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/30/2020] [Indexed: 12/19/2022] Open
Abstract
Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosanoids, such as epoxyeicosatrienoic acids (EETs), epoxyoctadecenoic acids (EpOMEs), epoxyeicosatetraenoic acids (EpETEs), and epoxydocosapentaenoic acids (EDPs), as well as hydroxyeicosatetraenoic acids (HETEs), in tumorigenesis and cancer progression have not been fully elucidated yet. Here we summarized the association of polymorphisms of CYP monooxygenases with cancers and the pleiotropic functions of CYP monooxygenase-mediated eicosanoids (EETs, EpOMEs, EpETE, EDPs, and 20-HETE) in the tumorigenesis and metastasis of multiple cancers, including but not limited to colon, liver, kidney, breast and prostate cancers, which hopefully provides valuable insights into cancer therapeutics. We believe that manipulation of CYPs with or without supplement of ω-3 PUFAs to regulate eicosanoid profile is a promising strategy to prevent and/or treat cancers.
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Affiliation(s)
- Ying Luo
- Department of Clinical Laboratory, Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Jun-Yan Liu
- Center for Novel Target & Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
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26
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Gender Matters: Characteristics of Hepatocellular Carcinoma in Women From a Large, Multicenter Study in the United States. Am J Gastroenterol 2020; 115:1486-1495. [PMID: 32453046 DOI: 10.14309/ajg.0000000000000643] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).
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27
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Ren J, Liu Y, Wang S, Wang Y, Li W, Chen S, Cui D, Yang S, Li MY, Feng B, Lai PBS, Chen GG. The FKH domain in FOXP3 mRNA frequently contains mutations in hepatocellular carcinoma that influence the subcellular localization and functions of FOXP3. J Biol Chem 2020; 295:5484-5495. [PMID: 32198183 PMCID: PMC7170510 DOI: 10.1074/jbc.ra120.012518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/12/2020] [Indexed: 01/16/2023] Open
Abstract
The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.
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Affiliation(s)
- Jianwei Ren
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute (SZRI), Chinese University of Hong Kong, Shenzhen 518057, China
| | - Yi Liu
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Shanshan Wang
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yu Wang
- Division of Cellular & Molecular Research, National Cancer Centre, Singapore 169610
| | - Wende Li
- Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510663, China
| | - Siyu Chen
- Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510663, China
| | - Dexuan Cui
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Shengli Yang
- Union Hospital Tumour Center, Wuhan 430022, China
| | - Ming-Yue Li
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510320, China
| | - Bo Feng
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Paul B S Lai
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China.
| | - George G Chen
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute (SZRI), Chinese University of Hong Kong, Shenzhen 518057, China; Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China; Department of Otorhinolaryngology, Head and Neck Surgery, Chinese University of Hong Kong, Hong Kong, China.
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28
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Morales-Prieto N, Huertas-Abril PV, López de Lerma N, Pacheco IL, Pérez J, Peinado R, Abril N. Pedro Ximenez sun-dried grape must: a dietary supplement for a healthy longevity. Food Funct 2020; 11:4387-4402. [DOI: 10.1039/d0fo00204f] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Sun-dried Pedro Ximénez white grapes must (PXM) is a potent antioxidant that regularizes apoptosis, proliferation, and regeneration of the structure and the function of aged mice liver. PXM consumption contributes to a healthy aging process.
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Affiliation(s)
- Noelia Morales-Prieto
- Departamento de Bioquímica y Biología Molecular
- Campus de Excelencia Internacional Agroalimentario CeiA3
- Universidad de Córdoba
- 14071 Córdoba
- Spain
| | - Paula V. Huertas-Abril
- Departamento de Bioquímica y Biología Molecular
- Campus de Excelencia Internacional Agroalimentario CeiA3
- Universidad de Córdoba
- 14071 Córdoba
- Spain
| | | | - Isabel. L. Pacheco
- Departamento de Anatomía y Anatomía Patológica Comparadas. Facultad de Veterinaria. Universidad de Córdoba
- 14071 Córdoba
- Spain
| | - José Pérez
- Departamento de Anatomía y Anatomía Patológica Comparadas. Facultad de Veterinaria. Universidad de Córdoba
- 14071 Córdoba
- Spain
| | - Rafael Peinado
- Departamento de Química Agrícola
- Universidad de Córdoba
- 14071 Córdoba
- Spain
| | - Nieves Abril
- Departamento de Bioquímica y Biología Molecular
- Campus de Excelencia Internacional Agroalimentario CeiA3
- Universidad de Córdoba
- 14071 Córdoba
- Spain
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29
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Zhang X, El-Serag HB, Thrift AP. Sex and Race Disparities in the Incidence of Hepatocellular Carcinoma in the United States Examined through Age-Period-Cohort Analysis. Cancer Epidemiol Biomarkers Prev 2019; 29:88-94. [PMID: 31712271 DOI: 10.1158/1055-9965.epi-19-1052] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Incidence rates for hepatocellular carcinoma (HCC) vary considerably by age, sex, and race/ethnicity. We assessed whether the underlying reasons for variations in HCC among subgroups of the population by age, sex, race/ethnicity, and birth cohort are uniform or whether they interact with one another or have changed over time. METHODS Data were from the U.S. Cancer Statistics registry. We assessed annual trends within population subgroups and examined for secular trends in the male-to-female ratio for HCC incidence. We used joinpoint regression to compute annual percent change and average annual percent change (AAPC) and corresponding 95% confidence intervals (CI). We also used age-period-cohort models to disentangle period and cohort effects. RESULTS Between 2001 and 2015, HCC rates increased in men and women ≥50 years, remained stable among women ages 40 to 49 years, but decreased among males ages 40 to 44 years (AAPC = -2.47%; 95% CI, -3.15% to -1.80%) and 45 to 49 years (AAPC = -3.49%; 95% CI, -4.78% to -2.17%). As a result, the male-to-female incidence rate ratio (IRR) among persons aged <50 years decreased from 4.63 in 2001 to 2.42 in 2015 but remained stable over time among persons aged ≥50 years. HCC rates were lower among successive cohorts of males born after circa 1956, whereas HCC rates among females born circa 1991 were higher than those among females born circa 1956 (IRR = 1.67; 95% CI, 1.05-2.65). CONCLUSIONS As a result of decreasing incidence among males aged <50 years and strong cohort effect, the epidemiology of HCC is changing from a disease with striking male predominance to one with less male predominance. IMPACT The sex and racial disparities and strong birth cohort effect on HCC risk identified in this study have important implications for population-based HCC prevention efforts.
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Affiliation(s)
- Xiaotao Zhang
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, Texas. .,Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Hashem B El-Serag
- Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Aaron P Thrift
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, Texas.,Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
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Monteiro M, Lechuga G, Lara L, Souto B, Viganó M, Bourguignon S, Calvet C, Oliveira F, Alves C, Souza-Silva F, Santos M, Pereira M. Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease. Eur J Med Chem 2019; 182:111610. [DOI: 10.1016/j.ejmech.2019.111610] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 08/08/2019] [Accepted: 08/09/2019] [Indexed: 10/26/2022]
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Motawi TMK, Sadik NAH, Sabry D, Shahin NN, Fahim SA. rs2267531, a promoter SNP within glypican-3 gene in the X chromosome, is associated with hepatocellular carcinoma in Egyptians. Sci Rep 2019; 9:6868. [PMID: 31053802 PMCID: PMC6499880 DOI: 10.1038/s41598-019-43376-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 04/23/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern in Egypt owing to the high prevalence of hepatitis C virus (HCV) infection. HCC incidence is characterized by obvious male predominance, yet the molecular mechanisms behind this gender bias are still unidentified. Functional variations in X-linked genes have more impact on males than females. Glypican-3 (GPC3) gene, located in the Xq26 region, has lately emerged as being potentially implicated in hepatocellular carcinogenesis. The current study was designed to examine the association of -784 G/C single nucleotide polymorphism (SNP) in GPC3 promoter region (rs2267531) with HCC susceptibility in male and female Egyptian HCV patients. Our results revealed a significant association between GPC3 and HCC risk in both males and females, evidenced by higher C allele and CC/C genotype frequencies in HCC patients when compared to controls. However, no such association was found when comparing HCV patients to controls. Moreover, GPC3 gene and protein expression levels were significantly higher in CC/C than in GG/G genotype carriers in males and females. The CC/C genotype exhibited a significant shorter overall survival than GG/G genotype in HCC patients. In conclusion, GPC3 rs2267531 on the X chromosome is significantly associated with HCC, but not with HCV infection, in the Egyptian population.
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Affiliation(s)
| | | | - Dina Sabry
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nancy Nabil Shahin
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sally Atef Fahim
- Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt.
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Li Y, Xu A, Jia S, Huang J. Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma. Oncol Lett 2019; 17:4222-4228. [PMID: 30988804 PMCID: PMC6447942 DOI: 10.3892/ol.2019.10127] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 01/25/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is more frequently observed and aggressive in men compared with women. Increasing evidence demonstrates that the sex disparity appears to be mediated by the stimulatory effects of androgens and the protective effects of estrogen in the development and progression of HCC. In the past few decades, studies on the sex difference of HCC mainly focused on the effect of sex hormones on the transactivation of hepatitis B virus X protein and the release of inflammatory cytokines, and these studies have further intensified in recent years. Sex hormones are also involved in genetic alterations and DNA damage repair in hepatocytes through binding to their specific cellular receptors and affecting the corresponding signaling pathways. Furthermore, the theory of sex chromosomes participating in HCC has been considered. The present review discussed the recent advances in the molecular mechanisms of sex disparity in HCC, with the aim of improving the understanding of the underlying critical factors and exploring more effective methods for the prevention and treatment of HCC.
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Affiliation(s)
- Yanmeng Li
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
| | - Anjian Xu
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
| | - Siyu Jia
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
| | - Jian Huang
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
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Matsushita H, Takaki A. Alcohol and hepatocellular carcinoma. BMJ Open Gastroenterol 2019; 6:e000260. [PMID: 31139422 PMCID: PMC6505979 DOI: 10.1136/bmjgast-2018-000260] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/04/2019] [Accepted: 01/12/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Alcohol is classified as a Group 1 carcinogen by the International Agency for Research on Cancer because it induces hepatocellular carcinoma (among other cancers) in humans. An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, and cirrhosis and eventually lead to hepatocellular carcinoma. It has been reported that alcohol abuse increases the relative risk of hepatocellular carcinoma by 3- to 10-fold. AIM AND METHODS To clarify the known mechanisms of alcohol-related carcinogenesis, we searched Pubmed using the terms alcohol and immune mechanism, alcohol and cancer, and immune mechanism and cancer and summarized the articles as a qualitative review. RESULTS From a clinical perspective, it is well known that alcohol interacts with other factors, such as smoking, viral hepatitis, and diabetes, leading to an increased risk of hepatocellular carcinoma. There are several possible mechanisms through which alcohol may induce liver carcinogenicity, including the mutagenic effects of acetaldehyde and the production of ROS due to the excessive hepatic deposition of iron. Furthermore, it has been reported that alcohol accelerates hepatitis C virus-induced liver tumorigenesis through TLR4 signaling. Despite intense investigations to elucidate the mechanisms, they remain poorly understood. CONCLUSION This review summarizes the recent findings of clinical and pathological studies that have investigated the carcinogenic effects of alcohol in the liver.
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Affiliation(s)
- Hiroshi Matsushita
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Liu ZZ, Yan LN, Dong CN, Ma N, Yuan MN, Zhou J, Gao P. Cytochrome P450 family members are associated with fast-growing hepatocellular carcinoma and patient survival: An integrated analysis of gene expression profiles. Saudi J Gastroenterol 2019; 25:167-175. [PMID: 30971588 PMCID: PMC6526731 DOI: 10.4103/sjg.sjg_290_18] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. Although many molecular tools have been developed to assist in stratification and prediction of patients by using microarray analysis, the classification and prediction are still improvable because the high-through microarray contains a large amount of information. Meanwhile, gene expression patterns and their prognostic value for HCC have not been systematically investigated. In order to explore new molecular diagnostic and prognostic biomarkers, the gene expression profiles between HCCs and adjacent nontumor tissues were systematically analyzed in the present study. MATERIALS AND METHODS In this study, gene expression profiles were obtained by repurposing five Gene Expression Omnibus databases. Differentially expressed genes were identified by using robust rank aggregation method. Three datasets (GSE14520, GSE36376, and GSE54236) were used to validate the associations between cytochrome P450 (CYP) family genes and HCC. GSE14520 was used as the training set. GSE36376 and GSE54236 were considered as the testing sets. RESULTS From the training set, a four-CYP gene signature was constructed to discriminate between HCC and nontumor tissues with an area under curve (AUC) of 0.991. Accuracy of this four-gene signature was validated in two testing sets (AUCs for them were 0.973 and 0.852, respectively). Moreover, this gene signature had a good performance to make a distinction between fast-growing HCC and slow-growing HCC (AUC = 0.898), especially for its high sensitivity of 95%. At last, CYP2C8 was identified as an independent risk factor of recurrence-free survival (hazard ratio [HR] =0.865, 95% confidence interval [CI], 0.754-0.992, P = 0.038) and overall survival (HR = 0.849; 95% CI, 0.716-0.995, P = 0.033). CONCLUSIONS In summary, our results confirmed for the first time that a four-CYP gene (CYP1A2, CYP2E1, CYP2A7, and PTGIS) signature is associated with fast-growing HCC, and CYP2C8 is associated with patient survival. Our findings could help to identify HCC patients at high risk of rapid growth and recurrence.
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Affiliation(s)
- Zhao-Zhen Liu
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Li-Na Yan
- Hebei Province Key Laboratory of Environment and Human Health, Hebei, China,Department of Epidemiology and Biostatistics, School of Public Health, Hebei Medical University, Hebei, China
| | - Chun-Nan Dong
- Department of Pathogenic Biology, Hebei Medical University, Hebei, China
| | - Ning Ma
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Mei-Na Yuan
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Jin Zhou
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Ping Gao
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China,Address for correspondence: Dr. Ping Gao, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, 050017, Hebei Province, China. E-mail:
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35
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Zhang C, He X, Kwok YK, Wang F, Xue J, Zhao H, Suen KW, Wang CC, Ren J, Chen GG, Lai PBS, Li J, Xia Y, Chan AM, Chan WY, Feng B. Homology-independent multiallelic disruption via CRISPR/Cas9-based knock-in yields distinct functional outcomes in human cells. BMC Biol 2018; 16:151. [PMID: 30593266 PMCID: PMC6310992 DOI: 10.1186/s12915-018-0616-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 11/28/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Cultured human cells are pivotal models to study human gene functions, but introducing complete loss of function in diploid or aneuploid cells has been a challenge. The recently developed CRISPR/Cas9-mediated homology-independent knock-in approach permits targeted insertion of large DNA at high efficiency, providing a tool for insertional disruption of a selected gene. Pioneer studies have showed promising results, but the current methodology is still suboptimal and functional outcomes have not been well examined. Taking advantage of the promoterless fluorescence reporter systems established in our previous study, here, we further investigated potentials of this new insertional gene disruption approach and examined its functional outcomes. RESULTS Exemplified by using hyperploid LO2 cells, we demonstrated that simultaneous knock-in of dual fluorescence reporters through CRISPR/Cas9-induced homology-independent DNA repair permitted one-step generation of cells carrying complete disruption of target genes at multiple alleles. Through knocking-in at coding exons, we generated stable single-cell clones carrying complete disruption of ULK1 gene at all four alleles, lacking intact FAT10 in all three alleles, or devoid of intact CtIP at both alleles. We have confirmed the depletion of ULK1 and FAT10 transcripts as well as corresponding proteins in the obtained cell clones. Moreover, consistent with previous reports, we observed impaired mitophagy in ULK1-/- cells and attenuated cytokine-induced cell death in FAT10-/- clones. However, our analysis showed that single-cell clones carrying complete disruption of CtIP gene at both alleles preserved in-frame aberrant CtIP transcripts and produced proteins. Strikingly, the CtIP-disrupted clones raised through another two distinct targeting strategies also produced varied but in-frame aberrant CtIP transcripts. Sequencing analysis suggested that diverse DNA processing and alternative RNA splicing were involved in generating these in-frame aberrant CtIP transcripts, and some infrequent events were biasedly enriched among the CtIP-disrupted cell clones. CONCLUSION Multiallelic gene disruption could be readily introduced through CRISPR/Cas9-induced homology-independent knock-in of dual fluorescence reporters followed by direct tracing and cell isolation. Robust cellular mechanisms exist to spare essential genes from loss-of-function modifications, by generating partially functional transcripts through diverse DNA and RNA processing mechanisms.
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Affiliation(s)
- Chenzi Zhang
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - Xiangjun He
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - Yvonne K Kwok
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - Feng Wang
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - Junyi Xue
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,Institute for Tissue Engineering and Regenerative Medicine (iTERM), The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,SBS Core Laboratory, CUHK Shenzhen Research Institute, Shenzhen, 518057, China
| | - Hui Zhao
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,Institute for Tissue Engineering and Regenerative Medicine (iTERM), The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,SBS Core Laboratory, CUHK Shenzhen Research Institute, Shenzhen, 518057, China
| | - Kin Wah Suen
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - Chi Chiu Wang
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - Jianwei Ren
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - George G Chen
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,State Key Laboratory in Oncology in South China, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China
| | - Paul B S Lai
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,State Key Laboratory in Oncology in South China, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,Prince of Wales Hospital, Shatin, New Territories, Hong Kong, Special Administrative Region of China
| | - Jiangchao Li
- Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Yin Xia
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,SBS Core Laboratory, CUHK Shenzhen Research Institute, Shenzhen, 518057, China
| | - Andrew M Chan
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.,SBS Core Laboratory, CUHK Shenzhen Research Institute, Shenzhen, 518057, China
| | - Wai-Yee Chan
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China. .,Institute for Tissue Engineering and Regenerative Medicine (iTERM), The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China. .,SBS Core Laboratory, CUHK Shenzhen Research Institute, Shenzhen, 518057, China. .,Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
| | - Bo Feng
- School of Biomedical Sciences, CUHK-GIBH CAS Joint Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China. .,Institute for Tissue Engineering and Regenerative Medicine (iTERM), The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China. .,SBS Core Laboratory, CUHK Shenzhen Research Institute, Shenzhen, 518057, China. .,Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
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36
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Elfaki I, Mir R, Almutairi FM, Duhier FMA. Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis. Asian Pac J Cancer Prev 2018; 19:2057-2070. [PMID: 30139042 PMCID: PMC6171375 DOI: 10.22034/apjcp.2018.19.8.2057] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.
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Affiliation(s)
- Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Kingdom of Saudi Arabia.
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37
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Sukocheva OA. Estrogen, estrogen receptors, and hepatocellular carcinoma: Are we there yet? World J Gastroenterol 2018; 24:1-4. [PMID: 29358876 PMCID: PMC5757114 DOI: 10.3748/wjg.v24.i1.1] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 12/06/2017] [Accepted: 12/12/2017] [Indexed: 02/06/2023] Open
Abstract
A protective role of the sex steroid hormone estrogen in hepatocellular carcinoma (HCC) was suggested a few decades ago according to clinical data showing higher HCC morbidity and mortality among males. Several recent studies further confirmed the anti-cancer effects of estrogen in the liver. However, it remains to be identified how to exploit estrogen signalling within clinical settings for HCC treatment. There are several unresolved issues related to the estrogen pathway in liver cells. The main problems include the absence of a clear understanding of which estrogen receptor (ER) isoform is predominantly expressed in normal and malignant liver cells, the ER isoform expression difference between males and females, and which ER isoform should be targeted when designing HCC therapy. Some of those questions were recently addressed by Iyer and co-authors. The current editorial review critically analyses the study by Iyer et al (WJG, 2017) that investigated the expression of ER subtypes in liver samples collected from patients with a healthy liver, hepatitis C virus cirrhosis, and HCC. ER presence was evaluated in association with gender, intracellular localization, inflammation marker NF-κB, and proliferation-related effector cyclin D1. The study limitations and advantages are discussed in light of recent advances in the HCC and estrogen signalling areas.
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Affiliation(s)
- Olga A Sukocheva
- School of Health Sciences, Flinders University of South Australia, Flinders Drive, Bedford Park 5042, Australia
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38
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Kohi MP. Gender-Related Differences in Hepatocellular Carcinoma: Does Sex Matter? J Vasc Interv Radiol 2017; 27:1338-1341. [PMID: 27566425 DOI: 10.1016/j.jvir.2016.06.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Revised: 06/28/2016] [Accepted: 06/28/2016] [Indexed: 02/07/2023] Open
Affiliation(s)
- Maureen P Kohi
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Ave., M-361, San Francisco, CA 94143.
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39
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Zheng B, Zhu YJ, Wang HY, Chen L. Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms. SCIENCE CHINA-LIFE SCIENCES 2017; 60:575-584. [PMID: 28547581 DOI: 10.1007/s11427-016-9043-9] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 02/20/2017] [Indexed: 02/07/2023]
Abstract
On the global scale, hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC) especially in regions of Asia where HBV infection is endemic. Epidemiological studies show that the incidence of inflammation-driven HCC in males is three times as high as in females. Recent studies suggest that sex hormones have a crucial role in the pathogenesis and development of HBV-induced HCC. We found that the estrogen/androgen signaling pathway is associated with decreased/increased transcription and replication of HBV genes and can promote the development of HBV infections by up/downregulating HBV RNA transcription and inflammatory cytokines levels, which in turn slow down the progression of HBV-induced HCC. Additionally, sex hormones can also affect HBV-related HCC by inducing epigenetic changes. The evidence that both morphology and function of the human liver are affected by sex hormones was found over 60 years ago. However, the underlying molecular mechanism largely remains to be elucidated. This review focuses mainly on the molecular mechanisms behind the sex difference in HCC associated with HBV and other factors. In addition, several potential treatment and therapeutic strategies for inflammation-driven HCC will be introduced in this review.
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Affiliation(s)
- Bo Zheng
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China.,National Center for Liver Cancer, Shanghai, 201805, China
| | - Yan-Jing Zhu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China.,National Center for Liver Cancer, Shanghai, 201805, China
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China. .,National Center for Liver Cancer, Shanghai, 201805, China. .,State Key Laboratory of Oncogenes and related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China. .,National Center for Liver Cancer, Shanghai, 201805, China.
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40
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Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways. Oncogene 2017; 36:5087-5097. [PMID: 28481866 PMCID: PMC5596209 DOI: 10.1038/onc.2017.114] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 02/27/2017] [Accepted: 03/18/2017] [Indexed: 12/13/2022]
Abstract
MYC activation at modest levels has been frequently found in hepatocellular carcinoma. However, its significance in hepatocarcinogenesis has remained obscure. Here we examined the role of Myc activation in mouse liver tumours induced by hepatocytic expression of myristoylated AKT (AKT) and/or mutant HRASV12 (HRAS) via transposon-mediated gene integration. AKT or HRAS alone required 5 months to induce liver tumours, whereas their combination generated hepatocellular carcinoma within 8 weeks. Co-introduction of AKT and HRAS induced lipid-laden preneoplastic cells that grew into nodules composed of tumour cells with or without intracytoplasmic lipid, with the latter being more proliferative and associated with spontaneous Myc expression. AKT/HRAS-induced tumorigenesis was almost completely abolished when MadMyc, a competitive Myc inhibitor, was expressed simultaneously. The Tet-On induction of MadMyc in preneoplastic cells significantly inhibited the progression of AKT/HRAS-induced tumours; its induction in transformed cells suppressed their proliferative activity with alterations in lipid metabolism and protein translation. Transposon-mediated Myc overexpression facilitated tumorigenesis by AKT or HRAS, and when it was co-introduced with AKT and HRAS, diffusely infiltrating tumours without lipid accumulation developed as early as 2 weeks. Examination of the dose-responses of Myc in the enhancement of AKT/HRAS-induced tumorigenesis revealed that a reduction to one-third retained enhancing effect but three-times greater introduction damped the process with increased apoptosis. Myc overexpression suppressed the mRNA expression of proteins involved in the synthesis of fatty acids, and when combined with HRAS introduction, it also suppressed the mRNA expression of proteins involved in their degradation. Finally, the MYC-positive human hepatocellular carcinoma was characterized by the cytoplasm devoid of lipid accumulation, prominent nucleoli and a higher proliferative activity. Our results demonstrate that in hepatocarcinogenesis induced by both activated AKT and HRAS, activation of endogenous Myc is an enhancing factor and adequate levels of Myc deregulation further facilitate the process with alterations in cellular metabolism.
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41
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Buzzetti E, Parikh PM, Gerussi A, Tsochatzis E. Gender differences in liver disease and the drug-dose gender gap. Pharmacol Res 2017; 120:97-108. [PMID: 28336373 DOI: 10.1016/j.phrs.2017.03.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 03/17/2017] [Accepted: 03/17/2017] [Indexed: 12/14/2022]
Abstract
Although gender-based medicine is a relatively recent concept, it is now emerging as an important field of research, supported by the finding that many diseases manifest differently in men and women and therefore, might require a different treatment. Sex-related differences regarding the epidemiology, progression and treatment strategies of certain liver diseases have long been known, but most of the epidemiological and clinical trials still report results only about one sex, with consequent different rate of response and adverse reactions to treatment between men and women in clinical practice. This review reports the data found in the literature concerning the gender-related differences for the most representative hepatic diseases.
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Affiliation(s)
- Elena Buzzetti
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.
| | - Pathik M Parikh
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Alessio Gerussi
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK; Internal Medicine Unit, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
| | - Emmanuel Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
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42
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Alternative splicing of estrogen receptor alpha in hepatocellular carcinoma. BMC Cancer 2016; 16:926. [PMID: 27899088 PMCID: PMC5129602 DOI: 10.1186/s12885-016-2928-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 11/06/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The role of estrogen receptor alpha (ERa), estrogen receptor beta (ERb) and ERa36 signaling in hepatocellular carcinoma (HCC) is not fully addressed. METHODS In this study, three cohorts were included: (i) primary HCC patients (N = 76, cohort P), (ii) colorectal liver metastasis (mCRC) (N = 32, cohort S), and (iii) HCC from The Cancer Genome Atlas (TCGA) (N = 121). The levels of ERa36 and wtER36 were measured and their correlation with clinicopathologic features was determined. RESULTS WtERa was downregulated and that ERa36 was upregulated in tumor tissues in both cohort P and TCGA data set. ERa36 was downregulated in tumor tissues in cohort S. In cohort P, wtERa was differentially expressed in gender (P < 0.000), age (P = 0.004), tumor number (P = 0.043), tumor size (P = 0.002), intrahepatic recurrence (P = 0.054). ERa36 was unequally expressed in different non-tumor liver status (P = 0.040). WtERa was negatively associated with overall survival (OS) and disease free survival (DFS) in cohort P. Compared with non-tumor tissues, the expression of ERa36 was increased in primary HCC but decreased in secondary HCC, showing opposite expression patterns of ERa36 between primary HCC and secondary HCC. CONCLUSIONS Primary HCC is associated with the decreased WtERa but increased ERa36. The expression pattern of ERa36 is different between primary HCC and secondary HCC, as the former with the increased ERa36 but the latter with the decreased ERa36. Therefore, the expression of ERa36 may be used to differentiate the primary HCC and the secondary one.
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