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Choudhuri S, Garg NJ. Hepatocyte Nuclear Factor 4 Alpha: A Key Regulator of Liver Disease Pathology and Haemostatic Disorders. Liver Int 2025; 45:e16245. [PMID: 40387433 DOI: 10.1111/liv.16245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/19/2024] [Accepted: 01/03/2025] [Indexed: 05/20/2025]
Abstract
OBJECTIVE Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte differentiation in fetal and adult liver and exerts its transcriptional role in determining physiological functions of the liver. The objective of this review is to address the current knowledge of molecular mechanisms involved in HNF4α regulation in multiple aspects of liver disease pathogenesis. METHODS Based on available literature, this review summarises the current state of knowledge onthe mechanism of HNF4α dysregulation, and the role of HNF4α activity inregulating early to advanced stages of various liver diseases. RESULTS Patients with deranged HNF4α expression are at higher risk for the development of liver diseases such as viral hepatitis, alcoholic/nonalcoholic fatty liver disease, hepatocellular carcinoma, and haematological disorders such as coagulopathy and bleeding disorders. DISCUSSION HNF4α interactions with nuclear receptors and target genes promote liver disease pathology by regulating various metabolic pathways. The strong correlation between deranged HNF4α expression and the severity of liver diseases suggests that targeting HNF4α expression can offer potential therapeutic strategy in the prevention of liver disease pathology and haemostatic disorders.
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Affiliation(s)
- Subhadip Choudhuri
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
| | - Nisha Jain Garg
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
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2
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Pan C, Lee LTO. Membrane drug transporters in cancer: From chemoresistance mechanism to therapeutic strategies. Biochim Biophys Acta Rev Cancer 2025; 1880:189272. [PMID: 39863184 DOI: 10.1016/j.bbcan.2025.189272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 01/16/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025]
Abstract
Chemoresistance is a multifactorial phenomenon and the primary cause to the ineffectiveness of oncotherapy and cancer recurrence. Membrane drug transporters are crucial for drug delivery and disposition in cancer cells. Changes in the expression and functionality of these transporters lead to decreased intracellular accumulation and reduced toxicity of antineoplastic drugs. As the mechanism has been better understood and genetic engineering technology progressed quickly in recent years, some novel targeting strategies have come to light. This article summarizes the regulatory mechanisms of membrane drug transporters and provides an extensive review of current approaches to address transporters-mediated chemoresistance. These strategies include the use of chemical inhibitors to block efflux transporters, the development of copper chelators to enhance platinum drug uptake, the delivery of genetic drugs to alter transporter expression, the regulation of transcription and post-translational modifications. Additionally, we provide information of the clinical trial performance of the related targeting strategies, along with the ongoing challenges. Even though some clinical trials failed due to unexpected side effects and limited therapeutic efficacy, the advent of targeting membrane drug transporters still presents a hopeful path for overcoming chemoresistance.
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Affiliation(s)
- Chao Pan
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Leo Tsz On Lee
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China; Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau, China.
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Yeung CLS, Ng TH, Lai CJ, Xue T, Mao X, Tey SK, Lo RCL, Sin C, Ng KM, Wong DKH, Mak L, Yuen M, Ng IO, Cao P, Gao Y, Yun JP, Yam JWP. Small Extracellular Vesicle-Derived Nicotinamide Phosphoribosyltransferase (NAMPT) Induces Acyl-Coenzyme A Synthetase SLC27A4-Mediated Glycolysis to Promote Hepatocellular Carcinoma. J Extracell Vesicles 2025; 14:e70071. [PMID: 40237223 PMCID: PMC12000932 DOI: 10.1002/jev2.70071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Tumour-derived small extracellular vesicles (sEV) are critical mediators within the tumour microenvironment (TME) and are known to regulate various metabolic pathways. In metastatic hepatocellular carcinoma (HCC), mass spectrometry protein analysis of HCC-derived sEV (HCC-sEV) identified an upregulation of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in maintaining cellular nicotinamide adenine dinucleotide (NAD+) levels. Our study demonstrates that sEV-NAMPT enhances glycolysis, tumorigenesis, and metastasis in HCC. Specifically, sEV-NAMPT activates the NF-κB transcription factor through toll-like receptor 4 (TLR4), leading to elevated SLC27A4 expression. SLC27A4 functions primarily as a long-chain fatty acid transporter and acyl-CoA synthetase. Lipidomic and metabolomic analyses revealed a positive correlation between SLC27A4 and intracellular levels of triacylglycerol (TG) and dihydroxyacetone phosphate (DHAP). Increased TG levels enhance lipolysis via hepatic lipase and facilitate the conversion of glycerol-3-P to DHAP, an intermediate that bridges lipid metabolism and glycolysis. This study uncovers a novel regulatory axis involving sEV-NAMPT and SLC27A4 in glycolysis, independent of traditional fatty acid metabolism pathways. Clinically, targeting sEV-NAMPT with the inhibitor FK866 significantly inhibited tumour growth in various HCC in vivo models, highlighting the potential of sEV-NAMPT as both a biomarker and therapeutic target in HCC.
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Affiliation(s)
- Cherlie Lot Sum Yeung
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Tung Him Ng
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Charlotte Jiaqi Lai
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Tingmao Xue
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Department of Hepatobiliary Surgery IIZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
| | - Xiaowen Mao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau
| | - Sze Keong Tey
- Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Regina Cheuk Lam Lo
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Chun‐Fung Sin
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Kwan Ming Ng
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Hong Kong Science ParkHong Kong
| | - Danny Ka Ho Wong
- Department of Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Lung‐Yi Mak
- Department of Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Man‐Fung Yuen
- Department of Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Irene Oi‐Lin Ng
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Peihua Cao
- Clinical Research Center, Zhujiang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Yi Gao
- Department of Hepatobiliary Surgery IIZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
| | - Jing Ping Yun
- Department of PathologySun Yat‐sen University Cancer CenterGuangzhouGuangdongChina
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
- Materials Innovation Institute for Life Sciences and Energy (MILES), HKU‐SIRIShenzhenChina
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Cheon I, Kim M, Kim KH, Ko S. Hepatic Nuclear Receptors in Cholestasis-to-Cholangiocarcinoma Pathology. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:409-421. [PMID: 39326734 PMCID: PMC11983697 DOI: 10.1016/j.ajpath.2024.07.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/22/2024] [Accepted: 07/26/2024] [Indexed: 09/28/2024]
Abstract
Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. It explores their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, it introduces available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discusses the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.
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Affiliation(s)
- Inyoung Cheon
- Department of Anesthesiology, Critical Care, and Pain Medicine and Center for Perioperative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas; Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Minwook Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kang Ho Kim
- Department of Anesthesiology, Critical Care, and Pain Medicine and Center for Perioperative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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Tao J, Liu Y, Tang X, Nie D, Wu K, Wang K, Tang N. Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119916. [PMID: 39938688 DOI: 10.1016/j.bbamcr.2025.119916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/10/2025] [Accepted: 02/02/2025] [Indexed: 02/14/2025]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality globally, with hypoxia recognized as a key factor in its progression. Solute carrier family 27 member 5 (SLC27A5/FATP5), a pivotal enzyme in hepatic fatty acid transport and bile acid metabolism, is frequently downregulated in hepatocellular carcinoma, resulting in poor prognosis. However, the link between hypoxia and the suppression of SLC27A5 in HCC remains to be elucidated. Here, we investigated the hypoxia-induced downregulation of SLC27A5 and its impact on HCC proliferation via the repression of hepatocyte nuclear factor 4 alpha (HNF4A). Utilizing in vitro and in vivo hepatocellular carcinoma models, we have demonstrated that hypoxic conditions significantly reduce SLC27A5 transcription, which is mediated by the suppression of HNF4A. This reduction leads to the activation of the AKT pathway and an increase in cyclin-dependent kinase 2 (CDK2) and Cyclin E1 (CCNE1) expression, promoting the transition from the G1 to S phase of the cell cycle and driving HCC proliferation. Furthermore, we show that the pharmacological activation of HNF4A using Benfluorex, in combination with the AKT inhibitor MK2206, significantly inhibits tumor growth in a subcutaneous MHCC-97H xenograft model, suggesting a synergistic therapeutic potential. Together, our study provides novel insights into the hypoxia-mediated regulatory mechanisms in HCC and highlights the HNF4A/SLC27A5/AKT axis as a promising target for combination therapy.
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Affiliation(s)
- Junji Tao
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Yuanyuan Liu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Xin Tang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Dan Nie
- Department of Gastroenterology, The Chongqing Hospital of Traditional Chinese Medicine, Chongqing College of Traditional Chinese Medicine, Chongqing 400011, China
| | - Kang Wu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Kai Wang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
| | - Ni Tang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
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Toriyama K, Uehara T, Iwakoshi A, Kawashima H, Hosoda W. HNF6 and HNF4α expression in adenocarcinomas of the liver, pancreaticobiliary tract, and gastrointestinal tract: an immunohistochemical study of 480 adenocarcinomas of the digestive system. Pathology 2024; 56:804-813. [PMID: 38926048 DOI: 10.1016/j.pathol.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/05/2024] [Accepted: 03/20/2024] [Indexed: 06/28/2024]
Abstract
Hepatocyte nuclear factors (HNF) 6 and 4α are master transcriptional regulators of development and maintenance of the liver and pancreaticobiliary tract in mice and humans. However, little is known about the prevalence of HNF6 and HNF4α expression in carcinomas of the hepatobiliary tract and pancreas. We aimed to reveal the diagnostic utility of HNF6 and HNF4α immunolabelling in adenocarcinomas of these organs. We investigated HNF6 and HNF4α expression by immunohistochemistry using a total of 480 adenocarcinomas of the digestive system, including 282 of the hepatobiliary tract and pancreas and 198 of the gastrointestinal tract. HNF6 expression was primarily restricted to intrahepatic cholangiocarcinomas (CCs) (63%, n=80) and gallbladder adenocarcinomas (43%, n=88), among others. Notably, small duct intrahepatic CCs almost invariably expressed HNF6 (90%, n=42), showing stark contrast to a low prevalence in large duct intrahepatic CCs (10%, n=21; p<0.0001). HNF6 expression was infrequent in extrahepatic CCs (9%, n=55) and pancreatic ductal adenocarcinomas (7%, n=58), and it was rare in adenocarcinomas of the gastrointestinal tract [oesophagus/oesophagogastric junction (EGJ) (2%, n=45), stomach (2%, n=86), duodenum (0%, n=25), and colorectum (0%, n=42)]. In contrast, HNF4α was widely expressed among adenocarcinomas of the digestive system, including intrahepatic CCs (88%), extrahepatic CCs (94%), adenocarcinomas of the gallbladder (98%), pancreas (98%), oesophagus/EGJ (96%), stomach (98%), duodenum (80%), and colorectum (100%). HNF6 was frequently expressed in and almost restricted to intrahepatic CCs of small duct type and gallbladder adenocarcinomas, while HNF4α was expressed throughout adenocarcinomas of the digestive system. HNF6 immunolabelling may be useful in distinguishing small duct intrahepatic CCs from other types of CC as well as metastatic gastrointestinal adenocarcinomas.
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Affiliation(s)
- Kazuhiro Toriyama
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akari Iwakoshi
- Department of Pathology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Waki Hosoda
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
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Kotulkar M, Paine-Cabrera D, Apte U. Role of Hepatocyte Nuclear Factor 4 Alpha in Liver Cancer. Semin Liver Dis 2024; 44:383-393. [PMID: 38901435 DOI: 10.1055/a-2349-7236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the incidence of HCC is on the rise. Liver cancers in general and HCC in particular do not respond to chemotherapy. Radiological ablation, surgical resection, and liver transplantation are the only medical therapies currently available. Hepatocyte nuclear factor 4 α (HNF4α) is an orphan nuclear receptor expressed only in hepatocytes in the liver. HNF4α is considered the master regulator of hepatic differentiation because it regulates a significant number of genes involved in various liver-specific functions. In addition to maintaining hepatic differentiation, HNF4α also acts as a tumor suppressor by inhibiting hepatocyte proliferation by suppressing the expression of promitogenic genes and inhibiting epithelial to mesenchymal transition in hepatocytes. Loss of HNF4α expression and function is associated with rapid progression of chronic liver diseases that ultimately lead to liver cirrhosis and HCC, including metabolism-associated steatohepatitis, alcohol-associated liver disease, and hepatitis virus infection. This review summarizes the role of HNF4α in liver cancer pathogenesis and highlights its potential as a potential therapeutic target for HCC.
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Affiliation(s)
- Manasi Kotulkar
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Diego Paine-Cabrera
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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Potapova EV, Zherebtsov EA, Shupletsov VV, Dremin VV, Kandurova KY, Mamoshin AV, Abramov AY, Dunaev AV. Detection of NADH and NADPH levels in vivo identifies shift of glucose metabolism in cancer to energy production. FEBS J 2024; 291:2674-2682. [PMID: 38311986 DOI: 10.1111/febs.17067] [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: 09/12/2023] [Revised: 11/15/2023] [Accepted: 01/17/2024] [Indexed: 02/06/2024]
Abstract
Profound changes in the metabolism of cancer cells have been known for almost 100 years, and many aspects of these changes have continued to be actively studied and discussed. Differences in the results of various studies can be explained by the diversity of tumours, which have differing processes of energy metabolism, and by limitations in the methods used. Here, using fluorescence lifetime needle optical biopsy in a hepatocellular carcinoma (HCC) mouse model and patients with HCC, we measured reduced nicotinamide adenine dinucleotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) in control liver, and in HCC tumours and their adjacent regions. We found that NADH level (mostly responsible for energy metabolism) is increased in tumours but also in adjacent regions of the same liver. NADPH level is significantly decreased in the tumours of patients but increased in the HCC mouse model. However, in the ex vivo tumour slices of mouse HCC, reactive oxygen species production and glutathione level (both dependent on NADPH) were significantly suppressed. Thus, glucose-dependent NADH and NADPH production in tumours changed but with a more pronounced shift to energy production (NADH), rather than NADPH synthesis for redox balance.
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Affiliation(s)
- Elena V Potapova
- Research and Development Center of Biomedical Photonics, Orel State University, Russia
| | | | - Valery V Shupletsov
- Research and Development Center of Biomedical Photonics, Orel State University, Russia
| | - Viktor V Dremin
- Research and Development Center of Biomedical Photonics, Orel State University, Russia
- College of Engineering and Physical Sciences, Aston University, Birmingham, UK
| | - Ksenia Y Kandurova
- Research and Development Center of Biomedical Photonics, Orel State University, Russia
| | - Andrian V Mamoshin
- Research and Development Center of Biomedical Photonics, Orel State University, Russia
- Orel Regional Clinical Hospital, Russia
| | - Andrey Y Abramov
- Research and Development Center of Biomedical Photonics, Orel State University, Russia
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Andrey V Dunaev
- Research and Development Center of Biomedical Photonics, Orel State University, Russia
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Wu T, Chen X, Xu K, Dai C, Li X, Zhang YWQ, Li J, Gao M, Liu Y, Liu F, Zhang X, Wang B, Xia P, Li Z, Ma W, Yuan Y. LIM domain only 7 negatively controls nonalcoholic steatohepatitis in the setting of hyperlipidemia. Hepatology 2024; 79:149-166. [PMID: 37676481 PMCID: PMC10718224 DOI: 10.1097/hep.0000000000000585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 07/19/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND AND AIMS Hyperlipidemia has been extensively recognized as a high-risk factor for NASH; however, clinical susceptibility to NASH is highly heterogeneous. The key controller(s) of NASH susceptibility in patients with hyperlipidemia has not yet been elucidated. Here, we aimed to reveal the key regulators of NASH in patients with hyperlipidemia and to explore its role and underlying mechanisms. APPROACH AND RESULTS To identify the predominant suppressors of NASH in the setting of hyperlipidemia, we collected liver biopsy samples from patients with hyperlipidemia, with or without NASH, and performed RNA-sequencing analysis. Notably, decreased Lineage specific Interacting Motif domain only 7 (LMO7) expression robustly correlated with the occurrence and severity of NASH. Although overexpression of LMO7 effectively blocked hepatic lipid accumulation and inflammation, LMO7 deficiency in hepatocytes greatly exacerbated diet-induced NASH progression. Mechanistically, lysine 48 (K48)-linked ubiquitin-mediated proteasomal degradation of tripartite motif-containing 47 (TRIM47) and subsequent inactivation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) cascade are required for the protective function of LMO7 in NASH. CONCLUSIONS These findings provide proof-of-concept evidence supporting LMO7 as a robust suppressor of NASH in the context of hyperlipidemia, indicating that targeting the LMO7-TRIM47 axis is a promising therapeutic strategy for NASH.
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Affiliation(s)
- Tiangen Wu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Xi Chen
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Kequan Xu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Caixia Dai
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Xiaomian Li
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Yang-Wen-Qing Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Jinghua Li
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Meng Gao
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Yingyi Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Fusheng Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Xutao Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Bicheng Wang
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Peng Xia
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Zhen Li
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Weijie Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, PR China
- TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, PR China
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10
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Li H, Seessle J, Staffer S, Tuma-Kellner S, Poschet G, Herrmann T, Chamulitrat W. FATP4 deletion in liver cells induces elevation of extracellular lipids via metabolic channeling towards triglycerides and lipolysis. Biochem Biophys Res Commun 2023; 687:149161. [PMID: 37931418 DOI: 10.1016/j.bbrc.2023.149161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/13/2023] [Accepted: 10/26/2023] [Indexed: 11/08/2023]
Abstract
Evidence from mice with global deletion of fatty-acid transport protein4 (FATP4) indicates its role on β-oxidation and triglycerides (TG) metabolism. We reported that plasma glycerol and free fatty acids (FA) were increased in liver-specific Fatp4 deficient (L-FATP4-/-) mice under dietary stress. We hypothesized that FATP4 may mediate hepatocellular TG lipolysis. Here, we demonstrated that L-FATP4-/- mice showed an increase in these blood lipids, liver TG, and subcutaneous fat weights. We therefore studied TG metabolism in response to oleate treatment in two experimental models using FATP4-knockout HepG2 (HepKO) cells and L-FATP4-/- hepatocytes. Both FATP4-deificient liver cells showed a significant decrease in β-oxidation products by ∼30-35% concomitant with marked upregulation of CD36, FATP2, and FATP5 as well as lipoprotein microsomal-triglyceride-transfer protein genes. By using 13C3D5-glycerol, HepKO cells displayed an increase in metabolically labelled TG species which were further increased with oleate treatment. This increase was concomitant with a step-wise elevation of TG in cells and supernatants as well as the secretion of cholesterol very low-density and high-density lipoproteins. Upon analyzing TG lipolytic enzymes, both mutant liver cells showed marked upregulated expression of hepatic lipase, while that of hormone-sensitive lipase and adipose-triglyceride lipase was downregulated. Lipolysis measured by extracellular glycerol and free FA was indeed increased in mutant cells, and this event was exacerbated by oleate treatment. Taken together, FATP4 deficiency in liver cells led to a metabolic shift from β-oxidation towards lipolysis-directed TG and lipoprotein secretion, which is in line with an association of FATP4 polymorphisms with blood lipids.
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Affiliation(s)
- Huili Li
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, Hubei, China
| | - Jessica Seessle
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Simone Staffer
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Sabine Tuma-Kellner
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Gernot Poschet
- Metabolomics Core Technology Platform, Centre for Organismal Studies, University of Heidelberg, 69120, Heidelberg, Germany
| | - Thomas Herrmann
- Westkuesten Hospital, Esmarchstraße 50, 25746, Heide, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany.
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11
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Wang Y, Meng B, Wang X, Wu A, Li X, Qian X, Wu J, Ying W, Xiao T, Rong W. Noninvasive urinary protein signatures combined clinical information associated with microvascular invasion risk in HCC patients. BMC Med 2023; 21:481. [PMID: 38049860 PMCID: PMC10696877 DOI: 10.1186/s12916-023-03137-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 10/30/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Microvascular invasion (MVI) is the main factor affecting the prognosis of patients with hepatocellular carcinoma (HCC). The aim of this study was to identify accurate diagnostic biomarkers from urinary protein signatures for preoperative prediction. METHODS We conducted label-free quantitative proteomic studies on urine samples of 91 HCC patients and 22 healthy controls. We identified candidate biomarkers capable of predicting MVI status and combined them with patient clinical information to perform a preoperative nomogram for predicting MVI status in the training cohort. Then, the nomogram was validated in the testing cohort (n = 23). Expression levels of biomarkers were further confirmed by enzyme-linked immunosorbent assay (ELISA) in an independent validation HCC cohort (n = 57). RESULTS Urinary proteomic features of healthy controls are mainly characterized by active metabolic processes. Cell adhesion and cell proliferation-related pathways were highly defined in the HCC group, such as extracellular matrix organization, cell-cell adhesion, and cell-cell junction organization, which confirms the malignant phenotype of HCC patients. Based on the expression levels of four proteins: CETP, HGFL, L1CAM, and LAIR2, combined with tumor diameter, serum AFP, and GGT concentrations to establish a preoperative MVI status prediction model for HCC patients. The nomogram achieved good concordance indexes of 0.809 and 0.783 in predicting MVI in the training and testing cohorts. CONCLUSIONS The four-protein-related nomogram in urine samples is a promising preoperative prediction model for the MVI status of HCC patients. Using the model, the risk for an individual patient to harbor MVI can be determined.
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Affiliation(s)
- Yaru Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Clinical Trial Research Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Bo Meng
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China
- Center for Advanced Measurement Science, National Institute of Metrology, Beijing, 100029, China
| | - Xijun Wang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Anke Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaoyu Li
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, China
| | - Xiaohong Qian
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, China
| | - Jianxiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wantao Ying
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China.
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100124, China.
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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12
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Xiang J, Wu X, Liu W, Wei H, Zhu Z, Liu S, Song C, Gu Q, Wei S, Zhang Y. Bioinformatic analyzes and validation of cystathionine gamma-lyase as a prognostic biomarker and related to immune infiltrates in hepatocellular carcinoma. Heliyon 2023; 9:e16152. [PMID: 37251842 PMCID: PMC10209420 DOI: 10.1016/j.heliyon.2023.e16152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 05/05/2023] [Accepted: 05/07/2023] [Indexed: 05/31/2023] Open
Abstract
Background The role of cystathionine γ-lyase (CTH) in the prognosis and immune invasion of hepatocellular carcinoma (HCC) remains poorly understood. Methods In this study, the clinical data of patients with HCC were analyzed, and the expression level of CTH was compared between HCC and normal tissues using the R package and various databases. Results We found that CTH expression was significantly decreased in HCC compared with normal tissues, and its expression was associated with various clinicopathological factors, including tumor stage, gender, tumor status, residual tumor, histologic stage, race, alpha-fetoprotein (AFP), albumin, drinking, and smoking. Our results suggest that CTH might be a protective factor for the survival of patients with HCC. Further functional analysis revealed that high CTH expression was enriched in the Reactome signaling by interleukins and the Reactome neutrophil degranulation. Moreover, CTH expression was closely correlated with a variety of immune cells, including a negative correlation with the CD56 (bright) NK cells and follicular helper T cell (TFH), while a positive correlation with Th17 cells and central memory T cell (Tcm). High expression of CTH in immune cells predicted a better prognosis of HCC. Our findings further indicated Pyridoxal phosphate, l-cysteine, Carboxymethylthio-3-(3-chlorophenyl)-1,2,4-oxadiazol, 2-[(3-Hydroxy-2-Methyl-5-Phosphonooxymethyl-Pyridin-4-Ylmethyl)-Imino]-5-phosphono-pent-3-enoic acid and L-2-amino-3-butynoic acid as potential target candidate medications for HCC treatment based on CTH. Conclusion Our study suggests that CTH can serve as a biomarker to predict the prognosis and immune infiltration of HCC.
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Affiliation(s)
- Jianfeng Xiang
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Xinrui Wu
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Wangrui Liu
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Huagen Wei
- Dental Materials Science, Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
| | - Zhu Zhu
- Medical School of Nantong University, China
| | - Shifan Liu
- Medical School of Nantong University, China
| | | | - Qiang Gu
- Affiliated Maternity and Child Health Care Hospital of Nantong University, China
| | - Shiyin Wei
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Yichi Zhang
- Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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13
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Rutten MGS, Lei Y, Hoogerland JH, Bloks VW, Yang H, Bos T, Krishnamurthy KA, Bleeker A, Koster MH, Thomas RE, Wolters JC, van den Bos H, Mithieux G, Rajas F, Mardinoglu A, Spierings DCJ, de Bruin A, van de Sluis B, Oosterveer MH. Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia. Cancer Metab 2023; 11:5. [PMID: 37085901 PMCID: PMC10122297 DOI: 10.1186/s40170-023-00305-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/21/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUND Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia. METHODS Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. RESULTS Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged. CONCLUSIONS In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.
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Affiliation(s)
- Martijn G. S. Rutten
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Yu Lei
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Joanne H. Hoogerland
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent W. Bloks
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hong Yang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Trijnie Bos
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Kishore A. Krishnamurthy
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Aycha Bleeker
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mirjam H. Koster
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rachel E. Thomas
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Justina C. Wolters
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hilda van den Bos
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Gilles Mithieux
- Institut National de La Santé Et de La Recherche Médicale, U1213 Lyon, France
- Université de Lyon, Lyon, France
- Université Lyon 1, Villeurbanne, France
| | - Fabienne Rajas
- Institut National de La Santé Et de La Recherche Médicale, U1213 Lyon, France
- Université de Lyon, Lyon, France
- Université Lyon 1, Villeurbanne, France
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Diana C. J. Spierings
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Alain de Bruin
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Bart van de Sluis
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Maaike H. Oosterveer
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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14
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Berasain C, Arechederra M, Argemí J, Fernández-Barrena MG, Avila MA. Loss of liver function in chronic liver disease: An identity crisis. J Hepatol 2023; 78:401-414. [PMID: 36115636 DOI: 10.1016/j.jhep.2022.09.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/24/2022] [Accepted: 09/07/2022] [Indexed: 01/24/2023]
Abstract
Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.
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Affiliation(s)
- Carmen Berasain
- Program of Hepatology, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra, IdiSNA, Pamplona, Spain.
| | - Maria Arechederra
- Program of Hepatology, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra, IdiSNA, Pamplona, Spain
| | - Josepmaria Argemí
- Centro de Investigación Biomédica en Red, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra, IdiSNA, Pamplona, Spain; Liver Unit, Clinica Universidad de Navarra, Pamplona, Spain
| | - Maite G Fernández-Barrena
- Program of Hepatology, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra, IdiSNA, Pamplona, Spain
| | - Matías A Avila
- Program of Hepatology, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra, IdiSNA, Pamplona, Spain.
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15
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Zheng S, Bian H, Li J, Shen Y, Yang Y, Hu W. Differentiation therapy: Unlocking phenotypic plasticity of hepatocellular carcinoma. Crit Rev Oncol Hematol 2022; 180:103854. [PMID: 36257532 DOI: 10.1016/j.critrevonc.2022.103854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/12/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
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16
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Fekry B, Ribas-Latre A, Drunen RV, Santos RB, Shivshankar S, Dai Y, Zhao Z, Yoo SH, Chen Z, Sun K, Sladek FM, Younes M, Eckel-Mahan K. Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis. FASEB J 2022; 36:e22482. [PMID: 35947136 PMCID: PMC10062014 DOI: 10.1096/fj.202101398r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 07/06/2022] [Accepted: 07/21/2022] [Indexed: 11/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.
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Affiliation(s)
- Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Aleix Ribas-Latre
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Rachel Van Drunen
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Rafael Bravo Santos
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Samay Shivshankar
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Yulin Dai
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.,Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, USA
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Zheng Chen
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Kai Sun
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, California, USA
| | - Mamoun Younes
- Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Kristin Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
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17
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Gunewardena S, Huck I, Walesky C, Robarts D, Weinman S, Apte U. Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans. Hepatology 2022; 76:372-386. [PMID: 35006629 PMCID: PMC9762158 DOI: 10.1002/hep.32326] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Hepatocyte nuclear factor 4 alpha (HNF4α) is indispensable for hepatocyte differentiation and critical for maintaining liver health. Here, we demonstrate that loss of HNF4α activity is a crucial step in the pathogenesis of chronic liver diseases (CLDs) that lead to development of HCC. APPROACH AND RESULTS We developed an HNF4α target gene signature, which can accurately determine HNF4α activity, and performed an exhaustive in silico analysis using hierarchical and K-means clustering, survival, and rank-order analysis of 30 independent data sets containing over 3500 individual samples. The association of changes in HNF4α activity to CLD progression of various etiologies, including HCV- and HBV-induced liver cirrhosis (LC), NAFLD/NASH, and HCC, was determined. Results revealed a step-wise reduction in HNF4α activity with each progressive stage of pathogenesis. Cluster analysis of LC gene expression data sets using the HNF4α signature showed that loss of HNF4α activity was associated with progression of Child-Pugh class, faster decompensation, incidence of HCC, and lower survival with and without HCC. A moderate decrease in HNF4α activity was observed in NAFLD from normal liver, but a further significant decline was observed in patients from NAFLD to NASH. In HCC, loss of HNF4α activity was associated with advanced disease, increased inflammatory changes, portal vein thrombosis, and substantially lower survival. CONCLUSIONS In conclusion, these data indicate that loss of HNF4α function is a common event in the pathogenesis of CLDs leading to HCC and is important from both diagnostic and therapeutic standpoints.
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Affiliation(s)
- Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - Ian Huck
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Chad Walesky
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Dakota Robarts
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Steven Weinman
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
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18
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Yoshinari K, Shizu R. Distinct Roles of the Sister Nuclear Receptors PXR and CAR in Liver Cancer Development. Drug Metab Dispos 2022; 50:1019-1026. [PMID: 35184041 DOI: 10.1124/dmd.121.000481] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 02/08/2022] [Indexed: 02/13/2025] Open
Abstract
Pregnane X receptor (PXR) and constitutively active receptor/constitutive androstane receptor (CAR) are xenobiotic-responsible transcription factors belonging to the same nuclear receptor gene subfamily and highly expressed in the liver. These receptors are activated by a variety of chemicals and play pivotal roles in many liver functions, including xenobiotic metabolism and disposition. Phenobarbital, an enzyme inducer and liver tumor promoter, activates both rodent and human CAR but causes liver tumors only in rodents. Although the precise mechanism for phenobarbital/CAR-mediated liver tumor formation remains to be established, intracellular pathways, including the Hippo pathway/Yes-associated protein-TEA-domain family members system and β-catenin signaling, seem to be involved. In contrast to CAR, previous findings by our group suggest that PXR activation does not promote hepatocyte proliferation but it enhances the proliferation induced by various stimuli. Moreover, and surprisingly, PXR may have antitumor effects in both rodents and humans by targeting inflammatory cytokine signals, angiogenesis and epithelial-mesenchymal transition. In this review, we summarize the current knowledge on the associations of PXR and CAR with hepatocyte proliferation and liver tumorigenesis and their molecular mechanisms and species differences. SIGNIFICANCE STATEMENT: Pregnane X receptor and constitutively active receptor/constitutive androstane receptor have very similar functions in the gene regulation associated with xenobiotic disposition, as suggested by their identification as xenosensors for enzyme induction. In contrast, recent reports clearly suggest that these receptors play distinct roles in the control of hepatocyte proliferation and liver cancer development. Understanding these differences at the molecular level may help us evaluate the human safety of chemical compounds and develop novel drugs targeting liver cancers.
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Affiliation(s)
- Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Ryota Shizu
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
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19
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Kochevalina MY, Bukharina AB, Trunov VG, Pento AV, Morozova OV, Kogun' GA, Simanovsky YO, Nikiforov SM, Rodionova EI. Changes in the urine volatile metabolome throughout growth of transplanted hepatocarcinoma. Sci Rep 2022; 12:7774. [PMID: 35546342 PMCID: PMC9095867 DOI: 10.1038/s41598-022-11818-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 04/27/2022] [Indexed: 11/26/2022] Open
Abstract
Trained detection dogs distinguish between urine samples from healthy organisms and organisms with malignant tumors, suggesting that the volatile urine metabolome contains information about tumor progression. The aim of this study was to determine whether the stage of tumor growth affects the chemical differences in the urine of mice and to what extent the "olfactory image of disease" perceived by dogs coincides with the "image of disease" recorded by the mass spectrometer. We used a novel laser ionization mass spectrometry method and propose a mass spectrometric analysis without detailed interpretation of the spectrum of volatile metabolomes in urine. The mass spectrometer we use works without sample preparation and registers volatile organic compounds in air at room temperature without changing the pH of the sample, i.e. under conditions similar to those in which dogs solve the same problem. The experimental cancer models were male BDF-f1 hybrid mice transplanted with hepatocarcinoma tissue, and similar mice transplanted with healthy liver tissue were used as controls. Our data show that both dogs and our proposed laser mass spectrometry method are able to detect both the entire spectrum of volatile organic compounds associated with the disease and minor changes in this spectrum during its course.
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Affiliation(s)
- M Yu Kochevalina
- Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
| | - A B Bukharina
- Prokhorov General Physics Institute of the Russian Academy of Sciences, Moscow, Russia
| | - V G Trunov
- Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
| | - A V Pento
- Prokhorov General Physics Institute of the Russian Academy of Sciences, Moscow, Russia
| | - O V Morozova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - G A Kogun'
- Cynological Division of Aviation Security Service, Aeroflot, Russian Airlines, Moscow, Russia
| | - Ya O Simanovsky
- Prokhorov General Physics Institute of the Russian Academy of Sciences, Moscow, Russia
| | - S M Nikiforov
- Prokhorov General Physics Institute of the Russian Academy of Sciences, Moscow, Russia
| | - E I Rodionova
- Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia.
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20
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Zherebtsov EA, Potapova EV, Mamoshin AV, Shupletsov VV, Kandurova KY, Dremin VV, Abramov AY, Dunaev AV. Fluorescence lifetime needle optical biopsy discriminates hepatocellular carcinoma. BIOMEDICAL OPTICS EXPRESS 2022; 13:633-646. [PMID: 35284175 PMCID: PMC8884204 DOI: 10.1364/boe.447687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 05/06/2023]
Abstract
This work presents results of in vivo and in situ measurements of hepatocellular carcinoma by a developed optical biopsy system. Here, we describe the technical details of the implementation of fluorescence lifetime and diffuse reflectance measurements by the system, equipped with an original needle optical probe, compatible with the 17.5G biopsy needle standard. The fluorescence lifetime measurements observed by the setup were verified in fresh solutions of NADH and FAD++, and then applied in a murine model for the characterisation of inoculated hepatocellular carcinoma (HCC) and adjacent liver tissue. The technique, applied in vivo and in situ and supplemented by measurements of blood oxygen saturation, made it possible to reveal statistically significant transformation in the set of measured parameters linked with the cellular pools of NADH and NADPH. In the animal model, we demonstrate that the characteristic changes in registered fluorescent parameters can be used to reliably distinguish the HCC tissue, liver tissue in the control, and the metabolically changed liver tissues of animals with the developed HCC tumour. For further transition to clinical applications, the optical biopsy system was tested during the routing procedure of the PNB in humans with suspected HCC. The comparison of the data from murine and human HCC tissues suggests that the tested animal model is generally representative in the sense of the registered fluorescence lifetime parameters, while statistically significant differences between their absolute values can still be observed.
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Affiliation(s)
- Evgenii A Zherebtsov
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
- Optoelectronics and Measurement Techniques unit, University of Oulu, Oulu, Finland
- Co-first authors with equal contribution
| | - Elena V Potapova
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
- Co-first authors with equal contribution
| | - Andrian V Mamoshin
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
- Orel Regional Clinical Hospital, Orel, Russia
| | - Valery V Shupletsov
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
| | - Ksenia Y Kandurova
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
| | - Viktor V Dremin
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
- College of Engineering and Physical Sciences, Aston University, Birmingham, UK
| | - Andrey Y Abramov
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Andrey V Dunaev
- Research & Development Center of Biomedical Photonics, Orel State University, Orel, Russia
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21
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Song J, Zhou H, Gu D, Xu Y. Hepatocellular Carcinoma Differentiation: Research Progress in Mechanism and Treatment. Front Oncol 2022; 11:790358. [PMID: 35096588 PMCID: PMC8790246 DOI: 10.3389/fonc.2021.790358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Although progress has been made in diagnosis and treatment, morbidity and mortality continue to rise. Chronic liver disease and liver cirrhosis are still the most important risk factors for liver cancer. Although there are many treatments, it can only be cured by orthotopic liver transplantation (OLT) or surgical resection. And the worse the degree of differentiation, the worse the prognosis of patients with liver cancer. Then it can be considered that restoring a better state of differentiation may improve the prognosis. The differentiation treatment of liver cancer is to reverse the dedifferentiation process of hepatocytes to liver cancer cells by means of drugs, improve the differentiation state of the tumor, and restore the normal liver characteristics, so as to improve the prognosis. Understanding the mechanism of dedifferentiation of liver cancer can provide ideas for drug design. Liver enrichment of transcription factors, imbalance of signal pathway and changes of tumor microenvironment can promote the occurrence and development of liver cancer, and restoring its normal level can inhibit the malignant behavior of tumor. At present, some drugs have been proved to be effective, but more clinical data are needed to support the effectiveness and reliability of drugs. The differentiation treatment of liver cancer is expected to become an important part of the treatment of liver cancer in the future.
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Affiliation(s)
- Jianning Song
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Guangzhou Medical University, Shenzhen, China
| | - Hongzhong Zhou
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Dayong Gu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China
| | - Yong Xu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Guangzhou Medical University, Shenzhen, China
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22
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Porukala M, Vinod PK. Systems-level analysis of transcriptome reorganization during liver regeneration. Mol Omics 2022; 18:315-327. [DOI: 10.1039/d1mo00382h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Tissue homeostasis and regeneration depend on the reversible transitions between quiescence (G0) and proliferation. The liver has a remarkable capacity to regenerate after injury or resection by cell growth and...
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23
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Shu Y, Hassan F, Ostrowski MC, Mehta KD. Role of hepatic PKCβ in nutritional regulation of hepatic glycogen synthesis. JCI Insight 2021; 6:149023. [PMID: 34622807 PMCID: PMC8525638 DOI: 10.1172/jci.insight.149023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 08/12/2021] [Indexed: 01/12/2023] Open
Abstract
The signaling mechanisms by which dietary fat and cholesterol signals regulate central pathways of glucose homeostasis are not completely understood. By using a hepatocyte-specific PKCβ-deficient (PKCβHep-/-) mouse model, we demonstrated the role of hepatic PKCβ in slowing disposal of glucose overload by suppressing glycogenesis and increasing hepatic glucose output. PKCβHep-/- mice exhibited lower plasma glucose under the fed condition, modestly improved systemic glucose tolerance and mildly suppressed gluconeogenesis, increased hepatic glycogen accumulation and synthesis due to elevated glucokinase expression and activated glycogen synthase (GS), and suppressed glucose-6-phosphatase expression compared with controls. These events were independent of hepatic AKT/GSK-3α/β signaling and were accompanied by increased HNF-4α transactivation, reduced FoxO1 protein abundance, and elevated expression of GS targeting protein phosphatase 1 regulatory subunit 3C in the PKCβHep-/- liver compared with controls. The above data strongly imply that hepatic PKCβ deficiency causes hypoglycemia postprandially by promoting glucose phosphorylation via upregulating glucokinase and subsequently redirecting more glucose-6-phosphate to glycogen via activating GS. In summary, hepatic PKCβ has a unique and essential ability to induce a coordinated response that negatively affects glycogenesis at multiple levels under physiological postprandial conditions, thereby integrating nutritional fat intake with dysregulation of glucose homeostasis.
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Affiliation(s)
- Yaoling Shu
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Faizule Hassan
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Michael C Ostrowski
- Department of Biochemistry & Molecular Biology, Holling Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kamal D Mehta
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.,Instacare Therapeutics, Dublin, Ohio, USA
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24
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Diaz-Aragon R, Coard MC, Amirneni S, Faccioli L, Haep N, Malizio MR, Motomura T, Kocas-Kilicarslan ZN, Ostrowska A, Florentino RM, Frau C. Therapeutic Potential of HNF4α in End-stage Liver Disease. Organogenesis 2021; 17:126-135. [PMID: 35114889 DOI: 10.1080/15476278.2021.1994273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
The prevalence of end-stage liver disease (ESLD) in the US is increasing at an alarming rate. It can be caused by several factors; however, one of the most common routes begins with nonalcoholic fatty liver disease (NAFLD). ESLD is diagnosed by the presence of irreversible damage to the liver. Currently, the only definitive treatment for ESLD is orthotopic liver transplantation (OLT). Nevertheless, OLT is limited due to a shortage of donor livers. Several promising alternative treatment options are under investigation. Researchers have focused on the effect of liver-enriched transcription factors (LETFs) on disease progression. Specifically, hepatocyte nuclear factor 4-alpha (HNF4α) has been reported to reset the liver transcription network and possibly play a role in the regression of fibrosis and cirrhosis. In this review, we describe the function of HNF4α, along with its regulation at various levels. In addition, we summarize the role of HNF4α in ESLD and its potential as a therapeutic target in the treatment of ESLD.
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Affiliation(s)
- Ricardo Diaz-Aragon
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Michael C Coard
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Sriram Amirneni
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Lanuza Faccioli
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Nils Haep
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Michelle R Malizio
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Takashi Motomura
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | - Alina Ostrowska
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rodrigo M Florentino
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Carla Frau
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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25
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Wang Z, Zhang Y, Zhang J, Deng Q, Liang H. Controversial roles of hepatocyte nuclear receptor 4 α on tumorigenesis. Oncol Lett 2021; 21:356. [PMID: 33747213 PMCID: PMC7968000 DOI: 10.3892/ol.2021.12617] [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: 09/08/2020] [Accepted: 02/09/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte nuclear receptor 4 α (HNF4α) is known to be a master transcription regulator of gene expression in multiple biological processes, particularly in liver development and liver function. To date, the function of HNF4α in human cancers has been widely investigated; however, the critical roles of HNF4α in tumorigenesis remain unclear. Numerous controversies exist, even in studies from different research groups but on the same type of cancer. In the present review, the critical roles of HNF4α in tumorigenesis will be summarized and discussed. Furthermore, HNF4α expression profile and alterations will be examined by pan-cancer analysis through bioinformatics, in order to provide a better understanding of the functional roles of this gene in human cancers.
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Affiliation(s)
- Zhu Wang
- Department of Urology, People's Hospital of Longhua, Southern Medical University, Shenzhen, Guangdong 518109, P.R. China
| | - Ying Zhang
- Department of Urology, People's Hospital of Longhua, Southern Medical University, Shenzhen, Guangdong 518109, P.R. China
| | - Jianwen Zhang
- Department of Urology, People's Hospital of Longhua, Southern Medical University, Shenzhen, Guangdong 518109, P.R. China
| | - Qiong Deng
- Department of Urology, People's Hospital of Longhua, Southern Medical University, Shenzhen, Guangdong 518109, P.R. China
| | - Hui Liang
- Department of Urology, People's Hospital of Longhua, Southern Medical University, Shenzhen, Guangdong 518109, P.R. China
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26
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Dong X, Wang F, Liu C, Ling J, Jia X, Shen F, Yang N, Zhu S, Zhong L, Li Q. Single-cell analysis reveals the intra-tumor heterogeneity and identifies MLXIPL as a biomarker in the cellular trajectory of hepatocellular carcinoma. Cell Death Discov 2021; 7:14. [PMID: 33462196 PMCID: PMC7814056 DOI: 10.1038/s41420-021-00403-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/11/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a globally prevailing cancer with a low 5-year survival rate. Little is known about its intricate gene expression profile. Single-cell RNA sequencing is an indispensable tool to explore the genetic characteristics of HCC at a more detailed level. In this study, we profiled the gene expression of single cells from human HCC tumor and para-tumor tissues using the Smart-seq 2 sequencing method. Based on differentially expressed genes, we identified heterogeneous subclones in HCC tissues, including five HCC and two hepatocyte subclones. We then carried out hub-gene co-network and functional annotations analysis followed pseudo-time analysis with regulated transcriptional factor co-networks to determine HCC cellular trajectory. We found that MLX interacting protein like (MLXIPL) was commonly upregulated in the single cells and tissues and associated with a poor survival rate in HCC. Mechanistically, MLXIPL activation is crucial for promoting cell proliferation and inhibits cell apoptosis by accelerating cell glycolysis. Taken together, our work identifies the heterogeneity of HCC subclones, and suggests MLXIPL might be a promising therapeutic target for HCC.
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Affiliation(s)
- Xiao Dong
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Fan Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chuan Liu
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Jing Ling
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Xuebing Jia
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Feifei Shen
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Ning Yang
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Sibo Zhu
- Center for Pharmacogenomics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Lin Zhong
- Department of Hepatobiliary and General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
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27
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Qiu MJ, Zhang L, Fang XF, Li QT, Zhu LS, Zhang B, Yang SL, Xiong ZF. Research on the circadian clock gene HNF4a in different malignant tumors. Int J Med Sci 2021; 18:1339-1347. [PMID: 33628089 PMCID: PMC7893568 DOI: 10.7150/ijms.49997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 01/04/2021] [Indexed: 11/28/2022] Open
Abstract
Background: The circadian rhythm is produced by multiple feedback loops formed by the core clock genes after transcription and translation, thus regulating various metabolic and physiological functions of the human body. We have shown previously that the abnormal expression of 14 clock genes is related closely to the occurrence and development of different malignant tumors, and these genes may play an anti-cancer or pro-cancer role in different tumors. HNF4a has many typical properties of clock proteins involved in the clock gene negative feedback loop regulation process. We need to explore the function of HNF4a as a circadian clock gene in malignant tumors further. Methods: We used The Cancer Genome Atlas (TCGA) database to download the clinicopathological information of twenty malignant tumors and the corresponding RNA-seq data. The HNF4a RNA-seq data standardized by R language and clinical information were integrated to reveal the relationship between HNF4a and prognosis of patients. Results: Analysis of TCGA data showed that the prognosis of HNF4a was significantly different in BLCA, KIRC, LUSC, and READ. High HNF4a expression is correlated with good prognosis in BLCA, KIRC, and READ but poor prognosis in LUSC. However, HNF4a was associated with the stages, T stages, and lymph node status only in BLCA. Conclusions: HNF4a plays different roles in different malignancies, and the abnormal expression of HNF4a has a great correlation with the biological characteristics of BLCA. The low expression of HNF4a could be a reference index for the metastasis, recurrence, and prognosis of BLCA.
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Affiliation(s)
- Meng-Jun Qiu
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Li Zhang
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Xie-Fan Fang
- Charles River Laboratories, Inc., 6995 Longley Lane, Reno NV 89511
| | - Qiu-Ting Li
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Li-Sheng Zhu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bin Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Sheng-Li Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhi-Fan Xiong
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
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28
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Kozaczek M, Bottje W, Kong B, Dridi S, Albataineh D, Lassiter K, Hakkak R. Long-Term Soy Protein Isolate Consumption Reduces Liver Steatosis Through Changes in Global Transcriptomics in Obese Zucker Rats. Front Nutr 2020; 7:607970. [PMID: 33363197 PMCID: PMC7759473 DOI: 10.3389/fnut.2020.607970] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
To determine how soy protein isolate (SPI) ameliorated liver steatosis in male obese Zucker rats, we conducted global transcriptomic expression (RNAseq) analysis on liver samples of male rats fed either the SPI or a control casein (CAS)-based diet (n = 8 per group) for 16 weeks. Liver transcriptomics were analyzed using an Ilumina HiSeq system with 2 × 100 base pair paired-end reads method. Bioinformatics was conducted using Ingenuity Pathway Analysis (IPA) software (Qiagen, CA) with P < 0.05 and 1.3-fold differential expression cutoff values. Regression analysis between RNAseq data and targeted mRNA expression analysis of 12 top differentially expressed genes (from the IPA program) using quantitative PCR (qPCR) revealed a significant regression analysis (r2 = 0.69, P = 0.0008). In addition, all qPCR values had qualitatively similar direction of up- or down-regulation compared to the RNAseq transcriptomic data. Diseases and function analyses that were based on differentially expressed target molecules in the dataset predicted that lipid metabolism would be enhanced whereas inflammation was predicted to be inhibited in SPI-fed compared to CAS-fed rats at 16 weeks. Combining upstream regulator and regulator effects functions in IPA facilitates the prediction of upstream regulators (e.g., transcription regulators) that could play important roles in attenuating or promoting liver steatosis due to SPI or CAS diets. Upstream regulators that were predicted to be activated (from expression of down-stream targets) linked to increased conversion of lipid and transport of lipid in SPI-fed rats included hepatocyte nuclear factor 4 alpha (HNF4A) and aryl hydrocarbon receptor (AHR). Upstream regulators that were predicted to be activated in CAS-fed rats linked to activation of phagocytosis and neutrophil chemotaxis included colony stimulating factor 2 and tumor necrosis factor. The results provide clear indication that long-term SPI-fed rats exhibited diminished inflammatory response and increased lipid transport in liver compared to CAS-fed rats that likely would contribute to reduced liver steatosis in this obese Zucker rat model.
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Affiliation(s)
- Melisa Kozaczek
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Walter Bottje
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Byungwhi Kong
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Sami Dridi
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Diyana Albataineh
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Kentu Lassiter
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Reza Hakkak
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States.,Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Arkansas Children's Research Institute, Little Rock, AR, United States
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29
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Liu W, Liu Q, Zhang B, Lin Z, Li X, Yang X, Pu M, Zou R, He Z, Wang F, Dou K. The mRNA of TCTP functions as a sponge to maintain homeostasis of TCTP protein levels in hepatocellular carcinoma. Cell Death Dis 2020; 11:974. [PMID: 33184257 PMCID: PMC7665032 DOI: 10.1038/s41419-020-03149-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/10/2020] [Accepted: 10/13/2020] [Indexed: 01/01/2023]
Abstract
Translationally controlled tumor protein (TCTP) is a highly conserved protein that accumulated in the tumorigenesis of various malignancies. Despite the important role of TCTP protein in tumor progression, the precise function and underlying mechanistic regulation of TCTP mRNA in hepatocellular carcinoma (HCC) remain unclear. In this study, we found that TCTP protein was overexpressed in HCC patients but TCTP mRNA expression levels were reversed. TCTP knockout HCC cells exhibited attenuated abilities of proliferation, migration, and invasion. The knockdown of TCTP by siRNA effectively reduced TCTP mRNA levels but not protein levels in HCC cells. Moreover, although the constitutive knockdown of TCTP inhibited almost 80% of TCTP protein expression levels in tumors of wildtype transgenic mice (TCTP KD/WT), partial restoration of TCTP protein expression was observed in the tumors of heterozygous TCTP mice (TCTP KD/TCTP±). The blockage of mRNA synthesis with ActD stimulated TCTP protein expression in HCC cells. In contrast, combined treatment with ActD and CHX or MG132 treatment alone did not lead to the TCTP protein accumulation in cells. Furthermore, following the introduction of exogenous TCTP in cells and orthotopic HCC tumor models, the endogenous TCTP protein did not change with the recombinational TCTP expression and kept a rather stable level. Dual-luciferase assays revealed that the coding sequence of TCTP mRNA functions as a sponge to regulate the TCTP protein expression. Collectively, our results indicated that the TCTP mRNA and protein formed a closed regulatory circuit and works as a buffering system to keep the homeostasis of TCTP protein levels in HCC.
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Affiliation(s)
- Wei Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200123, China.,Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Qi Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
| | - Beilei Zhang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, 710038, China
| | - Zhibin Lin
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
| | - Xia Li
- Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China
| | - Xisheng Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
| | - Meng Pu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
| | - Rongzhi Zou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200123, China. .,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China.
| | - Fu Wang
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710071, China.
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China.
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30
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Kochevalina MY, Trunov VG, Morozova OV, Kogun GA, Rodionova EI. Change in Urine Odor of Mice in the Dynamics of Formation of a Transplanted Hepatocarcinoma H33 Tumor. BIOL BULL+ 2020. [DOI: 10.1134/s1062359020050052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Optical percutaneous needle biopsy of the liver: a pilot animal and clinical study. Sci Rep 2020; 10:14200. [PMID: 32848190 PMCID: PMC7449966 DOI: 10.1038/s41598-020-71089-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 08/10/2020] [Indexed: 12/15/2022] Open
Abstract
This paper presents the results of the experiments which were performed using the optical biopsy system specially developed for in vivo tissue classification during the percutaneous needle biopsy (PNB) of the liver. The proposed system includes an optical probe of small diameter acceptable for use in the PNB of the liver. The results of the feasibility studies and actual tests on laboratory mice with inoculated hepatocellular carcinoma and in clinical conditions on patients with liver tumors are presented and discussed. Monte Carlo simulations were carried out to assess the diagnostic volume and to trace the sensing depth. Fluorescence and diffuse reflectance spectroscopy measurements were used to monitor metabolic and morphological changes in tissues. The tissue oxygen saturation was evaluated using a recently developed approach to neural network fitting of diffuse reflectance spectra. The Support Vector Machine Classification was applied to identify intact liver and tumor tissues. Analysis of the obtained results shows the high sensitivity and specificity of the proposed multimodal method. This approach allows to obtain information before the tissue sample is taken, which makes it possible to significantly reduce the number of false-negative biopsies.
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32
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Lavin DP, Tiwari VK. Unresolved Complexity in the Gene Regulatory Network Underlying EMT. Front Oncol 2020; 10:554. [PMID: 32477926 PMCID: PMC7235173 DOI: 10.3389/fonc.2020.00554] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 03/27/2020] [Indexed: 12/14/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) is the process whereby a polarized epithelial cell ceases to maintain cell-cell contacts, loses expression of characteristic epithelial cell markers, and acquires mesenchymal cell markers and properties such as motility, contractile ability, and invasiveness. A complex process that occurs during development and many disease states, EMT involves a plethora of transcription factors (TFs) and signaling pathways. Whilst great advances have been made in both our understanding of the progressive cell-fate changes during EMT and the gene regulatory networks that drive this process, there are still gaps in our knowledge. Epigenetic modifications are dynamic, chromatin modifying enzymes are vast and varied, transcription factors are pleiotropic, and signaling pathways are multifaceted and rarely act alone. Therefore, it is of great importance that we decipher and understand each intricate step of the process and how these players at different levels crosstalk with each other to successfully orchestrate EMT. A delicate balance and fine-tuned cooperation of gene regulatory mechanisms is required for EMT to occur successfully, and until we resolve the unknowns in this network, we cannot hope to develop effective therapies against diseases that involve aberrant EMT such as cancer. In this review, we focus on data that challenge these unknown entities underlying EMT, starting with EMT stimuli followed by intracellular signaling through to epigenetic mechanisms and chromatin remodeling.
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Affiliation(s)
| | - Vijay K. Tiwari
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
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Yang X, Chen X, Xia C, Li S, Zhu L, Xu C. Comparative analysis of the expression profiles of genes related to the Gadd45α signaling pathway in four kinds of liver diseases. Histol Histopathol 2020; 35:949-960. [PMID: 32298459 DOI: 10.14670/hh-18-218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gadd45α (growth arrest and DNA damage inducible alpha) is a member of a group of genes whose transcript levels are increased following stressful conditions that lead to growth arrest and treatment with agents that lead to DNA damage. Gadd45α is upregulated in liver cirrhosis (LC), hepatic cancer (HC), acute liver failure (AHF) and non-alcoholic fatty liver disease(NAFLD). Here, we investigated the essential differences in the Gadd45α signaling pathway in these diseases at the transcriptional level. The results showed that 44, 46, 71 and 27 genes significant changes in these diseases, and the H-cluster showed that the expression of the Gadd45α signaling-related genes was significantly different in the four liver diseases. DAVID functional analysis showed that the Gadd45α signaling pathway-related genes were mainly involved in cell adhesion and migration, cell proliferation, apoptosis, stress and inflammatory responses, etc. Ingenuity pathway analysis (IPA) software was used to predict the functions of the Gadd45α signaling-related genes, and the results indicated that there were significant changes in cell differentiation, DNA damage repair, autophagy, apoptosis and necrosis. Gadd45α signaling pathway is involved in four kinds of liver disease and regulates a variety of activities via P38 MAPK, NF-κB, mTOR/STAT3, P21, PCNA, PI3K/Akt and other signaling pathways. Modulation of Gadd45α may be exploited to prevent the progression of liver disease, and to identify specific treatments for different stages of liver disease. In summary, the Gadd45α signaling pathway is involved in four kinds of liver disease and regulates a variety of physiological activities through various signaling pathways.
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Affiliation(s)
- Xianguang Yang
- College of Life Science, Henan Normal University, Xinxiang, Henan Province, China. .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Bioengineering Key Laboratory, Henan Normal University, Xinxiang, Henan Province, China
| | - Xuelin Chen
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Bioengineering Key Laboratory, Henan Normal University, Xinxiang, Henan Province, China.,College of Life Science, Henan Normal University, Xinxiang, Henan Province, China
| | - Cong Xia
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Bioengineering Key Laboratory, Henan Normal University, Xinxiang, Henan Province, China.,College of Life Science, Henan Normal University, Xinxiang, Henan Province, China
| | - Shuaihong Li
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Bioengineering Key Laboratory, Henan Normal University, Xinxiang, Henan Province, China.,College of Life Science, Henan Normal University, Xinxiang, Henan Province, China
| | - Lin Zhu
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Bioengineering Key Laboratory, Henan Normal University, Xinxiang, Henan Province, China.,College of Life Science, Henan Normal University, Xinxiang, Henan Province, China
| | - Cunshuan Xu
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Bioengineering Key Laboratory, Henan Normal University, Xinxiang, Henan Province, China.,College of Life Science, Henan Normal University, Xinxiang, Henan Province, China
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34
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Yang G, Zhang M, Zhao Y, Pan Y, Kan M, Li J, He K, Zhang X. HNF-4α inhibits hepatocellular carcinoma cell proliferation through mir-122-adam17 pathway. PLoS One 2020; 15:e0230450. [PMID: 32210451 PMCID: PMC7094838 DOI: 10.1371/journal.pone.0230450] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 03/01/2020] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common human cancers, its prevalence and severity need us to discover novel early diagnostic biomarkers and new therapeutic strategies. MicroRNA-122 is the most abundant microRNA in the liver, and acts as a tumor suppressor and represses HCC development. In our study we showed that HNF-4α and MiR-122 were down-regulated significantly in hepatocellular carcinoma. Over-expression of HNF-4α inhibit hepatocellular carcinoma cells proliferation. And miR-122 is one of the downstream effector of HNF-4α. Up-regulated miR-122 inhibited hepatocellular carcinoma cells proliferation through regulating ADAM17. Collectively, our results suggested that HNF-4α could inhibit hepatocellular carcinoma proliferation with miR-122 being a downstream target of it. And miR-122 would inhibit hepatocellular carcinoma proliferation by regulating ADAM17 signal pathway.
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Affiliation(s)
- Guang Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Jilin University, Changchun, Jilin, China
| | - Min Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yawei Zhao
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yue Pan
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Mujie Kan
- Department of Biochemistry, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jing Li
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
- * E-mail: (XZ); (KH)
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Jilin University, Changchun, Jilin, China
- * E-mail: (XZ); (KH)
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35
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Sun P, Chen S, Li Y. The association between pretreatment serum alkaline phosphatase and prognosis in hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore) 2020; 99:e19438. [PMID: 32176073 PMCID: PMC7220248 DOI: 10.1097/md.0000000000019438] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Numerous studies have investigated the association between pretreatment serum alkaline phosphatase (ALP) and prognosis in hepatocellular carcinoma (HCC), but conclusions remain controversial. Thus, we performed a meta-analysis to assess systematically the relationship between ALP and prognosis in HCC. METHODS We searched the PubMed, EMBASE, and Web of Science databases for eligible studies up to October. A combined hazard ratio (HR) was determined to describe the correlation between pretreatment serum ALP level and prognosis in HCC patients. Overall survival (OS) was calculated from the date of treatment either to the end point of the follow-up period or to the date of death by any cause. Disease-free survival (DFS) and recurrence-free survival (RFS) were defined as the period from the date of treatment to the date of last follow-up or to the date of recurrence. OS was regarded as the major outcome. RESULTS Altogether, 21 studies about OS and 6 studies about DFS/RFS were included in this meta-analysis. Our combined results showed that there was an inverse association of pretreatment serum ALP level with OS (HR=1.15, 95% CI: 1.12-1.19) and RFS (HR=1.78, 95% CI: 1.37-2.31). CONCLUSION There was a close association between high pretreatment ALP level and poor survival in HCC patients, indicating that ALP may be used as a biomarker for prognosis. More high-quality studies are required to validate our findings further, considering the limitations of our meta-analysis.
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Affiliation(s)
- Ping Sun
- Department of Spleen and Stomach Diseases, Gansu Provincial Hospital of Traditional Chinese Medicine
| | - Shihai Chen
- Department of Pediatric Orthopaedics, Gansu Provincial Hospital of traditional Chinese Medicine, Lanzhou, Gansu Province, China
| | - Yanlong Li
- Department of Spleen and Stomach Diseases, Gansu Provincial Hospital of Traditional Chinese Medicine
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36
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Campos G, Schmidt-Heck W, De Smedt J, Widera A, Ghallab A, Pütter L, González D, Edlund K, Cadenas C, Marchan R, Guthke R, Verfaillie C, Hetz C, Sachinidis A, Braeuning A, Schwarz M, Weiß TS, Banhart BK, Hoek J, Vadigepalli R, Willy J, Stevens JL, Hay DC, Hengstler JG, Godoy P. Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease. Arch Toxicol 2020; 94:205-217. [PMID: 31919559 DOI: 10.1007/s00204-019-02630-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023]
Abstract
Inflammation has been recognized as essential for restorative regeneration. Here, we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function, and regeneration. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl4 (2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl4 intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl4-induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.
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Affiliation(s)
- Gisela Campos
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Wolfgang Schmidt-Heck
- Leibniz Institute for Natural Product Research and Infection Biology e.V., Hans-Knöll Institute, Jena, Germany
| | | | - Agata Widera
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Ahmed Ghallab
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
- Department of Forensic and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Larissa Pütter
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Daniela González
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Karolina Edlund
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Cristina Cadenas
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Rosemarie Marchan
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Reinhard Guthke
- Leibniz Institute for Natural Product Research and Infection Biology e.V., Hans-Knöll Institute, Jena, Germany
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- The Buck Institute for Research in Aging, Novato, CA, 94945, USA
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
| | - Agapios Sachinidis
- Medical Faculty, Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Albert Braeuning
- Department of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany
- Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Michael Schwarz
- Department of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany
| | - Thomas S Weiß
- Department of Pediatrics and Juvenile Medicine, Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany
| | - Benjamin K Banhart
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jan Hoek
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Rajanikanth Vadigepalli
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jeffrey Willy
- Vertex Pharmaceuticals, 3215 Merryfield Row, San Diego, CA, 92121, USA
| | - James L Stevens
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA
| | - David C Hay
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, E16 4UU, UK
| | - Jan G Hengstler
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany.
| | - Patricio Godoy
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany.
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Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence. Oncogene 2019; 39:1572-1589. [PMID: 31695151 PMCID: PMC7018660 DOI: 10.1038/s41388-019-1080-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022]
Abstract
Hepatocyte nuclear factor 4α (HNF4α, NR2A1) is a highly conserved member of the nuclear receptor superfamily. Recent advances reveal that it is a key transcriptional regulator of genes, broadly involved in xenobiotic and drug metabolism and also cancers of gastrointestinal tract. However, the exact functional roles of HNF4α in prostate cancer progression are still not fully understood. In this study, we determined the functional significance of HNF4α in prostate cancer. Our results showed that HNF4α exhibited a reduced expression pattern in clinical prostate cancer tissues, prostate cancer cell lines and xenograft model of castration-relapse prostate cancer. Stable HNF4α knockdown not only could promote cell proliferation and suppress doxorubicin (Dox)-induced cellular senescence in prostate cancer cells, but also confer resistance to paclitaxel treatment and enhance colony formation capacity and in vivo tumorigenicity of prostate cancer cells. On the contrary, ectopic overexpression of HNF4α could significantly inhibit the cell proliferation of prostate cancer cells, induce cell-cycle arrest at G2/M phase and trigger the cellular senescence in prostate cancer cells by activation of p21 signal pathway in a p53-independent manner via its direct transactivation of CDKN1A. Together, our results show that HNF4α performs a tumor suppressor function in prostate cancer via a mechanism of p21-driven cellular senescence.
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38
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Aydin Y, Kurt R, Song K, Lin D, Osman H, Youngquist B, Scott JW, Shores NJ, Thevenot P, Cohen A, Dash S. Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A- miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression. Cancers (Basel) 2019; 11:1407. [PMID: 31547152 PMCID: PMC6827087 DOI: 10.3390/cancers11101407] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/14/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection.
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Affiliation(s)
- Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Ramazan Kurt
- Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Dong Lin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Hanadi Osman
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Brady Youngquist
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - John W Scott
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Nathan J Shores
- Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Paul Thevenot
- Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA.
| | - Ari Cohen
- Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA.
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
- Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
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Gao Y, Yan Y, Guo J, Zhang Q, Bi D, Wang F, Chang Z, Lu L, Yao X, Wei Q. HNF‑4α downregulation promotes tumor migration and invasion by regulating E‑cadherin in renal cell carcinoma. Oncol Rep 2019; 42:1066-1074. [PMID: 31322246 PMCID: PMC6667891 DOI: 10.3892/or.2019.7214] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 06/18/2019] [Indexed: 12/19/2022] Open
Abstract
Renal cell carcinoma (RCC) is the most common malignant disease of the kidneys in adults. Patients with metastatic RCC have an unusually poor prognosis and exhibit resistance to all current therapies. Therefore, it is necessary to explore novel molecules involved in the progression of RCC and to identify effective therapeutic targets. Hepatocyte nuclear factor‑4α (HNF‑4α) serves an important role in hepatocyte differentiation and is involved in the progression of liver cancer; however, the functional role of HNF‑4α has not been well established in RCC. The present study reported that HNF‑4α expression was markedly downregulated in RCC tissue samples compared with in normal controls by immunohistochemistry and RNA‑sequencing analysis. Statistical analysis demonstrated that HNF‑4α downregulation was significantly associated with tumor stage, recurrence, metastasis and poor prognosis in patients with RCC. Furthermore, wound‑healing and Transwell assays revealed that downregulation of HNF‑4α promoted cell migration and invasion by transcriptionally regulating E‑cadherin in RCC. Finally, a positive correlation was revealed between HNF‑4α expression and E‑cadherin expression, and patients with low E‑cadherin expression also had a poor prognosis. These findings may provide novel insights into the biological effects of HNF‑4α and lay the foundation for the discovery of molecular therapeutic targets in RCC.
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MESH Headings
- Aged
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Case-Control Studies
- Cell Movement
- Cell Proliferation
- Female
- Follow-Up Studies
- Gene Expression Regulation, Neoplastic
- Hepatocyte Nuclear Factor 4/genetics
- Hepatocyte Nuclear Factor 4/metabolism
- Humans
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/secondary
- Male
- Middle Aged
- Neoplasm Invasiveness
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/pathology
- Prognosis
- Survival Rate
- Tumor Cells, Cultured
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Affiliation(s)
- Yaohui Gao
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Yang Yan
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Jing Guo
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Qian Zhang
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Dexi Bi
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Fen Wang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
- Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Zhengyan Chang
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Ling Lu
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Xudong Yao
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
| | - Qing Wei
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
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40
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Bisceglia F, Battistelli C, Noce V, Montaldo C, Zammataro A, Strippoli R, Tripodi M, Amicone L, Marchetti A. TGFβ Impairs HNF1α Functional Activity in Epithelial-to-Mesenchymal Transition Interfering With the Recruitment of CBP/p300 Acetyltransferases. Front Pharmacol 2019; 10:942. [PMID: 31543815 PMCID: PMC6728925 DOI: 10.3389/fphar.2019.00942] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 07/24/2019] [Indexed: 12/24/2022] Open
Abstract
The cytokine transforming growth factor β (TGFβ) plays a crucial role in the induction of both epithelial-to-mesenchymal transition (EMT) program and fibro-cirrhotic process in the liver, where it contributes also to organ inflammation following several chronic injuries. All these pathological situations greatly increase the risk of hepatocellular carcinoma (HCC) and contribute to tumor progression. In particular, late-stage HCCs are characterized by constitutive activation of TGFβ pathway and by an EMT molecular signature leading to the acquisition of invasive and metastatic properties. In these pathological conditions, the cytokine has been shown to induce the transcriptional downregulation of HNF1α, a master regulator of the epithelial/hepatocyte differentiation and of the EMT reverse process, the mesenchymal-to-epithelial transition (MET). Therefore, the restoration of HNF1α expression/activity has been proposed as targeted therapeutic strategy for liver fibro-cirrhosis and late-stage HCCs. In this study, TGFβ is found to trigger an early functional inactivation of HNF1α during EMT process that anticipates the effects of the transcriptional downregulation of its own gene. Mechanistically, the cytokine, while not affecting the HNF1α DNA-binding capacity, impaired its ability to recruit CBP/p300 acetyltransferases on target gene promoters and, consequently, its transactivating function. The loss of HNF1α capacity to bind to CBP/p300 and HNF1α functional inactivation have been found to correlate with a change of its posttranslational modification profile. Collectively, the results obtained in this work unveil a new level of HNF1α functional inactivation by TGFβ and contribute to shed light on the early events triggering EMT in hepatocytes. Moreover, these data suggest that the use of HNF1α as anti-EMT tool in a TGFβ-containing microenvironment may require the design of new therapeutic strategies overcoming the TGFβ-induced HNF1α inactivation.
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Affiliation(s)
- Francesca Bisceglia
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Cecilia Battistelli
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Valeria Noce
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudia Montaldo
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy
| | - Agatino Zammataro
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Raffaele Strippoli
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy
| | - Marco Tripodi
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy
| | - Laura Amicone
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Marchetti
- Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
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41
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Yeh MM, Bosch DE, Daoud SS. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases. World J Gastroenterol 2019; 25:4074-4091. [PMID: 31435165 PMCID: PMC6700705 DOI: 10.3748/wjg.v25.i30.4074] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.
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Affiliation(s)
- Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Dustin E Bosch
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Sayed S Daoud
- Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99210, United States
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Xie P, Hu X, Li D, Xie S, Zhou Z, Meng X, Shan H. Bioluminescence Imaging of Transplanted Mesenchymal Stem Cells by Overexpression of Hepatocyte Nuclear Factor4α: Tracking Biodistribution and Survival. Mol Imaging Biol 2019; 21:44-53. [PMID: 29761416 DOI: 10.1007/s11307-018-1204-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
PURPOSE The purposes of this study were to construct immortalized human bone marrow mesenchymal stem cells (UE7T-13) with overexpression of the hepatocyte nuclear factor4α (hHNF4α) and luciferase2-mKate2 dual-fusion reporter gene, further investigate their impact on treating acute liver injury (ALI) in rats, and track their biodistribution and survival by bioluminescence imaging (BLI). PROCEDURES The hHNF4α and luciferase2-mKate2 genes were transduced by a lentiviral vector into UE7T-13 cells (named E7-hHNF4α-R cells), and expression was verified by immunofluorescence, RT-PCR, and flow cytometry. E7-hGFP-R cells expressing the luciferase2-mKate2/hGFP gene served as a negative group. A correlation between the bioluminescence signal and cell number was detected by BLI. The ALI rats were established and divided into three groups: PBS, E7-hGFP-R, and E7-hHNF4α-R. After transplantation of 2.0 × 106 cells, BLI was used to dynamically track their biodistribution and survival. The restoration of biological functions was assessed by serum biochemical and histological analyses. RESULTS Stable high-level expression of hHNF4α and mKate2 protein was established in the E7-hHNF4α-R cells in vitro. The E7-hHNF4α-R cells strongly expressed hGFP, hHNF4α, and mKate2 proteins, and the hHNF4α gene. hGFP-mKate2 dual-positive cell expression reached approximately 93 %. BLI verified that a linear relationship existed between the cell number and bioluminescence signal (R2 = 0.9991). The cells improved liver function in vivo after transplantation into the ALI rat liver, as evidenced by the fact that AST and ALT temporarily returned to normal levels in the recipient ALI rats. The presence of the transplanted E7-hGFP-R and E7-hHNF4α-R cells in recipient rat livers was confirmed by BLI and immunohistochemistry. However, the cells were cleared by the immune system a short time after transplantation into ALI rats with a normal immune system. CONCLUSION Our data revealed that the E7-hHNF4α-R cells can transiently improve damaged liver function and were rapidly cleared by the immune system. In addition, BLI is a useful tool to track transplanted cell biodistribution and survival.
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Affiliation(s)
- Peiyi Xie
- Guang Dong Provincial Engineering Research Center of Molecular Imaging, Zhuhai, China.,Department of Radiology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaojun Hu
- Guang Dong Provincial Engineering Research Center of Molecular Imaging, Zhuhai, China.,Interventional Medicine Department, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.,Interventional Radiology Institute, Sun Yat-sen University, Zhuhai, China
| | - Dan Li
- Guang Dong Provincial Engineering Research Center of Molecular Imaging, Zhuhai, China.,Interventional Medicine Department, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.,Interventional Radiology Institute, Sun Yat-sen University, Zhuhai, China
| | - Sidong Xie
- The Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhiyang Zhou
- Department of Radiology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaochun Meng
- Department of Radiology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Hong Shan
- Guang Dong Provincial Engineering Research Center of Molecular Imaging, Zhuhai, China. .,Interventional Medicine Department, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China. .,Interventional Radiology Institute, Sun Yat-sen University, Zhuhai, China.
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Chen YR, Huang HC, Lin CC. Regulatory feedback loops bridge the human gene regulatory network and regulate carcinogenesis. Brief Bioinform 2019; 20:976-984. [PMID: 29194477 DOI: 10.1093/bib/bbx166] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 11/10/2017] [Indexed: 12/17/2022] Open
Abstract
The development of disease involves a systematic disturbance inside cells and is associated with changes in the interactions or regulations among genes forming biological networks. The bridges inside a network are critical in shortening the distances between nodes. We observed that, inside the human gene regulatory network, one strongly connected core bridged the whole network. Other regulations outside the core formed a weakly connected component surrounding the core like a peripheral structure. Furthermore, the regulatory feedback loops (FBLs) inside the core compose an interface-like structure between the core and periphery. We then denoted the regulatory FBLs as the interface core. Notably, both the cancer-associated and essential biomolecules and regulations were significantly overrepresented in the interface core. These results implied that the interface core is not only critical for the network structure but central in cellular systems. Furthermore, the enrichment of the cancer-associated and essential regulations in the interface core might be attributed to its bridgeness in the network. More importantly, we identified one regulatory FBL between HNF4A and NR2F2 that possesses the highest bridgeness in the interface core. Further investigation suggested that the disturbance of the HNF4A-NR2F2 FBL might protect tumor cells from apoptotic processes. Our results emphasize the relevance of the regulatory network properties to cellular systems and might reveal a critical role of the interface core in cancer.
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Affiliation(s)
- Yun-Ru Chen
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei
| | - Chen-Ching Lin
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei
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Wang P, Lei S, Wang X, Xu W, Hu P, Chen F, Zhang X, Yin C, Xie W. MicroRNA-134 deactivates hepatic stellate cells by targeting TGF-β activated kinase 1-binding protein 1. Biochem Cell Biol 2019; 97:505-512. [PMID: 30645141 DOI: 10.1139/bcb-2018-0211] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Aberrant expression of microRNAs is associated with liver fibrogenesis. We previously found that microRNA-134 (miR-134) expression was reduced in fibrosis-based hepatocarcinogenesis induced by diethylinitrosamine. Herein we investigate the role and mechanisms of miR-134 in hepatic fibrosis. Our data show that miR-134 expression is reduced in rat hepatic fibrogenesis induced by carbontetrachloride, bile duct ligation, and dimethylnitrosamine, as well as in activated hepatic stellate cells (HSCs). Moreover, miR-134 inhibited HSC proliferation, and decreased the expression of smooth muscle actin and collagen I in HSCs, whereas the miR-134 inhibitor increased HSC activation. MiR-134 also negatively regulated transforming growth factor-β-activated kinase 1-binding protein 1 (TAB1) expression in both human and rat HSCs by directly binding to its 3' untranslated region. Importantly, TAB1 expression was significantly elevated during liver fibrogenesis and HSC activation. Knockdown of TAB1 inhibited the proliferation and fibrogenic behavior of HSCs, and significantly reduced the effect of the miR-134 inhibitor on HSC proliferation. Collectively, these data suggest that miR-134 inhibits the activation of HSCs via directly targeting TAB1, and the restoration of miR-134 or targeting TAB1 is of clinical significance in the treatment of liver fibrosis.
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Affiliation(s)
- Peiqin Wang
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Shujuan Lei
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Xiaohang Wang
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Wenping Xu
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Pingfang Hu
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Fei Chen
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Xin Zhang
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Chuan Yin
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Weifen Xie
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
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Induction of Hepatic Metabolic Functions by a Novel Variant of Hepatocyte Nuclear Factor 4γ. Mol Cell Biol 2018; 38:MCB.00213-18. [PMID: 30224520 DOI: 10.1128/mcb.00213-18] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022] Open
Abstract
Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4γ was increased in liver-specific Hnf4a-null mice. The HNF4γ whose expression was increased contained two variants, a known short variant, designated HNF4γ1, and a novel long variant, designated HNF4γ2. HNF4G2 mRNA was highly expressed in small intestine, and the transactivation potential of HNF4γ2 was the strongest among these variants, but the potential of HNF4γ1 was the lowest. Cotransfection experiments revealed that HNF4γ1 repressed HNF4α- and HNF4γ2-dependent transactivation, while HNF4γ2 promoted HNF4α-dependent transactivation. HNF4γ1 and HNF4γ2 were able to bind to the HNF4α binding sites with an affinity similar to that of HNF4α. Furthermore, HNF4γ2, but not HNF4γ1, robustly induced the expression of typical HNF4α target genes to a greater degree than HNF4α. Additionally, HNF4γ2 suppressed proliferation of hepatoma cells as well as HNF4α and HNF4γ1 did, and HNF4γ2 induced critical hepatic functions, such as glucose and urea production, and cytochrome P450 1A2 activity more strongly than HNF4α and HNF4γ1 did. These results indicate that HNF4γ2 has potential for redifferentiation of HCC and thus may be explored as a target for HCC therapy.
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Jimenez M, Arechederra M, Ávila MA, Berasain C. Splicing alterations contributing to cancer hallmarks in the liver: central role of dedifferentiation and genome instability. Transl Gastroenterol Hepatol 2018; 3:84. [PMID: 30505971 DOI: 10.21037/tgh.2018.10.11] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 10/22/2018] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. HCCs are molecularly heterogeneous tumors, and this complexity is to a great extent responsible for their poor response to conventional and targeted therapies. In this review we summarize recent evidence indicating that imbalanced expression of mRNA splicing factors can be a relevant source for this heterogeneity. We also discuss how these alterations may play a driver role in hepatocarcinogenesis by impinging on the general hallmarks of cancer. Considering the natural history of HCC, we focused on two pathogenic features that are characteristic of liver tumors: chromosomal instability and phenotypic de-differentiation. We highlight mechanisms connecting splicing derangement with these two processes and the enabling capacities acquired by liver cells along their neoplastic transformation. A thorough understanding of the alterations in the splicing machinery may also help to identify new HCC biomarkers and to design novel therapeutic strategies.
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Affiliation(s)
- Maddalen Jimenez
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain
| | | | - Matías A Ávila
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Pamplona, Spain
| | - Carmen Berasain
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Pamplona, Spain
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47
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Krivtsova O, Makarova A, Lazarevich N. Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma. World J Hepatol 2018; 10:645-661. [PMID: 30386458 PMCID: PMC6206146 DOI: 10.4254/wjh.v10.i10.645] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/08/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors (TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.
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Affiliation(s)
- Olga Krivtsova
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
- M. V. Lomonosov Moscow State University, Moscow 119991, Russian
| | - Anna Makarova
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
| | - Natalia Lazarevich
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
- M. V. Lomonosov Moscow State University, Moscow 119991, Russian
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48
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Dai Y, Tang Z, Yang Z, Zhang L, Deng Q, Zhang X, Yu Y, Liu X, Zhu J. EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients. Cell Cycle 2018; 17:2386-2397. [PMID: 30328366 PMCID: PMC6237436 DOI: 10.1080/15384101.2018.1534511] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 09/17/2018] [Accepted: 10/05/2018] [Indexed: 02/08/2023] Open
Abstract
The roles of exonuclease 1 (EXO1) in hepatocellular carcinoma (HCC) tumorigenesis and progression remain unclear. This study aimed to assess the prognostic value and therapeutic potential of EXO1 in HCC. Exo1 gene copy numbers were obtained from three Oncomine microarray datasets (n = 447). EXO1 mRNA expression was validated by semi-quantitative PCR and QuantiGene® 2.0 assays. Cell growth curve and colony formation were performed to asses the cell proliferation. Clonogenic assay, flow cytometry, and immunofluorescence were adopted to acess the effects of EXO1 knockdown and radiation on cell survival, cell cycle distribution and DNA repair. Western blots were performed to reveal the related mechanism. A significant copy number variation (CNV) of the Exo1 gene was found in HCC specimens in three separate sets of published microarray data. In the 143 cases treated by our team, EXO1 expression levels were elevated (86.71%, 124/143). In addition, EXO1 overexpression was correlated with larger tumor size (P = 0.002), increased lymph node metastasis (P=0.033) and lower Edmondson grade (P = 0.018). High EXO1 expression unfavorably affected overall survival (OS) (P = 0.009). Both univariate and multivariate Cox regression analyses identified EXO1 as an independent predictor of OS (univariate, P = 0.012; multivariate, P = 0.039). Silencing of EXO1 in vitro reduced cell proliferation. EXO1 knockdown further suppressed clonogenic cell survival, abrogated radiation-induced G2/M phase arrest, and enhanced γ-H2AX foci after exposure to irradiation. The accumulation of ataxiatelangiectasia mutated (ATM) might partially regulate the EXO1 related radiosensitivity. In summary, EXO1 could be a promising prognostic marker, with a potential therapeutic value in HCC.
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Affiliation(s)
- Yaoyao Dai
- Department of Hepatology, Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zuxiong Tang
- Department of General surgery, the first affiliated hospital of soochow university, suzhou, China
| | - Zongguo Yang
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lan Zhang
- Department of Hepatology, Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qing Deng
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaofeng Zhang
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yongchun Yu
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xing Liu
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Biochip Corporation LTD./National Engineering Center for Biochip at Shanghai, Shanghai, China
| | - Junfeng Zhu
- Department of Hepatology, Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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49
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Fekry B, Ribas-Latre A, Baumgartner C, Deans JR, Kwok C, Patel P, Fu L, Berdeaux R, Sun K, Kolonin MG, Wang SH, Yoo SH, Sladek FM, Eckel-Mahan K. Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma. Nat Commun 2018; 9:4349. [PMID: 30341289 PMCID: PMC6195513 DOI: 10.1038/s41467-018-06648-6] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4α. This study reveals that P1-HNF4α, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4α, driven by an alternative promoter (P2-HNF4α), is induced in HNF4α-positive human hepatocellular carcinoma (HCC). P2-HNF4α represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4α. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4α in HCC, and demonstrate that forced expression of BMAL1 in HNF4α-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4α-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.
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Affiliation(s)
- Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Aleix Ribas-Latre
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Corrine Baumgartner
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Jonathan R Deans
- Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Christopher Kwok
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Pooja Patel
- Department of Pediatrics, Molecular and Cellular Biology, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Loning Fu
- Department of Pediatrics, Molecular and Cellular Biology, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Rebecca Berdeaux
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Kai Sun
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Mikhail G Kolonin
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Sidney H Wang
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Kristin Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA.
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA.
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The lncRNA HOTAIR transcription is controlled by HNF4α-induced chromatin topology modulation. Cell Death Differ 2018; 26:890-901. [PMID: 30154449 PMCID: PMC6461983 DOI: 10.1038/s41418-018-0170-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 07/02/2018] [Accepted: 07/03/2018] [Indexed: 01/16/2023] Open
Abstract
The expression of the long noncoding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is largely deregulated in epithelial cancers and positively correlates with poor prognosis and progression of hepatocellular carcinoma and gastrointestinal cancers. Furthermore, functional studies revealed a pivotal role for HOTAIR in the epithelial-to-mesenchymal transition, as this RNA is causal for the repressive activity of the master factor SNAIL on epithelial genes. Despite the proven oncogenic role of HOTAIR, its transcriptional regulation is still poorly understood. Here hepatocyte nuclear factor 4-α (HNF4α), as inducer of epithelial differentiation, was demonstrated to directly repress HOTAIR transcription in the mesenchymal-to epithelial transition. Mechanistically, HNF4α was found to cause the release of a chromatin loop on HOTAIR regulatory elements thus exerting an enhancer-blocking activity.
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