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Samban SS, Hari A, Nair B, Kumar AR, Meyer BS, Valsan A, Vijayakurup V, Nath LR. An Insight Into the Role of Alpha-Fetoprotein (AFP) in the Development and Progression of Hepatocellular Carcinoma. Mol Biotechnol 2024; 66:2697-2709. [PMID: 37782430 DOI: 10.1007/s12033-023-00890-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 09/04/2023] [Indexed: 10/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the primary malignancy of hepatocytes and the second most common cause of cancer-related mortality across the globe. Despite significant advancements in screening, diagnosis, and treatment modalities for HCC, the mortality-to-incidence ratio remain unacceptably high. A recent study indicates that a minor population of HCCs are AFP negative or express the normal range of AFP levels. Although it is a gold standard and a more reliable biomarker in the advanced stage of HCC and poorly differentiated tumors, it does not serve as a suitable means for screening HCC. AFP plays a significant role in the development and progression of HCC and understanding its role is crucial. By examining the molecular mechanisms involved in AFP-mediated tumorigenesis, we can better understand HCC pathogenesis and identify potential therapeutic targets. This article details the role of alpha-fetoprotein (AFP) in the carcinogenic transformation of hepatocytes. The article also focuses on information about the structure, biosynthesis, and regulation of AFP at the gene level. Additionally, it discusses the immune evasion, metastasis, and control of gene expression that AFP mediates during HCC.
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Affiliation(s)
- Swathy S Samban
- Department of Pharmacognosy, Amrita School of Pharmacy, AIMS Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara P.O., Kochi, Kerala, India
| | - Aparna Hari
- Department of Pharmacognosy, Amrita School of Pharmacy, AIMS Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara P.O., Kochi, Kerala, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, AIMS Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara P.O., Kochi, Kerala, India
| | - Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, AIMS Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara P.O., Kochi, Kerala, India
| | - Benjamin S Meyer
- Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, 32610, USA
| | - Arun Valsan
- Department of Gastroenterology and Hepatology, Amrita Institute of Medical Science, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala, India
| | - Vinod Vijayakurup
- Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, 32610, USA.
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, AIMS Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara P.O., Kochi, Kerala, India.
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2
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Liu J, Zhang H. Zinc Finger and BTB Domain-Containing 20: A Newly Emerging Player in Pathogenesis and Development of Human Cancers. Biomolecules 2024; 14:192. [PMID: 38397429 PMCID: PMC10887282 DOI: 10.3390/biom14020192] [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: 01/12/2024] [Revised: 01/30/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Zinc finger and BTB domain-containing 20 (ZBTB20), which was initially identified in human dendritic cells, belongs to a family of transcription factors (TFs) with an N-terminal BTB domain and one or more C-terminal DNA-binding zinc finger domains. Under physiological conditions, ZBTB20 acts as a transcriptional repressor in cellular development and differentiation, metabolism, and innate immunity. Interestingly, multiple lines of evidence from mice and human systems have revealed the importance of ZBTB20 in the pathogenesis and development of cancers. ZBTB20 is not only a hotspot of genetic variation or fusion in many types of human cancers, but also a key TF or intermediator involving in the dysregulation of cancer cells. Given the diverse functions of ZBTB20 in both health and disease, we herein summarize the structure and physiological roles of ZBTB20, with an emphasis on the latest findings on tumorigenesis and cancer progression.
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Affiliation(s)
| | - Han Zhang
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China;
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Stoyanov D, Stoyanov GS, Ivanov MN, Spasov RH, Tonchev AB. Transcription Factor Zbtb20 as a Regulator of Malignancy and Its Practical Applications. Int J Mol Sci 2023; 24:13763. [PMID: 37762065 PMCID: PMC10530547 DOI: 10.3390/ijms241813763] [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: 08/03/2023] [Revised: 08/30/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
Zbtb20 (zinc finger and BTB domain-containing protein 20) is a transcription factor with a zinc finger DNA binding domain and a BTB domain responsible for protein-protein interaction. Recently, this TF has received attention because new data showed its pivotal involvement in normal neural development and its regulatory effects on proliferation and differentiation in different tissues. Zbtb20 was shown to increase proliferation and migration and confer resistance to apoptosis in the contexts of many malignant tumors like hepatocellular carcinoma, non-small-cell lung carcinoma, gastric adenocarcinoma, glioblastoma multiforme, breast cancer, and acute myeloid leukemia. The involvement of Zbtb20 in tumor biology is best studied in hepatocellular carcinoma, where it is a promising candidate as an immunohistochemical tumor marker or may be used in patient screening. Here we review the current data connecting Zbtb20 with malignant tumors.
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Affiliation(s)
- Dimo Stoyanov
- Department of Anatomy and Cell Biology, Medical University of Varna, 9000 Varna, Bulgaria
| | - George S. Stoyanov
- Department of Clinical Pathology, Complex Oncology Center, 9700 Shumen, Bulgaria
| | - Martin N. Ivanov
- Department of Anatomy and Cell Biology, Medical University of Varna, 9000 Varna, Bulgaria
- Department of Stem Cell Biology, Research Institute, Medical University of Varna, 9000 Varna, Bulgaria
| | - Radoslav H. Spasov
- Department of Anatomy and Cell Biology, Medical University of Varna, 9000 Varna, Bulgaria
| | - Anton B. Tonchev
- Department of Anatomy and Cell Biology, Medical University of Varna, 9000 Varna, Bulgaria
- Department of Stem Cell Biology, Research Institute, Medical University of Varna, 9000 Varna, Bulgaria
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Zhang J, Zhang T, Guan G, Wen J, Chen CC, Liu J, Duan Y, Liu Y, Chen X. AUF1 promotes hepatocellular carcinoma progression and chemo-resistance by post-transcriptionally upregulating alpha-fetoprotein expression. Pathol Res Pract 2023; 245:154441. [PMID: 37060820 DOI: 10.1016/j.prp.2023.154441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/28/2023] [Accepted: 04/02/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND The target genes of AU-rich Element RNA-binding Protein 1 (AUF1), which is an RNA binding protein, and its role in the progression of hepatocellular carcinoma (HCC) is still elusive. This study aims to investigate the biological function and the underlying target genes of AUF1 in HCC. METHODS RNA sequencing data and the Liver Cancer Institute (LCI) database were used to screen candidate targets of AUF1. LCI database, TCGA database, and a retrospective HCC cohort were used to investigate the correlation between AUF1 and alpha-fetoprotein (AFP) and their prognostic values in HCC patients. Huh-7, HepG2, and HepAD38 cell lines were used to investigate the underlying mechanism of AUF1 regulating the AFP expression. Cell Counting Kit-8, colony formation, EdU incorporation, and flow cytometry assays were performed to detect the effect of AUF1-AFP axis on the progression and doxorubicin resistance of HCC cells. RESULTS A combined analysis of the transcriptome data from Huh-7 cells after knockdown of AUF1 and gene expression data from LCI database revealed that AFP was the most significantly downregulated gene after AUF1 depletion. AUF1 expression was positively associated with AFP expression in HCC tissues and the high expression of both AUF1 and AFP were correlated with a worse prognosis in HCC patients of LCI and TCGA databases, as well as our retrospective cohort. Mechanistically, AUF1 bound to the 3' untranslation region (UTR) of AFP mRNA to enhance the mRNA stability of AFP, thereby upregulating AFP. Functional tests showed that AFP knockdown inhibited tumor growth and doxorubicin resistance of HCC cells induced by AUF1. CONCLUSIONS AFP may be an important target gene of AUF1. AUF1 promoted HCC progression and doxorubicin resistance by upregulating AFP expression via increasing its mRNA stability.
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Affiliation(s)
- Jing Zhang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Ting Zhang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Guiwen Guan
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jiyun Wen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Chia-Chen Chen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jia Liu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yuan Duan
- School of Medicine, Shihezi University, Shihezi 832002, China
| | - Yanna Liu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Gastroenterology and Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
| | - Xiangmei Chen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; School of Medicine, Shihezi University, Shihezi 832002, China.
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Chen YF, Liu SY, Cheng QJ, Wang YJ, Chen S, Zhou YY, Liu X, Jiang ZG, Zhong WW, He YH. Intracellular alpha-fetoprotein mitigates hepatocyte apoptosis and necroptosis by inhibiting endoplasmic reticulum stress. World J Gastroenterol 2022; 28:3201-3217. [PMID: 36051342 PMCID: PMC9331527 DOI: 10.3748/wjg.v28.i26.3201] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/22/2022] [Accepted: 05/13/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Endoplasmic reticulum (ER) stress contributes to the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified. Alpha-fetoprotein (AFP) is secreted by hepatoma cells and elevated levels of serum AFP are associated with development of liver malignancies. AIM To investigate whether and how AFP could regulate ER stress and hepatocyte injury. METHODS The distribution of AFP and the degrees of ER stress in liver tissues and liver injury were characterized by histology, immunohistochemistry, and Western blot in biopsied human liver specimens, two mouse models of liver injury and a cellular model. The levels of AFP in sera and the supernatants of cultured cells were quantified by chemiluminescence. RESULTS High levels of intracellular AFP were detected in liver tissues, particularly in the necrotic areas, from patients with chronic liver diseases and mice after carbon tetrachloride (CCl4) administration or induction of ER stress, but not from the controls. The induced intracellular AFP was accompanied by elevated activating transcription factor-6 (ATF6) expression and protein kinase R-like ER kinase (PERK) phosphorylation in mouse livers. ER stress induced AFP expression in LO2 cells and decreased their viability. ATF6, but not PERK, silencing mitigated the ER-stress-induced AFP expression in LO2 cells. Conversely, AFP silencing deteriorated the ER stress-mediated LO2 cell injury and CCl4 administration-induced liver damages by increasing levels of cleaved caspase-3, the C/enhancer binding protein homologous protein expression, mixed lineage kinase domain-like pseudokinase and PERK phosphorylation, but decreasing ATF6 expression. CONCLUSION ER stress upregulated intra-hepatocyte AFP expression by activating ATF6 during the process of liver injury and intracellular AFP attenuated hepatocyte apoptosis and necroptosis by alleviating ER stress.
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Affiliation(s)
- Yun-Fen Chen
- Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Si-Ying Liu
- Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Qi-Jiao Cheng
- Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yu-Jiao Wang
- Department of General Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Shuang Chen
- Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yi-Yang Zhou
- Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Xia Liu
- Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Zhi-Gang Jiang
- School of Public Health, Zunyi Medical University, Zunyi 563099, Guizhou Province, China
| | - Wei-Wei Zhong
- Department of Endoscopy, Jingmen No.1 People’s Hospital, Jingmen 448000, Hubei Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Li H, Liu G, Wan X, Zhou L, Qin ZB, Ma XH, Su K, Liu YJ, Yuan J, Wei CC, Ren AJ, Chen YX, Young SG, Zhang H, Xie Z, Zhang WJ. The zinc finger and BTB domain containing protein ZBTB20 regulates plasma triglyceride metabolism by repressing lipoprotein lipase gene transcription in hepatocytes. Hepatology 2022; 75:1169-1180. [PMID: 34580885 PMCID: PMC9118135 DOI: 10.1002/hep.32176] [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: 08/04/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Lipoprotein lipase (LPL) is responsible for the lipolytic processing of triglyceride-rich lipoproteins, the deficiency of which causes severe hypertriglyceridemia. Liver LPL expression is high in suckling rodents but relatively low at adulthood. However, the regulatory mechanism and functional significance of liver LPL expression are incompletely understood. We have established the zinc finger protein ZBTB20 as a critical factor for hepatic lipogenesis. Here, we evaluated the role of ZBTB20 in regulating liver Lpl gene transcription and plasma triglyceride metabolism. APPROACH AND RESULTS Hepatocyte-specific inactivation of ZBTB20 in mice led to a remarkable increase in LPL expression at the mRNA and protein levels in adult liver, in which LPL protein was mainly localized onto sinusoidal epithelial cells and Kupffer cells. As a result, the LPL activity in postheparin plasma was substantially increased, and postprandial plasma triglyceride clearance was significantly enhanced, whereas plasma triglyceride levels were decreased. The dysregulated liver LPL expression and low plasma triglyceride levels in ZBTB20-deficient mice were normalized by inactivating hepatic LPL expression. ZBTB20 deficiency protected the mice against high-fat diet-induced hyperlipidemia without causing excessive triglyceride accumulation in the liver. Chromatin immunoprecipitation and gel-shift assay studies revealed that ZBTB20 binds to the LPL promoter in the liver. A luciferase reporter assay revealed that ZBTB20 inhibits the transcriptional activity of LPL promoter. The regulation of LPL expression by ZBTB20 is liver-specific under physiological conditions. CONCLUSIONS Liver ZBTB20 serves as a key regulator of LPL expression and plasma triglyceride metabolism and could be a therapeutic target for hypertriglyceridemia.
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Affiliation(s)
- Hao Li
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Gan Liu
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Xiaoqing Wan
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Luting Zhou
- Department of Pathophysiology, Naval Medical University, Shanghai, China
- Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhen-Bang Qin
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xian-Hua Ma
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Kai Su
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Ya-Jin Liu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Jinghao Yuan
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Chun-Chun Wei
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - An-Jing Ren
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Yu-Xia Chen
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Stephen G. Young
- Departments of Medicine and Human Genetics, University of California, Los Angeles, USA
| | - Hai Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Zhifang Xie
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Weiping J. Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai, China
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
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Zhang C, Zhao HJ, Wang J, Zhou WY, Zhang TJ, Zhang CB. Structural Analysis of the 5'-Flanking Region of Human Alpha-Fetoprotein Encoding Gene. Mol Biol 2021; 55:863-869. [DOI: 10.1134/s0026893321050174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 04/16/2021] [Accepted: 05/19/2021] [Indexed: 01/12/2025]
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Xu Y, Guo Q, Wei L. The Emerging Influences of Alpha-Fetoprotein in the Tumorigenesis and Progression of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13205096. [PMID: 34680245 PMCID: PMC8534193 DOI: 10.3390/cancers13205096] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/01/2021] [Accepted: 10/07/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and its mortality rate is the third-highest, after lung cancer and colorectal cancer. Currently, systematic targeted therapies for HCC mainly include multiple kinase inhibitors and immunotherapy. However, these drugs carry a black-box warning about the potential for inducing severe toxicity, and they do not significantly prolong the survival period of patients due to the highly heterogeneous characteristics of HCC etiology. In order to improve the prediction, effective treatment and prognosis of HCC, the tools and different biomarkers in clinical practices are recommended. Alpha-fetoprotein (AFP) is the earliest and the most widely used serum marker in the detection of HCC. Interestingly, serum AFP and cytoplasmic AFP show different, even opposite, roles in the cancer progression of HCC. This review focuses on biological characteristics, regulatory mechanisms for gene expression, emerging influences of AFP in HCC and its possible implications in HCC-targeted therapy.
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Affiliation(s)
| | | | - Libin Wei
- Correspondence: ; Tel./Fax: +86-25-83271055
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Hayashi M, Yamada S, Takano N, Okamura Y, Takami H, Inokawa Y, Sonohara F, Tanaka N, Shimizu D, Hattori N, Kanda M, Tanaka C, Nakayama G, Koike M, Kodera Y. Different Characteristics of Serum Alfa Fetoprotein and Serum Des-gamma-carboxy Prothrombin in Resected Hepatocellular Carcinoma. In Vivo 2021; 35:1749-1760. [PMID: 33910859 DOI: 10.21873/invivo.12434] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/06/2021] [Accepted: 02/10/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM Hepatocellular carcinoma (HCC) mainly develops in the damaged liver from hepatitis C virus (HCV) or hepatitis B virus (HBV) infection in Japan. On the other hand, the occurrence of HCCs derived from the liver without viral infection has recently been increasing. Our aim was to identify characteristics specific to HCCs with virus-infected liver (HCC-BC) or those with non-B- and non-C-infected liver (HCC-NBNC), Patients and Methods: We collected preoperative serum α-fetoprotein (AFP) and Des-Gamma-Carboxy Prothrombin (DCP), also known as PIVKA-II values from surgically resected HCC cases during 1994-2017 in our department. RESULTS Preoperative serum AFP values of HCC-BC cases (n=284) were higher compared to HCC-NBNC cases (n=88) (p=0.016), whereas serum DCP values of HCC-NBNC cases were higher compared to HCC-BC cases (p<0.001). Multivariable analyses indicated that abnormal serum AFP [hazard ratio (HR)=1.46, 95% conficdence interval (CI)=1.03-2.07, p=0.035) was one of the significant recurrence-free survival predictors of HCC-BC cases, while abnormal serum DCP (HR=4.99, 95%CI=1.91-13.01, p=0.001) was one of the significant recurrence-free survival predictors of HCC-NBNC cases. CONCLUSION HCC-NBNC cases have a different tumor marker profile from HCC-BC cases. Elevated DCP could be both a diagnostic and prognostic marker of HCC-NBNC patients.
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Affiliation(s)
- Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan;
| | - Nao Takano
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukiyasu Okamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobutake Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norifumi Hattori
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Shen S, Feng H, Liu L, Su W, Yu L, Wu J. TCP10L negatively regulates alpha-fetoprotein expression in hepatocellular carcinoma. BMB Rep 2021. [PMID: 32438969 PMCID: PMC7473475 DOI: 10.5483/bmbrep.2020.53.8.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Alpha-fetoprotein (AFP) is one of the most commonly used and reliable biomarkers for Hepatocellular carcinoma（HCC). However, the underlying mechanism of AFP expression in HCC is poorly understood. In this study, we found that TCP10L, a gene specifically expressed in the liver, is down-regulated in HCC and that its expression inversely correlates with AFP expression. Moreover, overexpression of TCP10L suppresses AFP expression whereas knockdown of TCP10L increases AFP ex-pression, suggesting that TCP10L might be a negative regulator of AFP. We found that TCP10L is associated with the AFP promoter and inhibits AFP promoter-driven transcriptional acti-vity. Taken together, these results indicate that TCP10L nega-tively regulates AFP expression in HCC and that it could be a potential prognostic marker and therapeutic target for HCC.
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Affiliation(s)
- Suqin Shen
- The State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Science, Fudan University, Shanghai 200438, China
| | - Huan Feng
- The State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Science, Fudan University, Shanghai 200438, China
| | - Longjiang Liu
- The State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Science, Fudan University, Shanghai 200438, China
| | - Wei Su
- The State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Science, Fudan University, Shanghai 200438, China
| | - Long Yu
- The State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Science, Fudan University, Shanghai 200438, China
| | - Jiaxue Wu
- The State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Science, Fudan University, Shanghai 200438, China
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11
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Zheng Y, Zhu M, Li M. Effects of alpha-fetoprotein on the occurrence and progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 2020; 146:2439-2446. [DOI: 10.1007/s00432-020-03331-6] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023]
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12
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Melis D, Carvalho D, Barbaro-Dieber T, Espay AJ, Gambello MJ, Gener B, Gerkes E, Hitzert MM, Hove HB, Jansen S, Jira PE, Lachlan K, Menke LA, Narayanan V, Ortiz D, Overwater E, Posmyk R, Ramsey K, Rossi A, Sandoval RL, Stumpel C, Stuurman KE, Cordeddu V, Turnpenny P, Strisciuglio P, Tartaglia M, Unger S, Waters T, Turnbull C, Hennekam RC. Primrose syndrome: Characterization of the phenotype in 42 patients. Clin Genet 2020; 97:890-901. [PMID: 32266967 PMCID: PMC7384157 DOI: 10.1111/cge.13749] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/20/2020] [Accepted: 03/24/2020] [Indexed: 12/13/2022]
Abstract
Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down‐slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha‐fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype‐phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
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Affiliation(s)
- Daniela Melis
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Salerno, Italy.,Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Daniel Carvalho
- Medical Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasilia, Brazil
| | | | - Alberto J Espay
- Department of Neurology, University of Cincinnati, Gardner Family Center for Parkinson's Disease and Movement Disorders, Cincinnati, Ohio, USA
| | - Michael J Gambello
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Blanca Gener
- Department of Genetics, BioCruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, Spain
| | - Erica Gerkes
- Department of Genetics, University of Groningen, UMC Groningen, Groningen, The Netherlands
| | - Marrit M Hitzert
- Department of Genetics, University of Groningen, UMC Groningen, Groningen, The Netherlands
| | - Hanne B Hove
- Department of Pediatrics, Division of Rare Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sandra Jansen
- Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands
| | - Petr E Jira
- Department of Pediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands
| | - Katherine Lachlan
- Wessex Clinical Genetics Service, University Hospitals of Southampton NHS Trust, Southampton, UK
| | - Leonie A Menke
- Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands
| | - Vinodh Narayanan
- Translational Genomic Research Institute, Center for Rare Childhood Disorders, Phoenix, Arizona, USA
| | - Damara Ortiz
- Medical Genetics Department, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pensylvania, USA
| | - Eline Overwater
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Renata Posmyk
- Department of Clinical Genetics, Podlaskie Medical Center, Bialystok, Poland
| | - Keri Ramsey
- Translational Genomic Research Institute, Center for Rare Childhood Disorders, Phoenix, Arizona, USA
| | - Alessandro Rossi
- Department of Translational Medical Science, Federico II University, Naples, Italy
| | | | - Constance Stumpel
- Department of Clinical Genetics and GROW School for Oncology and Developmental Biology, Maastricht UMC, Maastricht, The Netherlands
| | - Kyra E Stuurman
- Department of Clinical Genetics Erasmus Medical Center, Rotterdam, The Netherlands
| | - Viviana Cordeddu
- Department of Hematology, Oncology and Molecular Medicine, National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Peter Turnpenny
- Clinical Genetics Department, Royal Devon & Exeter Healthcare NHS, Exeter, UK
| | - Pietro Strisciuglio
- Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Sheela Unger
- Division of Genetic Medicine, University of Lausanne, Lausanne, Switzerland
| | - Todd Waters
- North Florida Regional Medical Center, Gainesville, Florida, USA
| | - Clare Turnbull
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Raoul C Hennekam
- Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands
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13
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Li G, Ma X, Xu L. The roles of zinc finger proteins in non-alcoholic fatty liver disease. LIVER RESEARCH 2020. [DOI: 10.1016/j.livres.2020.01.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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14
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Lin YH, Wu MH, Huang YH, Yeh CT, Lin KH. TUG1 Is a Regulator of AFP and Serves as Prognostic Marker in Non-Hepatitis B Non-Hepatitis C Hepatocellular Carcinoma. Cells 2020; 9:cells9020262. [PMID: 31973032 PMCID: PMC7072672 DOI: 10.3390/cells9020262] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/17/2020] [Accepted: 01/19/2020] [Indexed: 02/07/2023] Open
Abstract
Thyroid hormone (T3) and its receptor (TR) are involved in cell metabolism and cancer progression. Hypothyroidism is associated with significantly elevated risk of hepatocellular carcinoma (HCC). Levels of the glycoprotein alpha-fetoprotein (AFP) are increased in the majority of patients with HCC and may be useful in diagnosis and follow-up. However, the relationship between T3/TR and AFP levels in HCC is currently unclear. The expression profiles of long non-coding RNAs (lncRNAs) were compared in microarrays of HepG2-TRα1 cells treated with/without T3 and HCC specimens. The effects of T3 on taurine upregulated gene 1 (TUG1) and AFP expression were validated using qRT-PCR. A correlation between TUG1 and AFP was confirmed via RNAi and clustered regularly interspaced short palindromic repeats (CRISPR) strategies. Finally, overall and recurrence-free survival rates were analyzed using the Kaplan–Meier method and confirmed in online datasets. T3/TR treatment reduced TUG1 expression in vitro, resulting in the downregulation of AFP mRNA. Knockdown of TUG1 suppressed cell cycle progression and soft agar colony formation and induced cellular senescence. Our data support the involvement of TUG1 in the T3/TR-mediated suppression of cell growth. AFP mRNA levels showed strong positive correlations with TUG1 and unfavorable prognosis in patients with non-hepatitis B/non-hepatitis C HCC (NBNC-HCC). T3/TR, TUG1, and AFP may potentially serve as effective prognostic markers for NBNC-HCC.
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Affiliation(s)
- Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
- Department of Biochemistry, College of Medicine, Chang Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan;
| | - Meng-Han Wu
- Department of Biochemistry, College of Medicine, Chang Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan;
| | - Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
- Correspondence: (C.-T.Y.); (K.-H.L.); Tel./Fax: +886-3-2118263 (K.-H.L.)
| | - Kwang-Huei Lin
- Liver Research Center, Chang Gung Memorial Hospital, 15 Wen-hwa 1 Road, Linkou, Taoyuan 333, Taiwan; (Y.-H.L.); (Y.-H.H.)
- Department of Biochemistry, College of Medicine, Chang Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan;
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: (C.-T.Y.); (K.-H.L.); Tel./Fax: +886-3-2118263 (K.-H.L.)
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15
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Vriend J, Tate RB. Differential Expression of Genes for Ubiquitin Ligases in Medulloblastoma Subtypes. THE CEREBELLUM 2019; 18:469-488. [PMID: 30810905 DOI: 10.1007/s12311-019-1009-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Using publically available datasets on gene expression in medulloblastoma (MB) subtypes, we selected genes for ubiquitin ligases and identified statistically those that best predicted each of the four major MB subgroups as separate disease entities. We identify a gene coding for an ubiquitin ligase, ZNRF3, whose overexpression alone can predict the WNT subgroup for 100% in the Pfister dataset. For the SHH subgroup, we identify a gene for a regulatory subunit of the protein phosphatase 2A (PP2A), PPP2R2C, as the major predictor among the E3 ligases genes. The ubiquitin and ubiquitin-like conjugation database (UUCD) lists PPP2R2C as coding for a Cullin Ring ubiquitin ligase adaptor. For group 3 MBs, the best ubiquitin ligase predictor was PPP2R2B, a gene which codes for another regulatory subunit of the PP2A holoenzyme. For group 4, the best E3 gene predictors were MID2, ZBTB18, and PPP2R2A, which codes for a third PP2A regulatory subunit. Heatmap analysis of the E3 gene data shows that expression of ten genes for ubiquitin ligases can be used to classify MBs into the four major consensus subgroups. This was illustrated by analysis of gene expression of ubiquitin ligases of the Pfister dataset and confirmed in the dataset of Cavalli. We conclude that genes for ubiquitin ligases can be used as genetic markers for MB subtypes and that the proteins coded for by these genes should be investigated as subtype specific therapeutic targets for MB.
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Affiliation(s)
- Jerry Vriend
- Department of Human Anatomy & Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Rm134, BMSB, 745 Bannatyne Avenue, Winnipeg, Manitoba, R3E 0J9, Canada.
| | - Robert B Tate
- Department of Community Health Sciences, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
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16
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Fine Tuning of Hepatocyte Differentiation from Human Embryonic Stem Cells: Growth Factor vs. Small Molecule-Based Approaches. Stem Cells Int 2019; 2019:5968236. [PMID: 30805010 PMCID: PMC6362496 DOI: 10.1155/2019/5968236] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 10/29/2018] [Accepted: 11/13/2018] [Indexed: 12/11/2022] Open
Abstract
Human embryonic stem cells (hESCs) are being utilized in diverse areas of studies such as development and disease modeling, cell replacement therapy, or drug toxicity testing because of their potential to be differentiated into any cell type in the body. The directed differentiation of hESCs into hepatocytes could provide an invaluable source of liver cells for various liver-based applications. Therefore, several protocols have been established in the past for hESC-hepatocyte differentiation based on the knowledge of signaling pathways and growth factors involved in different stages of embryonic hepatogenesis. Although successful derivation of hepatocytes has been achieved through these protocols, the efficiency is not always ideal. Herein, we have tested several combinations of published protocols, for example, growth factor vs. small molecule and different time durations of treatment for definitive endoderm (DE) induction and further hepatocyte differentiation to develop an efficient DE induction and hepatocyte differentiation in a highly reproducible manner based on the stage-specific marker expression and functional analysis.
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17
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Stellacci E, Steindl K, Joset P, Mercurio L, Anselmi M, Cecchetti S, Gogoll L, Zweier M, Hackenberg A, Bocchinfuso G, Stella L, Tartaglia M, Rauch A. Clinical and functional characterization of two novel ZBTB20
mutations causing Primrose syndrome. Hum Mutat 2018; 39:959-964. [DOI: 10.1002/humu.23546] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/23/2018] [Accepted: 04/26/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Emilia Stellacci
- Dipartimento di Oncologia e Medicina Molecolare; Istituto Superiore di Sanità; Rome Italy
| | - Katharina Steindl
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Pascal Joset
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Laura Mercurio
- Dipartimento di Oncologia e Medicina Molecolare; Istituto Superiore di Sanità; Rome Italy
| | - Massimiliano Anselmi
- Dipartimento di Scienze e Tecnologie Chimiche; Università di Roma ‘‘Tor Vergata,’’ Rome; Italy
| | - Serena Cecchetti
- Servizio grandi strumentazioni e core facilities; Istituto Superiore di Sanità; Rome Italy
| | - Laura Gogoll
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Markus Zweier
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Annette Hackenberg
- Division of Paediatric Neurology; University Children's Hospital Zurich; Zürich Switzerland
| | - Gianfranco Bocchinfuso
- Dipartimento di Scienze e Tecnologie Chimiche; Università di Roma ‘‘Tor Vergata,’’ Rome; Italy
| | - Lorenzo Stella
- Dipartimento di Scienze e Tecnologie Chimiche; Università di Roma ‘‘Tor Vergata,’’ Rome; Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division; Ospedale Pediatrico Bambino Gesù; Rome Italy
| | - Anita Rauch
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
- radiz-Rare Disease Initiative Zürich; Clinical Research Priority Program for Rare Diseases University of Zurich; Zurich Switzerland
- Neuroscience Center Zurich; University of Zurich and ETH Zurich; Zurich Switzerland
- Zurich Center for Integrative Human Physiology; University of Zurich; Zurich Switzerland
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18
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Zhang H, Shi JH, Jiang H, Wang K, Lu JY, Jiang X, Ma X, Chen YX, Ren AJ, Zheng J, Xie Z, Guo S, Xu X, Zhang WJ. ZBTB20 regulates EGFR expression and hepatocyte proliferation in mouse liver regeneration. Cell Death Dis 2018; 9:462. [PMID: 29700307 PMCID: PMC5920068 DOI: 10.1038/s41419-018-0514-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 03/21/2018] [Accepted: 03/22/2018] [Indexed: 12/14/2022]
Abstract
Liver has a unique regenerative capacity, however, its regulatory mechanism is not fully defined. We have established the zinc-finger protein ZBTB20 as a key transcriptional repressor for alpha-fetoprotein (AFP) gene in liver. As a marker of hepatic differentiation, AFP expression is closely associated with hepatocyte proliferation. Unexpectedly, here we showed that ZBTB20 acts as a positive regulator of hepatic replication and is required for efficient liver regeneration. The mice specifically lacking ZBTB20 in hepatocytes exhibited a remarkable defect in liver regeneration after partial hepatectomy, which was characterized by impaired hepatocyte proliferation along with delayed cyclin D1 induction and diminished AKT activation. Furthermore, we found that epithelial growth factor receptor (EGFR) expression was dramatically reduced in the liver in the absence of ZBTB20, thereby substantially attenuating the activation of EGFR signaling pathway in regenerating liver. Adenovirus-mediated EGFR overexpression in ZBTB20-deficient hepatocytes could largely restore AKT activation in response to EGFR ligands in vitro, as well as hepatocyte replication in liver regeneration. Furthermore, ZBTB20 overexpression could significantly restore hepatic EGFR expression and cell proliferation after hepatectomy in ZBTB20-deficient liver. Taken together, our data point to ZBTB20 as a critical regulator of EGFR expression and hepatocyte proliferation in mouse liver regeneration, and may serve as a potential therapeutic target in clinical settings of liver regeneration.
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Affiliation(s)
- Hai Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Jian-Hui Shi
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Hui Jiang
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Kejia Wang
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Jun-Yu Lu
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Xuchao Jiang
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Xianhua Ma
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Yu-Xia Chen
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - An-Jing Ren
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Jianming Zheng
- Department of Pathology, Changhai Hospital, Shanghai, 200433, China
| | - Zhifang Xie
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China
| | - Shaodong Guo
- Department of Nutrition and Metabolism, Texas University of Agriculture and Mechanics, College Station, TX, 77843, USA
| | - Xiongfei Xu
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China.
| | - Weiping J Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, China.
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19
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Casertano A, Fontana P, Hennekam RC, Tartaglia M, Genesio R, Dieber TB, Ortega L, Nitsch L, Melis D. Alterations in metabolic patterns have a key role in diagnosis and progression of primrose syndrome. Am J Med Genet A 2017; 173:1896-1902. [DOI: 10.1002/ajmg.a.38124] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 11/18/2016] [Accepted: 12/09/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Alberto Casertano
- Department of Translational Medical Sciences; Section of Pediatrics; Federico II University; Naples Italy
| | - Paolo Fontana
- Department of Molecular Medicine and Medical Biotechnology; Federico II University; Naples Italy
| | - Raoul C. Hennekam
- Department of Pediatrics; Academic Medical Center; University of Amsterdam; Amsterdam the Netherlands
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division; Ospedale pediatrico Bambino Gesù; Rome Italy
| | - Rita Genesio
- Department of Molecular Medicine and Medical Biotechnology; Federico II University; Naples Italy
| | | | | | - Lucio Nitsch
- Department of Molecular Medicine and Medical Biotechnology; Federico II University; Naples Italy
| | - Daniela Melis
- Department of Translational Medical Sciences; Section of Pediatrics; Federico II University; Naples Italy
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20
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Regulation of hepatic lipogenesis by the zinc finger protein Zbtb20. Nat Commun 2017; 8:14824. [PMID: 28327662 PMCID: PMC5364431 DOI: 10.1038/ncomms14824] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/03/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatic de novo lipogenesis (DNL) converts carbohydrates into triglycerides and is known to influence systemic lipid homoeostasis. Here, we demonstrate that the zinc finger protein Zbtb20 is required for DNL. Mice lacking Zbtb20 in the liver exhibit hypolipidemia and reduced levels of liver triglycerides, along with impaired hepatic lipogenesis. The expression of genes involved in glycolysis and DNL, including that of two ChREBP isoforms, is decreased in livers of knockout mice. Zbtb20 binds to and enhances the activity of the ChREBP-α promoter, suggesting that altered metabolic gene expression is mainly driven by ChREBP. In addition, ChREBP-β overexpression largely restores hepatic expression of genes involved in glucose and lipid metabolism, and increases plasma and liver triglyceride levels in knockout mice. Finally, we show that Zbtb20 ablation protects from diet-induced liver steatosis and improves hepatic insulin resistance. We suggest ZBTB20 is an essential regulator of hepatic lipogenesis and may be a therapeutic target for the treatment of fatty liver disease. De novo lipogenesis is tightly controlled by hormonal and nutritional signals and plays an important role in energy homoeostasis. Here, Liu et al. show that zinc finger protein ZBTB20 regulates the expression of key glycolytic and lipogenic genes by modulating ChREBP expression and transcriptional activity.
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21
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Sauzay C, Petit A, Bourgeois AM, Barbare JC, Chauffert B, Galmiche A, Houessinon A. Alpha-foetoprotein (AFP): A multi-purpose marker in hepatocellular carcinoma. Clin Chim Acta 2016; 463:39-44. [PMID: 27732875 DOI: 10.1016/j.cca.2016.10.006] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 10/05/2016] [Accepted: 10/06/2016] [Indexed: 12/13/2022]
Abstract
Alpha-foetoprotein (AFP), one of the first protein tumour markers discovered, is widely used today in clinical practice. Its application for the screening and diagnosis of hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour, is a matter of extensive debate. In addition to the studies focused on the role of the AFP in the diagnosis of HCC, in recent years AFP has been used to guide the therapeutic choice in HCC and monitor the treatment. Here, we summarize the latest studies that show the interest of AFP quantification in determining the suitability of liver transplantation or to follow-up on patients receiving the targeted treatment sorafenib. We also highlight the recent studies showing the active role of AFP in tumour progression, and the new modes of regulation of this tumour marker. Among these is the regulation of AFP through tumour proteostasis and the Unfolded Protein Response (UPR). We discuss the implications of this new knowledge in the therapeutic context, in terms of interpreting serum levels of AFP, and the new perspectives offered by AFP for the study of tumour proteostasis.
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Affiliation(s)
- Chloé Sauzay
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France
| | - Alexandra Petit
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France
| | | | | | | | - Antoine Galmiche
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
| | - Aline Houessinon
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France
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22
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Qu Z, Zhang H, Huang M, Shi G, Liu Z, Xie P, Li H, Wang W, Xu G, Zhang Y, Yang L, Huang G, Takahashi JS, Zhang WJ, Xu Y. Loss of ZBTB20 impairs circadian output and leads to unimodal behavioral rhythms. eLife 2016; 5:e17171. [PMID: 27657167 PMCID: PMC5033604 DOI: 10.7554/elife.17171] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 09/01/2016] [Indexed: 12/15/2022] Open
Abstract
Many animals display morning and evening bimodal activities in the day/night cycle. However, little is known regarding the potential components involved in the regulation of bimodal behavioral rhythms in mammals. Here, we identified that the zinc finger protein gene Zbtb20 plays a crucial role in the regulation of bimodal activities in mice. Depletion of Zbtb20 in nerve system resulted in the loss of early evening activity, but the increase of morning activity. We found that Zbtb20-deficient mice exhibited a pronounced decrease in the expression of Prokr2 and resembled phenotypes of Prok2 and Prokr2-knockout mice. Injection of adeno-associated virus-double-floxed Prokr2 in suprachiasmatic nucleus could partly restore evening activity in Nestin-Cre; Zbtb20fl/fl (NS-ZB20KO) mice. Furthermore, loss of Zbtb20 in Foxg1 loci, but intact in the suprachiasmatic nucleus, was not responsible for the unimodal activity of NS-ZB20KO mice. Our study provides evidence that ZBTB20-mediated PROKR2 signaling is critical for the evening behavioral rhythms.
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Affiliation(s)
- Zhipeng Qu
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Hai Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai, China
| | - Moli Huang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Guangsen Shi
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Zhiwei Liu
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Pancheng Xie
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Hui Li
- Department of Pathophysiology, Second Military Medical University, Shanghai, China
| | - Wei Wang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Guoqiang Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Yang Zhang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Ling Yang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Guocun Huang
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
| | - Joseph S Takahashi
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
| | - Weiping J Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai, China
| | - Ying Xu
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
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23
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Chen Y, Yang S, Hu J, Yu C, He M, Cai Z. Increased Expression of SETD7 Promotes Cell Proliferation by Regulating Cell Cycle and Indicates Poor Prognosis in Hepatocellular Carcinoma. PLoS One 2016; 11:e0154939. [PMID: 27183310 PMCID: PMC4868314 DOI: 10.1371/journal.pone.0154939] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/21/2016] [Indexed: 12/28/2022] Open
Abstract
Purpose To investigate the role of SET domain containing 7 (SETD7) in hepatocellular carcinoma (HCC) and determine whether SETD7 can be used as a predictor of overall survival in HCC patients. Methods mRNAs and proteins of SETD7 and related genes in HCC tumor samples and paired adjacent non-tumorous liver tissues (ANLTs) (n = 20) or culture cells were determined by quantitative real-time PCR and Western blot. Cell proliferation and apoptosis with SETD7 knockdown SMMC-7721 cells or SETD7 overexpressed HepG2 cells were analyzed by CCK8 assay or flow cytometry. Gene expression alterations in SETD7 knockdown of SMMC-7721 cells were determined by digital gene expression (DGE) profiling. Defined data on patients (n = 225) with HCC were retrieved for the further study. Tissue microarrays (TMAs) were performed using paraffin tissues with tumor and ANLTs. SETD7 and related proteins were determined by TMAs immunohistochemistry. Statistical analyses were conducted to associate SETD7 expression with tumor features and patient outcomes, as well as related proteins expression. Results SETD7 expression was significantly higher in HCC tumor tissues than in ANLTs. SETD7 overexpression in vitro can promote HepG2 cell proliferation, whereas SETD7 knockdown can inhibit SMMC-7721 cell proliferation by regulating the cell cycle. SETD7 expression was significantly correlated with five genes expression. Increased SETD7 is associated with metastasis, recurrence, large tumor size, and poor tumor differentiation, and indicates poor prognosis in HCC patients. Conclusions SETD7 plays a critical role in HCC, and its immunohistochemistry signature provides potential clinical significance for personalized prediction of HCC prognosis.
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Affiliation(s)
- Yuanyuan Chen
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, 200433, China
| | - Shengsheng Yang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, 200433, China
| | - Jiewei Hu
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, 200433, China
| | - Chaoqin Yu
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Miaoxia He
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
- * E-mail: (ZC); (MH)
| | - Zailong Cai
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, 200433, China
- * E-mail: (ZC); (MH)
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24
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Cao D, Ma X, Cai J, Luan J, Liu AJ, Yang R, Cao Y, Zhu X, Zhang H, Chen YX, Shi Y, Shi GX, Zou D, Cao X, Grusby MJ, Xie Z, Zhang WJ. ZBTB20 is required for anterior pituitary development and lactotrope specification. Nat Commun 2016; 7:11121. [PMID: 27079169 PMCID: PMC4835541 DOI: 10.1038/ncomms11121] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 02/22/2016] [Indexed: 01/03/2023] Open
Abstract
The anterior pituitary harbours five distinct hormone-producing cell types, and their cellular differentiation is a highly regulated and coordinated process. Here we show that ZBTB20 is essential for anterior pituitary development and lactotrope specification in mice. In anterior pituitary, ZBTB20 is highly expressed by all the mature endocrine cell types, and to some less extent by somatolactotropes, the precursors of prolactin (PRL)-producing lactotropes. Disruption of Zbtb20 leads to anterior pituitary hypoplasia, hypopituitary dwarfism and a complete loss of mature lactotropes. In ZBTB20-null mice, although lactotrope lineage commitment is normally initiated, somatolactotropes exhibit profound defects in lineage specification and expansion. Furthermore, endogenous ZBTB20 protein binds to Prl promoter, and its knockdown decreases PRL expression and secretion in a lactotrope cell line MMQ. In addition, ZBTB20 overexpression enhances the transcriptional activity of Prl promoter in vitro. In conclusion, our findings point to ZBTB20 as a critical regulator of anterior pituitary development and lactotrope specification.
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Affiliation(s)
- Dongmei Cao
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Xianhua Ma
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Jiao Cai
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Jing Luan
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.,Department of Pathophysiology, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China
| | - An-Jun Liu
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.,Department of Cell Biology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Rui Yang
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Yi Cao
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.,Department of Endocrinology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China
| | - Xiaotong Zhu
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.,Department of Pathophysiology, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China
| | - Hai Zhang
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Yu-Xia Chen
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Yuguang Shi
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245, USA
| | - Guang-Xia Shi
- Department of Pathophysiology, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China
| | - Dajin Zou
- Department of Endocrinology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China
| | - Xuetao Cao
- National Key Laboratory of Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, 9 Dongdan Santiao, Beijing, 100005, China
| | - Michael J Grusby
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Avenue, Boston, Massachusetts, 02115, USA
| | - Zhifang Xie
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.,Department of Cell Biology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Weiping J Zhang
- Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
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