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Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, Borkowski V, Segal M, Mukhtar M, Mohammed M, Boateng E, Nemer M, Panahiazar M, Hadley D, Jalil S, Mumtaz K. Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data. World J Gastrointest Oncol 2022; 14:1856-1873. [PMID: 36187396 PMCID: PMC9516659 DOI: 10.4251/wjgo.v14.i9.1856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/26/2022] [Accepted: 08/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.
AIM To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.
METHODS We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis.
RESULTS Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.
CONCLUSION This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Rohr
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Saad Syed
- Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
| | - Eli Cohen
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Naima Hashi
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Sharjeel Syed
- Department of Medicine, University of Chicago Hospitals, Chicago, IL 60637, United States
| | - Kamal Khorfan
- Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno, Fresno, CA 93701, United States
| | - Hisham Aljabban
- Department of Medicine, Barry University, Miami, FL 33161, United States
| | - Vincent Borkowski
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Segal
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Mohamed Mukhtar
- Department of Medicine, Michigan State University College of Human Medicine, Lansing, MI 49503, United States
| | - Mohammed Mohammed
- Department of Medicine, Windsor University School of Medicine, Frankfort, IL 60423, United States
| | - Emmanuel Boateng
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Mary Nemer
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, United States
| | - Dexter Hadley
- Department of Pathology, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Sajid Jalil
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Khalid Mumtaz
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
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Shaw RPH, Kolyvas P, Dang N, Hyon A, Bailey K, Anakk S. Loss of Hepatic Small Heterodimer Partner Elevates Ileal Bile Acids and Alters Cell Cycle-related Genes in Male Mice. Endocrinology 2022; 163:bqac052. [PMID: 35451003 PMCID: PMC9113360 DOI: 10.1210/endocr/bqac052] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Indexed: 11/19/2022]
Abstract
Small heterodimer partner (Shp) regulates several metabolic processes, including bile acid levels, but lacks the conserved DNA binding domain. Phylogenetic analysis revealed conserved genetic evolution of SHP, FXR, CYP7A1, and CYP8B1. Shp, although primarily studied as a downstream target of Farnesoid X Receptor (Fxr), has a distinct hepatic role that is poorly understood. Here, we report that liver-specific Shp knockout (LShpKO) mice have impaired negative feedback of Cyp7a1 and Cyp8b1 on bile acid challenge and demonstrate that a single copy of the Shp gene is sufficient to maintain this response. LShpKO mice also exhibit elevated total bile acid pool with ileal bile acid composition mimicking that of cholic acid-fed control mice. Agonistic activation of Fxr (GW4064) in the LShpKO did not alter the elevated basal expression of Cyp8b1 but lowered Cyp7a1 expression. We found that deletion of Shp led to an enrichment of distinct motifs and pathways associated with circadian rhythm, copper ion transport, and DNA synthesis. We confirmed increased expression of metallothionein genes that can regulate copper levels in the absence of SHP. LShpKO livers also displayed a higher basal proliferation that was exacerbated specifically with bile acid challenge either with cholic acid or 3,5-diethoxycarbonyl-1,4-dihydrocollidine but not with another liver mitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. Overall, our data indicate that hepatic SHP uniquely regulates certain proliferative and metabolic cues.
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Affiliation(s)
| | - Peter Kolyvas
- Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA
| | - Nathanlown Dang
- Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA
| | - Angela Hyon
- Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA
| | - Keith Bailey
- Veterinary Diagnostic Laboratory, Urbana, IL 61801, USA
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, Urbana, IL 61801, USA
- Division of Nutritional Sciences, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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Park YY. Genomic analysis of nuclear receptors and miRNAs identifies a role for the NR3C1/miR-200 axis in colon cancer. Genes Genomics 2021; 43:913-920. [PMID: 34021858 DOI: 10.1007/s13258-021-01112-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 04/29/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Nuclear receptors (NRs) are crucial transcription factors involved in cell proliferation, metabolism and homeostasis. Through the development of novel genomic approaches, unknown NR functions have recently been uncovered. NR networks derived from gene expression profiles revealed that NRs are tightly linked to human disease and that targeting these links could provide new therapeutic options. MicroRNAs (miRNAs) have known functions as transcriptional regulators of NR function. OBJECTIVE I attempted to construct an NR-miRNA transcriptional network based on genomic data from human cancer. METHODS I performed comprehensive analysis with genomic data. Correlation, clustering and survival analysis were done to identify the NR and miRNA correlation in cancer. RESULTS Correlation analysis of genomic data revealed relationships between the expression levels of several NRs and miRNAs in human cancer. Based on my NR-miRNA correlation data, I found that NR3C1 expression was highly correlated with that of miR-200 in colon cancer. In most cases, miRNAs suppress expression of their target genes. Thus, miRNAs function as negative regulators during transcription. My analysis revealed that the miR-200 expression level is negatively correlated with that of NR3C1, demonstrating that miR-200 is a negative regulator of NR3C1 in colon cancer. It is known that miR-200 is a master regulator of EMT and that NR3C1 has a link with an EMT marker. CONCLUSIONS Overall, my genomic analysis revealed that the NR3C1 expression level is correlated with that of miR-200 and that this functional relationship might contribute to colon cancer cell survival. Modulating this axis could be a promising target for treating colon cancer patients.
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Affiliation(s)
- Yun-Yong Park
- Department of Life Science, College of Natural Science, Daejin University, Pocheon, 11159, Republic of Korea. .,Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
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Zhu R, Tu Y, Chang J, Xu H, Li JC, Liu W, Do AD, Zhang Y, Wang J, Li B. The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers. Front Oncol 2021; 11:691199. [PMID: 34055653 PMCID: PMC8162207 DOI: 10.3389/fonc.2021.691199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 04/26/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Liver cancer is a leading cause of cancer death worldwide, and novel prognostic factor is needed for early detection and therapeutic responsiveness monitoring. The orphan nuclear receptor NR0B2 was reported to suppress liver cancer development in a mouse model, and its expression levels were reduced in liver cancer tissues and cell lines due to hypermethylation within its promoter region. However, it is not clear if NR0B2 expression is associated with cancer survival or disease progression and how NR0B2 gene expression is regulated at the molecular level. METHODS Multiple cancer databases were utilized to explore NR0B2 gene expression profiles crossing a variety of human cancers, including liver cancers, on several publicly assessable bioinformatics platforms. NR0B2 gene expression with or without kinase inhibitor treatment was analyzed using the qPCR technique, and NR0B2 protein expression was assessed in western blot assays. Two human hepatocellular carcinoma cell lines HepG2 and Huh7, were used in these experiments. NR0B2 gene activation was evaluated using NR0B2 promoter-driven luciferase reporter assays. RESULTS NR0B2 gene is predominantly expressed in liver tissue crossing human major organs or tissues, but it is significantly downregulated in liver cancers. NR0B2 expression is mostly downregulated in most common cancers but also upregulated in a few intestinal cancers. NR0B2 gene expression significantly correlated with patient overall survival status in multiple human malignancies, including lung, kidney, breast, urinary bladder, thyroid, colon, and head-neck cancers, as well as liposarcoma and B-cell lymphoma. In liver cancer patients, higher NR0B2 expression is associated with favorite relapse-free and progression-free survival, especially in Asian male patients with viral infection history. In addition, NR0B2 expression negatively correlated with immune infiltration and PIK3CA and PIK3CG gene expression in liver cancer tissues. In HepG2 and Huh7 cells, NR0B2 expression at the transcription level was drastically reduced after MAPK inhibition but was significantly enhanced after PI3K inhibition. CONCLUSION NR0B2 gene expression is altered mainly in most human malignancies and significantly reduced in liver cancers. NR0B2 is a prognosis factor for patient survival in liver cancers. MAPK and PI3K oppositely modulate NR0B2 expression, and NR0B2 gene upregulation might serve as a therapeutic responsiveness factor in anti-PI3K therapy for liver cancer.
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Affiliation(s)
- Runzhi Zhu
- The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China,Zhejiang University Cancer Center, Hangzhou, China,Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States,*Correspondence: Runzhi Zhu, ; Benyi Li,
| | - Yanjie Tu
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Jingxia Chang
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Haixia Xu
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Jean C. Li
- Department of Pharmacology, Toxicology & Therapeutics, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Wang Liu
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Ahn-Dao Do
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Jinhu Wang
- The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China,Zhejiang University Cancer Center, Hangzhou, China
| | - Benyi Li
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States,*Correspondence: Runzhi Zhu, ; Benyi Li,
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Lam KK, Sethi R, Tan G, Tomar S, Lo M, Loi C, Tang CL, Tan E, Lai PS, Cheah PY. The orphan nuclear receptor
NR0B2
could be a novel susceptibility locus associated with microsatellite‐stable,
APC
mutation‐negative early‐onset colorectal carcinomas with metabolic manifestation. Genes Chromosomes Cancer 2020; 60:61-72. [DOI: 10.1002/gcc.22904] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 12/15/2022] Open
Affiliation(s)
- Kuen Kuen Lam
- Department of Colorectal Surgery Singapore General Hospital Singapore Singapore
| | - Raman Sethi
- Department of Paediatrics, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
| | - Grace Tan
- Department of Paediatrics, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
| | - Swati Tomar
- Department of Paediatrics, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
| | - Michelle Lo
- Department of Colorectal Surgery Singapore General Hospital Singapore Singapore
| | - Carol Loi
- Department of Colorectal Surgery Singapore General Hospital Singapore Singapore
| | - Choong Leong Tang
- Department of Colorectal Surgery Singapore General Hospital Singapore Singapore
| | - Emile Tan
- Department of Colorectal Surgery Singapore General Hospital Singapore Singapore
| | - Poh San Lai
- Department of Paediatrics, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Genome Institute of Singapore, A*STAR Singapore Singapore
| | - Peh Yean Cheah
- Department of Colorectal Surgery Singapore General Hospital Singapore Singapore
- Saw Swee Hock School of Public Health National University of Singapore Singapore Singapore
- Duke‐NUS Medical School National University of Singapore Singapore Singapore
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Kudryavtseva AV, Nyushko KM, Zaretsky AR, Shagin DA, Sadritdinova AF, Fedorova MS, Savvateeva MV, Guvatova ZG, Pudova EA, Alekseev BY, Dmitriev AA, Snezhkina AV. Suppression of NR0B2 gene in Clear Cell Renal Cell Carcinoma Is Associated with Hypermethylation of Its Promoter. Mol Biol 2018. [DOI: 10.1134/s0026893318030081] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Suresh S, Durakoglugil D, Zhou X, Zhu B, Comerford SA, Xing C, Xie XJ, York B, O’Donnell KA. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. PLoS Genet 2017; 13:e1006650. [PMID: 28273073 PMCID: PMC5362238 DOI: 10.1371/journal.pgen.1006650] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 03/22/2017] [Accepted: 02/23/2017] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver.
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Affiliation(s)
- Shruthy Suresh
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America
| | - Deniz Durakoglugil
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America
| | - Xiaorong Zhou
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America
- Department of Immunology, Nantong University School of Medicine, Nantong, China
| | - Bokai Zhu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America
| | - Sarah A. Comerford
- Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, United States of America
| | - Chao Xing
- Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, United States of America
- McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, United States of America
| | - Xian-Jin Xie
- Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, United States of America
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States of America
| | - Brian York
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Kathryn A. O’Donnell
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States of America
- * E-mail:
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8
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Prestin K, Olbert M, Hussner J, Isenegger TL, Gliesche DG, Böttcher K, Zimmermann U, Meyer Zu Schwabedissen HE. Modulation of expression of the nuclear receptor NR0B2 (small heterodimer partner 1) and its impact on proliferation of renal carcinoma cells. Onco Targets Ther 2016; 9:4867-78. [PMID: 27540300 PMCID: PMC4982508 DOI: 10.2147/ott.s106926] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Mammalian nuclear receptors (NRs) are transcription factors regulating the expression of target genes that play an important role in drug metabolism, transport, and cellular signaling pathways. The orphan and structurally unique receptor small heterodimer partner 1 (syn NR0B2) is not only known for its modulation of drug response, but has also been reported to be involved in hepatocellular carcinogenesis. Indeed, previous studies show that NR0B2 is downregulated in human hepatocellular carcinoma, suggesting that NR0B2 acts as a tumor suppressor via inhibition of cellular growth and activation of apoptosis in this tumor entity. The aim of our study was to elucidate whether NR0B2 may also play a role in other tumor entities. Comparing NR0B2 expression in renal cell carcinoma and adjacent nonmalignant transformed tissue revealed significant downregulation in vivo. Additionally, the impact of heterologous expression of NR0B2 on cell cycle progression and proliferation in cells of renal origin was characterized. Monitoring fluorescence intensity of resazurin turnover in RCC-EW cells revealed no significant differences in metabolic activity in the presence of NR0B2. However, there was a significant decrease of cellular proliferation in cells overexpressing this NR, and NR0B2 was more efficient than currently used antiproliferative agents. Furthermore, flow cytometry analysis showed that heterologous overexpression of NR0B2 significantly reduced the amount of cells passing the G1 phase, while on the other hand, more cells in S/G2 phase were detected. Taken together, our data suggest that downregulation of NR0B2 may also play a role in renal cell carcinoma development and progression.
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Affiliation(s)
- Katharina Prestin
- Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland
| | - Maria Olbert
- Center of Drug Absorption and Transport, Institute of Pharmacology
| | - Janine Hussner
- Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland
| | - Tamara L Isenegger
- Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland
| | - Daniel G Gliesche
- Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland
| | - Kerstin Böttcher
- Center of Drug Absorption and Transport, Institute of Pharmacology
| | - Uwe Zimmermann
- Department of Urology, University Medicine Greifswald, Greifswald, Germany
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Zou A, Lehn S, Magee N, Zhang Y. New Insights into Orphan Nuclear Receptor SHP in Liver Cancer. NUCLEAR RECEPTOR RESEARCH 2015; 2. [PMID: 26504773 PMCID: PMC4618403 DOI: 10.11131/2015/101162] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Small heterodimer partner (SHP; NR0B2) is a unique orphan nuclear receptor (NR) that contains a putative ligand-binding domain but lacks a DNA-binding domain. SHP is a transcriptional corepressor affecting diverse metabolic processes including bile acid synthesis, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology via interaction with multiple NRs and transcriptional factors (TFs). Hepatocellular carcinoma (HCC) is one of the most deadly human cancers worldwide with few therapeutic options and poor prognosis. Recently, it is becoming clear that SHP plays an antitumor role in the development of liver cancer. In this review, we summarize the most recent findings regarding the new SHP interaction partners, new structural insights into SHP’s gene repressing activity, and SHP protein posttranslational modifications by bile acids. We also discuss the pleiotropic role of SHP in regulating cell proliferation, apoptosis, DNA methylation, and inflammation that are related to antitumor role of SHP in HCC. Improving our understanding of SHP’s antitumor role in the development of liver cancer will provide new insights into developing novel treatments or prevention strategies. Future research will focus on developing more efficacious and specific synthetic SHP ligands for pharmaceutical applications in liver cancer and several metabolic diseases such as hypercholesterolemia, obesity, diabetes, and fatty liver disease.
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Affiliation(s)
- An Zou
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Sarah Lehn
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Nancy Magee
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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10
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Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. Biochem Biophys Res Commun 2015; 463:961-7. [DOI: 10.1016/j.bbrc.2015.06.042] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 06/05/2015] [Indexed: 11/21/2022]
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11
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Cheng YY, Tao WJ, Chen JL, Sun LN, Zhou LY, Song Q, Wang DS. Genome-wide identification, evolution and expression analysis of nuclear receptor superfamily in Nile tilapia, Oreochromis niloticus. Gene 2015; 569:141-52. [PMID: 26024593 DOI: 10.1016/j.gene.2015.05.057] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 04/22/2015] [Accepted: 05/22/2015] [Indexed: 01/19/2023]
Abstract
The nuclear receptor (NR) superfamily, which is divided into 7 subfamilies, constitutes one of the largest classes of transcription factors. In this study, through comprehensive database search, we identified all NRs (including 4 novel members) from the tilapia (75), common carp (137), zebrafish (73), fugu (73), tetraodon (72), stickleback (70), medaka (69), coelacanth (55), spotted gar (51) and elephant shark (50). For 21 NRs, two duplicates were found in teleosts, while only one in tetrapods. These duplicates, except those of DAX1, SHP and GCNF found in the elephant shark, were derived from 3R (third round of genome duplication). The linkage duplication of 5 syntenic blocks (comprising 14 duplicated NR couples) in teleosts further supported their 3R origin. Based on transcriptome data from adult tilapia, 53 NRs were found to be expressed in more than one tissue (brain, head kidney, heart, liver, kidney, muscle, ovary and testis), and 4 were tissue-specific, indicating their essential roles in the corresponding tissue. Based on the XX and XY gonadal transcriptome data from four developmental stages, 65 NRs were detected in gonads, with 21, 31, 11 and 29 expressed sexual dimorphically at 5, 30, 90 and 180days after hatching, respectively. The expression of four selected genes was examined by in situ hybridization (ISH) and quantitative PCR (qPCR) to validate the spatial and temporal expression profiles of NRs. Comparative analyses of the expression profiles of duplicated NRs revealed divergence in gene expression as well as gene function. Our results demonstrated that NRs may play important roles in sex determination and gonadal development in teleosts.
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Affiliation(s)
- Yun-Ying Cheng
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, 400715, Chongqing, PR China
| | - Wen-Jing Tao
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, 400715, Chongqing, PR China
| | - Jin-Lin Chen
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, 400715, Chongqing, PR China
| | - Li-Na Sun
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, 400715, Chongqing, PR China
| | - Lin-Yan Zhou
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, 400715, Chongqing, PR China
| | - Qiang Song
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, 400715, Chongqing, PR China
| | - De-Shou Wang
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, 400715, Chongqing, PR China.
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12
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Chen L, Chu C, Kong X, Huang G, Huang T, Cai YD. A hybrid computational method for the discovery of novel reproduction-related genes. PLoS One 2015; 10:e0117090. [PMID: 25768094 PMCID: PMC4358884 DOI: 10.1371/journal.pone.0117090] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 12/13/2014] [Indexed: 12/12/2022] Open
Abstract
Uncovering the molecular mechanisms underlying reproduction is of great importance to infertility treatment and to the generation of healthy offspring. In this study, we discovered novel reproduction-related genes with a hybrid computational method, integrating three different types of method, which offered new clues for further reproduction research. This method was first executed on a weighted graph, constructed based on known protein-protein interactions, to search the shortest paths connecting any two known reproduction-related genes. Genes occurring in these paths were deemed to have a special relationship with reproduction. These newly discovered genes were filtered with a randomization test. Then, the remaining genes were further selected according to their associations with known reproduction-related genes measured by protein-protein interaction score and alignment score obtained by BLAST. The in-depth analysis of the high confidence novel reproduction genes revealed hidden mechanisms of reproduction and provided guidelines for further experimental validations.
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Affiliation(s)
- Lei Chen
- College of Information Engineering, Shanghai Maritime University, Shanghai, 201306, People’s Republic of China
| | - Chen Chu
- State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, People’s Republic of China
| | - Xiangyin Kong
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, People’s Republic of China
| | - Guohua Huang
- Institute of Systems Biology, Shanghai University, Shanghai, 200444, People’s Republic of China
| | - Tao Huang
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, People’s Republic of China
- * E-mail: (TH); (YDC)
| | - Yu-Dong Cai
- Institute of Systems Biology, Shanghai University, Shanghai, 200444, People’s Republic of China
- * E-mail: (TH); (YDC)
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13
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Sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells in mice. Sci Rep 2015; 5:8055. [PMID: 25623887 PMCID: PMC4306913 DOI: 10.1038/srep08055] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 01/02/2015] [Indexed: 01/07/2023] Open
Abstract
We evaluated the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells. Adult C57BL/6 mice were daily exposed to 0, 2, 10, 50, and 250 mGy γ-ray for 1 month in succession, respectively. The damage of hematopoietic stem/progenitor cells in bone marrow were investigated within 2 hours (acute phase) or at 3 months (chronic phase) after the last exposure. Daily exposure to over 10 mGy γ-ray significantly decreased the number and colony-forming capacity of hematopoietic stem/progenitor cells at acute phase, and did not completely recover at chronic phase with 250 mGy exposure. Interestingly, the daily exposure to 10 or 50 mGy γ-ray decreased the formation of mixed types of colonies at chronic phase, but the total number of colonies was comparable to control. Immunostaining analysis showed that the formation of 53BP1 foci in c-kit+ stem/progenitor cells was significantly increased with daily exposure to 50 and 250 mGy at acute phase, and 250 mGy at chronic phase. Many genes involved in toxicity responses were up- or down-regulated with the exposures to all doses. Our data have clearly shown the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells of mice with daily exposures to 2 ~ 250 mGy γ-ray.
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14
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Abstract
Bile acids (BAs) are not only facilitators participating in the absorption of dietary lipids and soluble vitamins, but are also important signaling molecules exerting versatile biophysiological effects. Three major signaling pathways, including the MAPK pathways, the nuclear hormone receptor farnesoid X receptor a-mediated pathways and the G protein-coupled receptor TGR5/M-BAR-mediated pathways, have been identified to be the targets of BAs. BAs, the biologically many-sided and toxic molecules, regulate the homeostasis of themselves via these signaling pathways. BAs also affect diverse metabolic status including glucose metabolism, lipid metabolism, energy expenditure, immunity and others. BAs and their related signaling mechanisms are attractive therapeutic targets of various diseases such as metabolic syndrome.
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Affiliation(s)
- Kohkichi Morimoto
- a Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Hiroshi Itoh
- a Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
- b Graduate School of Media and Governance, Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan.
| | - Mitsuhiro Watanabe
- a Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
- b Graduate School of Media and Governance, Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan.
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15
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Zhang Y, Andrews GK, Wang L. Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP. Nucleic Acids Res 2012; 40:4850-60. [PMID: 22362755 PMCID: PMC3367194 DOI: 10.1093/nar/gks159] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 01/24/2012] [Accepted: 01/28/2012] [Indexed: 11/14/2022] Open
Abstract
Dnmt1 is frequently overexpressed in cancers, which contributes significantly to cancer-associated epigenetic silencing of tumor suppressor genes. However, the mechanism of Dnmt1 overexpression remains elusive. Herein, we elucidate a pathway through which nuclear receptor SHP inhibits zinc-dependent induction of Dnmt1 by antagonizing metal-responsive transcription factor-1 (MTF-1). Zinc treatment induces Dnmt1 transcription by increasing the occupancy of MTF-1 on the Dnmt1 promoter while decreasing SHP expression. SHP in turn represses MTF-1 expression and abolishes zinc-mediated changes in the chromatin configuration of the Dnmt1 promoter. Dnmt1 expression is increased in SHP-knockout (sko) mice but decreased in SHP-transgenic (stg) mice. In human hepatocellular carcinoma (HCC), increased DNMT1 expression is negatively correlated with SHP levels. Our study provides a molecular explanation for increased Dnmt1 expression in HCC and highlights SHP as a potential therapeutic target.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Cell Line
- Cell Line, Tumor
- DNA (Cytosine-5-)-Methyltransferase 1
- DNA (Cytosine-5-)-Methyltransferases/biosynthesis
- DNA (Cytosine-5-)-Methyltransferases/genetics
- DNA (Cytosine-5-)-Methyltransferases/metabolism
- DNA-Binding Proteins/antagonists & inhibitors
- DNA-Binding Proteins/metabolism
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Hepatocytes/enzymology
- Humans
- Liver/enzymology
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Mice
- Mice, Knockout
- Mice, Transgenic
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Repressor Proteins/metabolism
- Transcription Factors/antagonists & inhibitors
- Transcription Factors/metabolism
- Transcription, Genetic/drug effects
- Zinc/pharmacology
- Transcription Factor MTF-1
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Affiliation(s)
- Yuxia Zhang
- Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 and Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Glen K. Andrews
- Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 and Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Li Wang
- Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 and Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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16
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A pleiotropic role for the orphan nuclear receptor small heterodimer partner in lipid homeostasis and metabolic pathways. J Lipids 2012; 2012:304292. [PMID: 22577560 PMCID: PMC3346990 DOI: 10.1155/2012/304292] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 12/05/2011] [Indexed: 12/29/2022] Open
Abstract
Nuclear receptors (NRs) comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. Small heterodimer partner (SHP; NR0B2) is a unique orphan NR lacking a DNA-binding domain but contains a putative ligand-binding domain. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. About half of all mammalian NRs and several transcriptional coregulators can interact with SHP. The SHP-mediated repression of target transcription factors includes at least three mechanisms including direct interference with the C-terminal activation function 2 (AF2) coactivator domains of NRs, recruitment of corepressors, or direct interaction with the surface of NR/transcription factors. Future research must focus on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities. Current understanding about the pleiotropic role of SHP is examined in this paper, and principal metabolic aspects connected with SHP function will be also discussed.
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17
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Yang Z, Wang L. An autoregulatory feedback loop between Mdm2 and SHP that fine tunes Mdm2 and SHP stability. FEBS Lett 2012; 586:1135-40. [PMID: 22575647 DOI: 10.1016/j.febslet.2012.03.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 03/06/2012] [Accepted: 03/12/2012] [Indexed: 02/07/2023]
Abstract
Mdm2 is a crucial negative regulator of the tumor suppressor function of p53. However, little is known about Mdm2 protein stability regulation by other tumor suppressors. Nuclear receptor small heterodimer partner (SHP, NROB2) functions as a tumor suppressor in liver cancer. We show here a surprising finding of a feedback regulatory loop between SHP and Mdm2. SHP stabilizes Mdm2 protein by abrogating Mdm2 self-ubiquitination, and Mdm2 in turn attenuates SHP protein levels under p53-deficient conditions. Such cross-regulation critically depends on the physical interaction of SHP with Mdm2 through the SHP K170 residue. The Mdm2-SHP interplay represents a novel component of Mdm2 signaling that is likely to dictate Mdm2 activity and function.
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Affiliation(s)
- Zhihong Yang
- Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, United States
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18
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Wilczek E, Szparecki G, Lukasik D, Koperski L, Winiarska M, Wilczynski GM, Wasiutynski A, Gornicka B. Loss of the orphan nuclear receptor SHP is more pronounced in fibrolamellar carcinoma than in typical hepatocellular carcinoma. PLoS One 2012; 7:e30944. [PMID: 22292081 PMCID: PMC3264646 DOI: 10.1371/journal.pone.0030944] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 12/27/2011] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major problem in oncology. The molecular mechanisms which underlie its pathogenesis are poorly understood. Recently the Small Heterodimer Partner (SHP), an orphan nuclear receptor, was suggested to be involved as a tumor suppressor in hepatocellular carcinoma development. To date, there are no such studies regarding fibrolamellar carcinoma, a less common variant of HCC, which usually affects young people and displays distinct morphological features. The aim of our project was to evaluate the SHP levels in typical and fibrolamellar hepatocellular carcinoma with respect to the levels of one of the cell cycle regulators, cyclin D1. We assessed the immunoreactivity levels of SHP and cyclin D1 in 48 typical hepatocellular carcinomas, 9 tumors representing the fibrolamellar variant, 29 non malignant liver tissues and 7 macroregenerative nodules. We detected significantly lower SHP immunoreactivity in hepatocellular carcinoma when compared to non malignant liver tissue. Moreover, we found that SHP immunoreactivity is reduced in fibrolamellar carcinoma when compared to typical hepatocellular carcinoma. We also found that SHP is more commonly lost in HCC which arises in the liver with steatosis. The comparison between the cyclin D1 and SHP expression revealed the negative correlation between these proteins in the high grade HCC. Our results indicate that the impact of loss of SHP protein may be even more pronounced in fibrolamellar carcinoma than in a typical form of HCC. Further investigation of mechanisms through which the loss of SHP function may influence HCC formation may provide important information in order to design more effective HCC therapy.
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Affiliation(s)
- Ewa Wilczek
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland.
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19
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Nuclear receptor small heterodimer partner in apoptosis signaling and liver cancer. Cancers (Basel) 2011; 3:198-212. [PMID: 24212613 PMCID: PMC3756356 DOI: 10.3390/cancers3010198] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Revised: 12/30/2010] [Accepted: 01/04/2011] [Indexed: 01/01/2023] Open
Abstract
Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction with multiple nuclear receptors and transcriptional factors. SHP is a critical transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology. Recently, we and others have demonstrated that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer. In this review, we summarize recent major findings regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer. Future study will be focused on identifying SHP associated novel pro-oncogenes and anti-oncogenes in liver cancer progression and applying the knowledge gained on SHP in liver cancer prevention, diagnosis and treatment.
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