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Zhao J, Li Y, Zhu J, Li H, Jin X. Ubiquitination in hepatocellular carcinoma immunity. J Transl Med 2025; 23:574. [PMID: 40410880 PMCID: PMC12102898 DOI: 10.1186/s12967-025-06592-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 05/08/2025] [Indexed: 05/25/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide, and represents a major global health challenge. While surgical resection at early stages offers favorable prognosis with 5-year survival rates exceeding 70%, the clinical reality in China reveals a contrasting scenario, where over 60% of patients present with advanced disease, resulting in a dramatic decline in 5-year survival to below 12.5%. The immunological landscape plays a pivotal role in HCC pathogenesis and progression, comprising two complementary arms: the innate immune system's rapid-response mechanism for immediate tumor surveillance and the adaptive immune system's antigen-specific targeting with immunological memory capabilities. Emerging evidence has highlighted ubiquitination, a sophisticated post-translational modification system, as a critical regulator of immune homeostasis in HCC pathogenesis. This molecular process exerts precise control through three primary mechanisms: (1) Modulation of immune cell activation thresholds via proteasomal degradation of signaling proteins, (2) Orchestrating immune cell differentiation through stability regulation of transcriptional factors, and (3) Maintenance of immune tolerance by dynamic modification of checkpoint regulators. Such multifaceted regulation affects both innate immune recognition pathways (e.g., NF-κB and STING signaling) and adaptive immune effectors (particularly T cell receptor signaling cascades). This comprehensive review establishes a threefold Objective: First, to elucidate the mechanistic interplay between ubiquitination networks and HCC-related immune dysregulation; Second, to systematically analyze how innate immune-associated ubiquitination events drive hepatocarcinogenesis through chronic inflammation modulation; and third, to critically evaluate recent clinical advances combining ubiquitination-targeted therapies (e.g., proteasome inhibitors and E3 ligase modulators) with immunotherapeutic regimens. Our synthesis revealed that strategic manipulation of ubiquitination pathways can potentiate PD-1/PD-L1 blockade efficacy while mitigating therapeutic resistance, particularly through modulation of tumor-associated macrophages and exhausted T cell populations. By integrating fundamental mechanistic insights with translational clinical data, this review provides a conceptual framework for the development of next-generation diagnostic biomarkers and rational therapeutic combinations. The proposed strategy of ubiquitination-immune axis modulation holds significant potential to transform current HCC management paradigms, offering new avenues for precision immunotherapy for this challenging malignancy.
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Affiliation(s)
- Jianan Zhao
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China
| | - Yuxuan Li
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China
| | - Jie Zhu
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China
| | - Hong Li
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China.
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China.
| | - Xiaofeng Jin
- Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, P. R. China.
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, P. R. China.
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Marino L, Kim A, Ni B, Celi FS. Thyroid hormone action and liver disease, a complex interplay. Hepatology 2025; 81:651-669. [PMID: 37535802 PMCID: PMC11737129 DOI: 10.1097/hep.0000000000000551] [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: 06/09/2023] [Accepted: 07/05/2023] [Indexed: 08/05/2023]
Abstract
Thyroid hormone action is involved in virtually all physiological processes. It is well known that the liver and thyroid are intimately linked, with thyroid hormone playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Clinical and mechanistic research studies have shown that thyroid hormone can be involved in chronic liver diseases, including alcohol-associated or NAFLD and HCC. Thyroid hormone action and synthetic thyroid hormone analogs can exert beneficial actions in terms of lowering lipids, preventing chronic liver disease and as liver anticancer agents. More recently, preclinical and clinical studies have indicated that some analogs of thyroid hormone could also play a role in the treatment of liver disease. These synthetic molecules, thyromimetics, can modulate lipid metabolism, particularly in NAFLD/NASH. In this review, we first summarize the thyroid hormone signaling axis in the context of liver biology, then we describe the changes in thyroid hormone signaling in liver disease and how liver diseases affect the thyroid hormone homeostasis, and finally we discuss the use of thyroid hormone-analog for the treatment of liver disease.
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Affiliation(s)
- Luigi Marino
- Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
| | - Adam Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
| | - Bin Ni
- Alliance Pharma, Philadelphia, Pennsylvania, USA
| | - Francesco S. Celi
- Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
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Das A, Giri S, Dey P. Cell-cell junctional proteins in cancer. Adv Clin Chem 2024; 125:93-142. [PMID: 39988409 DOI: 10.1016/bs.acc.2024.11.006] [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] [Indexed: 02/25/2025]
Abstract
A hallmark change during carcinogenesis is disruption or dysregulation of cell-cell junctions. It enables a transformed cell to adopt mesenchymal phenotype and acquire higher potential to migrate and invade. This ultimately leads to cancer metastasis. During this process, junctional proteins undergo remarkable changes in terms of their expressional pattern, localization, and activity. De-localized junctional proteins may adopt atypical roles which might act to either suppress tumorigenesis or facilitate cancer development, depending on several factors. In this chapter, the authors attempt to know the expression pattern of junctional proteins in different types of cancer, understand its significance, and gather knowledge about the mechanisms by which they regulate tumorigenesis and cancer development.
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Affiliation(s)
- Aparajita Das
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Sarbani Giri
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
| | - Pubali Dey
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
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Zhang S, Jiang Y, Shi L, Wei T, Lai Z, Feng X, Li S, Tang D. Identification and analysis of key genes related to efferocytosis in colorectal cancer. BMC Med Genomics 2024; 17:198. [PMID: 39107816 PMCID: PMC11304617 DOI: 10.1186/s12920-024-01967-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
The impact of efferocytosis-related genes (ERGs) on the diagnosis of colorectal cancer (CRC) remains unclear. In this study, efferocytosis-associated biomarkers for the diagnosis of CRC were identified by integrating data from transcriptome sequencing and public databases. Finally, the expression of biomarkers was validated by real-time quantitative polymerase chain reaction (RT-qPCR). Our study may provide a reference for CRC diagnosis. BACKGROUND It has been shown that some efferocytosis related genes (ERGs) are associated with the development of cancer. However, it is still uncertain how ERGs may influence the diagnosis of colorectal cancer (CRC). METHODS In our study, the CRC cohorts were gained from transcriptome sequencing and the gene expression omnibus (GEO) database (GSE71187). Efferocytosis related biomarkers with diagnostic utility for CRC were identified through combining differentially expressed analysis, machine learning algorithms, and receiver operating characteristic (ROC) analysis. Then, infiltration abundance of immune cells between CRC and control was evaluated. The regulatory networks (including mRNA-miRNA-lncRNA and miRNA/transcription factors (TF)-mRNA networks) were created. Finally, the expression of biomarkers was validated via real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS There were 3 biomarkers (ELMO3, P2RY12, and PDK4) related diagnosis for CRC patients gained. ELMO3 was highly expressed in CRC group, while P2RY12 and PDK4 was lowly expressed. Besides, the infiltrating abundance of 3 immune cells between CRC and control groups was significantly differential, namely activated CD4 memory T cells, macrophages M0, and resting mast cells. We then constructed a mRNA-miRNA-lncRNA network containing 3 mRNAs, 33 miRNAs, and 22 lncRNAs, and a miRNA/TF-mRNA network including 3 mRNAs, 33 miRNAs, and 7 TFs. Additionally, RT-qPCR results revealed that the expression trends of all biomarkers were consistent with the transcriptome sequencing data and GSE71187. CONCLUSION Taken together, this study provides three efferocytosis related biomarkers (ELMO3, P2RY12, and PDK4) for diagnosis of CRC, providing a scientific reference for further studies of CRC.
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Affiliation(s)
- Shengliang Zhang
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China
| | - Ying Jiang
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China
| | - Lei Shi
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China
| | - Tianning Wei
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China
| | - Zhiwen Lai
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China
| | - Xuan Feng
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China
| | - Shiyuan Li
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China
| | - Detao Tang
- Department of Gastrointestinal and Breast Surgery, Guizhou University of Traditional Chinese Medicine, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine of China, Guizhou, China.
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Leung Y, Lee S, Wang J, Guruvaiah P, Rusch NJ, Ho S, Park C, Kim K. The Loss of an Orphan Nuclear Receptor NR2E3 Augments Wnt/β-catenin Signaling via Epigenetic Dysregulation that Enhances Sp1-β catenin-p300 Interactions in Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308539. [PMID: 38790135 PMCID: PMC11304255 DOI: 10.1002/advs.202308539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 04/02/2024] [Indexed: 05/26/2024]
Abstract
The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player that modulates chromatin accessibility to activate p53 during liver injury. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) development remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/β-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation accompanied by enhanced activation of Wnt/β-catenin signaling pathway and inactivation of p53 signaling. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/β-catenin pathway with increased chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, β-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 activates Wnt/β-catenin signaling at cellular and organism levels and this dysregulation is associated with aggressive HCC development and poor clinical outcomes. In summary, NR2E3 is a novel tumor suppressor with a significant prognostic value, maintaining epigenetic homeostasis to suppress the Wnt/β-catenin signaling pathway that promotes HCC development.
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Affiliation(s)
- Yuet‐Kin Leung
- Department of Pharmacology and ToxicologyCollege of MedicineUniversity of Arkansas Medical SciencesLittle RockAR72205USA
| | - Sung‐Gwon Lee
- School of Biological Sciences and TechnologyChonnam National UniversityGwangju500‐757Republic of Korea
| | - Jiang Wang
- Department of Pathology and Laboratory MedicineCollege of MedicineUniversity of Cincinnati231 Albert Sabin WayCincinnatiOH45267USA
| | - Ponmari Guruvaiah
- Department of Pharmacology and ToxicologyCollege of MedicineUniversity of Arkansas Medical SciencesLittle RockAR72205USA
| | - Nancy J Rusch
- Department of Pharmacology and ToxicologyCollege of MedicineUniversity of Arkansas Medical SciencesLittle RockAR72205USA
| | - Shuk‐Mei Ho
- Department of Pharmacology and ToxicologyCollege of MedicineUniversity of Arkansas Medical SciencesLittle RockAR72205USA
| | - Chungoo Park
- School of Biological Sciences and TechnologyChonnam National UniversityGwangju500‐757Republic of Korea
| | - Kyounghyun Kim
- Department of Pharmacology and ToxicologyCollege of MedicineUniversity of Arkansas Medical SciencesLittle RockAR72205USA
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Wang X, Yuan Z, Li Z, He X, Zhang Y, Wang X, Su J, Wu X, Li M, Du F, Chen Y, Deng S, Zhao Y, Shen J, Yi T, Xiao Z. Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances. Front Immunol 2024; 15:1354313. [PMID: 38426090 PMCID: PMC10902128 DOI: 10.3389/fimmu.2024.1354313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.
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Affiliation(s)
- Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhengbo Li
- Department of Laboratory Medicine, The Longmatan District People’s Hospital, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
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Ding Y, Ning Y, Kang H, Yuan Y, Lin K, Wang C, Yi Y, He J, Li L, He X, Chang Y. ZMIZ2 facilitates hepatocellular carcinoma progression via LEF1 mediated activation of Wnt/β-catenin pathway. Exp Hematol Oncol 2024; 13:5. [PMID: 38254216 PMCID: PMC10802047 DOI: 10.1186/s40164-024-00475-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high lethality rate. ZMIZ2 is a transcriptional co-activator implicated in various human diseases. However, the role and molecular mechanism of ZMIZ2 in HCC remains to be elucidated. METHODS The expression and prognostic value of ZMIZ2 in HCC was excavated from public databases and explored by bioinformatic analysis. Then the expression of ZMIZ2 and related genes was further validated by quantitative RT-PCR, western blotting, and immunohistochemistry. Loss and gain-of-function experiments were performed in vitro and in vivo to investigate the function of ZMIZ2 in HCC. In addition, transcriptome sequencing and immunoprecipitation was conducted to explore the potential molecular mechanisms of ZMIZ2. RESULTS ZMIZ2 was highly expressed in HCC and associated with poor prognosis. Silencing ZMIZ2 significantly inhibited HCC cell proliferation, cell cycle process, migration, and invasion in vitro, and also inhibited the progression of HCC in vivo. Additionally, ZMIZ2 expression was correlated with immune cell infiltration in HCC samples. Somatic mutation analysis showed that ZMIZ2 and TP53 mutations jointly affected the progression of HCC. Mechanistically, ZMIZ2 interacted with LEF1 to regulate malignant progression of HCC by activating the Wnt/β-catenin pathway. CONCLUSION ZMIZ2 was overexpressed in HCC and associated with poor prognosis. The overexpression of ZMIZ2 was corelated with malignant phenotype, and it facilitated HCC progression via LEF1-mediated activation of the Wnt/β-catenin pathway. Furthermore, ZMIZ2 could be served as a prognostic biomarker and a new therapeutic target for HCC.
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Affiliation(s)
- Yang Ding
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yumei Ning
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Hui Kang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yuan Yuan
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Kun Lin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Chun Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yun Yi
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jianghua He
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Lurao Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xingxing He
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
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Tsai HW, Cheng SW, Chen CC, Chen IW, Ho CL. A combined bioinformatics and experimental approach identifies RMI2 as a Wnt/β-catenin signaling target gene related to hepatocellular carcinoma. BMC Cancer 2023; 23:1025. [PMID: 37875822 PMCID: PMC10594864 DOI: 10.1186/s12885-023-10655-2] [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: 08/10/2022] [Accepted: 02/15/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND The Wnt/β-catenin signaling pathway plays an important role in embryogenesis and tumorigenesis. In human cancer, abnormal activity of Wnt/β-catenin signaling pathway induces overexpressed of downstream genes, and initiate oncogene. There are several target genes known to be key players in tumorigenesis, such as c-myc, cyclin D1, MMPs or survivin. Therefore, identifying the target genes of Wnt/β-catenin signaling pathway is important to understanding Wnt/β-catenin-mediated carcinogenesis. In this study, we developed a combined bioinformatics and experimental approach to find potential target genes. METHODS Luciferase reporter assay was used to analyze the promoter activity of RMI2. WST1 cell proliferation assays and transwell assays were performed to determine the proliferation and migration capacities of RMI2 overexpressing or knockdown stable hepatic cells. Finally, xenograft experiments were performed to measure the tumor formation capacity in vivo. RESULTS The results showed that RMI2 mRNA was upregulated after LiCl treatment and Wnt3a-conditioned medium in a culture of SK-hep-1 cell lines. A chromatin immunoprecipitation (ChIP) assay showed that the β-catenin/T cell-specific factor (TCF) complex binds to the putative TCF binding site of the RMI2 promoter. We then found a TCF binding site at - 333/- 326 of the RMI2 promoter, which is crucial for β-catenin responsiveness in liver cell lines. RMI2 was overexpressed in hepatoma tissue and cell lines, and it promoted the migration and invasion of HCC cells. Moreover, RMI2 upregulated the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt3a/β-catenin-related genes, but silencing RMI2 had the opposite effects. Notably, the expression of RMI2 was positively correlated with the clinical data of HCC patients who had significantly shorter overall survival (OS) and disease-free survival (DFS) (Both: P < 0.05). In addition, a total of 373 HCC patients' data from the Caner Genome Atlas project (TCGA) were used to validate our findings. CONCLUSIONS Taking all these findings together, we determined that RMI2 was a new target gene of the Wnt/β-catenin signaling pathway. We also found that RMI2 promotes EMT markers, HCC cell invasion, and metastasis, which indicated that RMI2 is a potential target for preventing or at least mitigating the progression of HCC.
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Affiliation(s)
- Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan
| | - Shu-Wen Cheng
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan
| | - Chou-Cheng Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Business Management, CTBC Business School, Tainan, Taiwan
| | - I-Wen Chen
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Awad B, Hamza AA, Al-Maktoum A, Al-Salam S, Amin A. Combining Crocin and Sorafenib Improves Their Tumor-Inhibiting Effects in a Rat Model of Diethylnitrosamine-Induced Cirrhotic-Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4063. [PMID: 37627094 PMCID: PMC10452334 DOI: 10.3390/cancers15164063] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/28/2023] [Accepted: 07/29/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies, with continuously increasing cases and fatalities. Diagnosis often occurs in the advanced stages, confining patients to systemic therapies such as sorafenib. Sorafenib (SB), a multi-kinase inhibitor, has not yet demonstrated sufficient efficacy against advanced HCC. There is a strong argument in favor of studying its use in combination with other medications to optimize the therapeutic results. According to our earlier work, crocin (CR), a key bioactive component of saffron, hinders HCC development and liver cancer stemness. In this study, we investigated the therapeutic use of CR or its combination with SB in a cirrhotic rat model of HCC and evaluated how effectively SB and CR inhibited tumor growth in this model. Diethylnitrosamine (DEN) was administered intraperitoneally to rats once a week for 15 weeks, leading to cirrhosis, and then 19 weeks later, leading to multifocal HCC. After 16 weeks of cancer induction, CR (200 mg/kg daily) and SB (10 mg/kg daily) were given orally to rats for three weeks, either separately or in combination. Consistently, the combination treatment considerably decreased the incidence of dyschromatic nodules, nodule multiplicity, and dysplastic nodules when compared to the HCC group of single therapies. Combined therapy also caused the highest degree of apoptosis, along with decreased proliferating and β-catenin levels in the tumor tissues. Additionally, when rats received combined therapy with CR, it showed anti-inflammatory characteristics where nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (Cox-2) were considerably and additively lowered. As a result, CR potentiates the suppressive effects of SB on tumor growth and provides the opportunity to strengthen the therapeutic effects of SB in the treatment of HCC.
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Affiliation(s)
- Basma Awad
- Biology Department, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (B.A.); (A.A.-M.)
| | - Alaaeldin Ahmed Hamza
- National Organization for Drug Control and Research, Giza 12611, Egypt;
- National Committee for Biochemistry and Molecular Biology and Medical Research Council, Academy of Scientific Research, Cairo 11334, Egypt
| | - Amna Al-Maktoum
- Biology Department, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (B.A.); (A.A.-M.)
| | - Suhail Al-Salam
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Amr Amin
- Biology Department, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (B.A.); (A.A.-M.)
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10
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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11
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Baokbah TAS. Attenuation of diethylnitrosamine-induced hepatocellular carcinoma in a rat model by combination therapy of diacerein and gold nanoparticles: a histopathological and immunohistochemical study. J Histotechnol 2023; 46:5-16. [PMID: 36214360 DOI: 10.1080/01478885.2022.2129935] [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: 03/01/2023]
Abstract
The purpose of this study was to investigate the effect of combined therapy of diacerein and gold nanoparticles (AuNP) on diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in a rat model. Normal healthy and DEN-induced (HCC) rats were divided into five groups. Group I healthy rats served as normal control, Group II untreated HCC rats, Group III HCC rats administered diacerein, Group IV HCC rats administered AuNP, and Group V HCC rats administered diacerein and AuNP. All treatments were given once daily for 4 weeks. Liver morphology and necroinflammation in all groups were evaluated using hematoxylin and eosin (H&E), Masson's trichrome for fibrosis, and immunohistochemistry assays for expression of TNF-α, IL-6, β-catenin, and caspase-3. Liver sections from Group II HCC rats showed loss of lobular architecture, thick fibrous tissue deposition, leukocyte infiltration, degenerated hepatocytes and HCC neoplastic nodules surrounded by extensive fibrosis. Group II had high expression of TNF-α, IL-6, and β-catenin, and low caspase-3 expression as compared to Group I. HCC rats treated with the combined therapy of diacerein and AuNP (Group V) showed markedly decreased HCC lesions, significant necroinflammation reduction (p ˂ 0.05) and 90% reduction in fibrosis as compared to Group II HCC + diacerein. This combined therapy also reduced (p ˂ 0.05) TNF-α, IL-6, β-catenin expression and increased caspase-3 expression. In conclusion, diacerein combined with AuNP synergistically attenuated the severity of HCC lesions by reducing necroinflammation and fibrosis, decreased TNF-α, IL-6, β-catenin expression, and increased caspase-3 expression for apoptosis.
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Affiliation(s)
- Tourki A S Baokbah
- Department of Medical Emergency Services, Al-Qunfudah Health Sciences College, Umm Al-Qura University, Makkah, Saudi Arabia
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12
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Context dependent role of p53 during the interaction of hepatocellular carcinoma and endothelial cells. Microvasc Res 2022; 142:104374. [PMID: 35523268 DOI: 10.1016/j.mvr.2022.104374] [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: 12/09/2021] [Revised: 04/27/2022] [Accepted: 04/27/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND During the progression of hepatocellular carcinoma (HCC), several angiogenic factors are overexpressed in the hepatic microenvironment, which play a critical role in governing the phenotype of the endothelial cells. Mutation in the p53 gene (TP53) is a common event in HCC that may dysregulate the angiogenic signals. However, their functional messages remain largely unexplored at the onset of metastasis. METHODS Role of p53 was studied by siRNA mediated silencing of p53 in HepG2 cells (WTp53), collecting and analyzing their conditioned medium, followed by indirect co-culture with endothelial cells (HUVECs). Gene and protein expression in HCC cells and endothelial cells was studied by RT-qPCR and western blotting respectively. β-catenin protein expression and localization were analyzed by immunocytochemistry. RESULTS We have studied a cell-to-cell interaction model to investigate the crosstalk of endothelial and hepatoma cells by either knocking down p53 or by using p53 null low metastatic HCC cell line. In the absence of p53, the HCC cells influence the migration and vascular network formation of endothelial cells through paracrine signaling of VEGF. Secretory VEGF activated the VEGF receptor-2 along with the survival signaling in endothelial cells. However, the β-catenin signal is upregulated in endothelial cells only during interaction with metastatic set up irrespective of absence and presence of p53, indicating context-dependent participation of p53 during communication between hepatoma cells and endothelial cells. CONCLUSION This study highlights that the role of p53 on cellular responses during interaction of hepatocellular carcinoma and endothelial cells is distinct to cell types and context.
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Abstract
Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.
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Affiliation(s)
- Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhong Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA
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14
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ARID1A Is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2022; 2022:3163955. [PMID: 35028302 PMCID: PMC8752298 DOI: 10.1155/2022/3163955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/16/2021] [Accepted: 12/18/2021] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE ARID1A has been discovered as a potential cancer biomarker. But its role in hepatocellular carcinoma (HCC) is subject to considerable dispute. METHODS The relationship between ARID1A and clinical factors was investigated. Clinicopathological variables related to overall survival in HCC subjects were identified using Cox and Kaplan-Meier studies. The connection between immune infiltrating cells and ARID1A expression was investigated using the tumor Genome Atlas (TCGA) dataset for gene set enrichment analysis (GSEA). Finally, a cell experiment was used to confirm it. RESULTS The gender and cancer topography (T) categorization of HCC were linked to increased ARID1A expression. Participants with advanced levels of ARID1A expression had a worse prognosis than someone with lower levels. ARID1A was shown to be a risk indicator of overall survival on its own. ARID1A expression is inversely proportional to immune cell infiltration. In vitro, decreasing ARID1A expression substantially slowed the cell cycle and decreased HCC cell proliferation, migration, and invasion. CONCLUSION The expression of ARID1A could be used to predict the outcome of HCC. It is closely related to tumor immune cell infiltration.
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15
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Akbari S, Kunter I, Azbazdar Y, Ozhan G, Atabey N, Firtina Karagonlar Z, Erdal E. LGR5/R-Spo1/Wnt3a axis promotes stemness and aggressive phenotype in hepatoblast-like hepatocellular carcinoma cell lines. Cell Signal 2021; 82:109972. [PMID: 33684507 DOI: 10.1016/j.cellsig.2021.109972] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/03/2021] [Accepted: 03/03/2021] [Indexed: 11/16/2022]
Abstract
Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a newly defined stem cell marker in endoderm-derived organs such as the small intestine, colon and pancreas. Recently, LGR5 was demonstrated to be an important factor in liver regeneration and stem cell maintenance. Moreover, LGR5 expression is highly up-regulated in various cancers including hepatocellular carcinoma. Herein, we demonstrate that LGR5 expression is specifically observed in certain subset of HCC cell lines with "hepatoblast-like" appearance, characterized by the expression of liver fetal/progenitor markers. Notably, the activation of the canonical Wnt pathway significantly increases the expression of LGR5 in this subset of cell lines, whereas it does not cause any induction of LGR5 expression in mesenchymal like cell lines SNU-475 and SNU-449. Furthermore, we showed that treatment of the hepatoblast-like HCC cell lines HuH-7 and Hep3B with LGR5 ligand R-Spo1 significantly amplifies the induction of LGR5 expression, the phosphorylation of LRP6 and β-catenin resulting in enhanced TCF/LEF activity either alone or in combination with Wnt3a. Consistently, the silencing of the LGR5 gene attenuates the co-stimulatory effect of R-Spo1/Wnt3a on TCF/LEF activity while overexpression of LGR5 enhances it. On the contrary, overexpression of LGR5 does not change TCF/LEF activity induced by R-Spo1/Wnt3a in mesenchymal-like HCC line, SNU-449. Importantly, LGR5-overexpressing cells have increased expression of several Wnt target genes and stemness-related genes including EpCAM and CK19 upon R-Spo1/Wnt3a treatment. LGR5-overexpressing cells also have increased spheroid forming, migration and invasion abilities and stimulation with R-Spo1/Wnt3a augments these abilities of LGR5-overexpressing cells. In addition, ectopic overexpression of LGR5 significantly increases cell proliferation rate independent of R-Spo1/Wnt3a stimulation. Moreover, in vitro tubulogenesis assay demonstrates that treatment with R-Spo1/Wnt3a enhances the sprouting of capillary tubules in only LGR5-overexpressing cells. Finally, R-Spo1/Wnt3a significantly promotes dissemination of LGR5-overexpressing cells in vivo in a zebrafish xenograft model. Our study unravels a tumor-promoting role for LGR5 through activation of canonical Wnt/β-catenin signaling in the hepatoblast-like HCCs. In conclusion, our results suggest that LGR5/R-Spo1/Wnt3a generates an axis that mediates the acquisition of aggressive phenotype specifically in hepatoblast-like subset of HCCs and might represent a valuable target for treatment of HCC tumors with aberrant activation of Wnt/β-catenin pathway.
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Affiliation(s)
- Soheil Akbari
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey
| | - Imge Kunter
- Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey
| | - Yagmur Azbazdar
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, 35340 Izmir, Turkey
| | - Gunes Ozhan
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, 35340 Izmir, Turkey
| | - Nese Atabey
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey
| | | | - Esra Erdal
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey.
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16
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Zou Y, Zhao X, Li Y, Duan S. miR-552: an important post-transcriptional regulator that affects human cancer. J Cancer 2020; 11:6226-6233. [PMID: 33033505 PMCID: PMC7532495 DOI: 10.7150/jca.46613] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022] Open
Abstract
MiR-552 is a small non-coding RNA located on chromosome 1p34.3, and its expression level is significantly up-regulated in tissues or cells of various tumors. miR-552 can target multiple genes. These targeted genes play important regulatory roles in biological processes such as gene transcription and translation, cell cycle progression, cell proliferation, apoptosis, cell migration, and invasion. Besides, miR-552 may affect the efficacy of various anticancer drugs by targeting genes such as TP53 and RUNX3. This review summarizes the biological functions and clinical expressions of miR-552 in human cancer. Our goal is to explore the potential value of miR-552 in the diagnosis, prognosis, and treatment of human cancer.
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Affiliation(s)
- Yuhao Zou
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Xin Zhao
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Yin Li
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Shiwei Duan
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
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17
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Tang Y, Zhao Y, Ran J, Wang Y. MicroRNA-21 promotes cell metastasis in cervical cancer through modulating epithelial-mesenchymal transition. Oncol Lett 2020; 19:3289-3295. [PMID: 32256824 PMCID: PMC7074379 DOI: 10.3892/ol.2020.11438] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Accepted: 01/13/2020] [Indexed: 12/21/2022] Open
Abstract
MicroRNA (miR)-21 is known to act as an oncogene in cervical cancer by promoting cell proliferation and migration; however, the underlying molecular mechanisms have remained to be fully elucidated. The present study revealed that the gene expression levels of miR-21 and epithelial-mesenchymal transition (EMT)-associated transcription factor Zinc finger E-box-binding homeobox 1 (ZEB1), in cervical cancer and lymphatic metastatic carcinoma tissues were significantly higher than those in normal tissues (P<0.05). Furthermore, the gene expression levels of miR-21 and ZEB1 were positively associated with muscular infiltration depth, parametrical invasion and lymph node metastasis in patients with cervical cancer. Immunohistochemistry assays indicated that the expression levels of ZEB1 and the mesenchymal cell marker Vimentin in cervical cancer tissues were significantly higher than those in normal cervical tissues (P<0.05). Overexpression of miR-21 in HeLa and SiHa cells caused the upregulation of the mesenchymal cell markers Vimentin and N-cadherin, and downregulation of the epithelial cell marker E-cadherin at the proteins level. In addition, overexpression of miR-21 enhanced the invasiveness of HeLa and SiHa cells. These results demonstrated that miR-21 was upregulated in cervical cancer tissues and promoted cell metastasis through modulating EMT. A better understanding of the role of miR-21 and EMT may lead to the development of more effective therapies for patients with cervical cancer.
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Affiliation(s)
- Yaling Tang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Yan Zhao
- Central Laboratory, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Jing Ran
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Yifeng Wang
- Department of Obstetrics and Gynecology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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18
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Zhan W, Li Y, Liu X, Zheng C, Fu Y. ZNF671 Inhibits the Proliferation and Metastasis of NSCLC via the Wnt/β-Catenin Pathway. Cancer Manag Res 2020; 12:599-610. [PMID: 32158264 PMCID: PMC6986545 DOI: 10.2147/cmar.s235933] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/31/2019] [Indexed: 01/01/2023] Open
Abstract
Background Lung cancer is the most common cancer in the world and is the main cause of cancer-related death. Revealing the potential mechanism of malignant characteristics of lung cancer is urgent for treating this disease effectively. Zinc finger protein 671 (ZNF671) is a member of the largest transcription factor family in the human genome. The role of ZNF671 in non-small-cell lung cancer (NSCLC) remains unknown. The purpose of this study was to investigate the function and mechanism of ZNF671 in NSCLC. Methods ZNF671 expression in NSCLC cells and tissues were detected by Real-Time PCR, Western blot and TCGA databases. Then, we evaluated the prognostic value of ZNF671 expression in NSCLC using the Kaplan–Meier plotter (KM plotter) and TCGA databases. Moreover, the function of ZNF671 in the proliferation and metastasis of lung cancer was investigated by MTT assay, colony formation assay, in vivo experiment, EdU assay, wound healing assay, transwell assay, and 3D culture assay. Luciferase reporter and subcellular fractionation assays were performed to determine the underlying mechanism of ZNF671-mediated proliferation and metastasis of NSCLC. Results ZNF671 expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls. The survival analysis results indicated that the downregulation of ZNF671 significantly correlates with poor prognosis and predicts a shorter overall survival and post-progression survival among NSCLC patients. Ectopic overexpression of ZNF671 dramatically restrains, whereas silencing ZNF671 enhanced, cell proliferation and metastasis of NSCLC. Mechanically, gene set enrichment analysis (GSEA) showed that the expression of ZNF671 was significantly correlated with Wnt/β-catenin signaling. Simultaneously, our results confirm that the overexpression of ZNF671 inhibits cell cycle progression and metastasis by weakening the Wnt/β-catenin pathway, and then downregulating the expression of downstream target genes CyclinD1 and MMP9. Conclusion This study found that the overexpression of ZNF671 restrains the proliferation and metastasis of lung cancer through inhibiting Wnt/β-catenin signaling pathway. Furthermore, our current results provide important insights into ZNF671 as an excellent predictive biomarker for NSCLC, thus providing a novel perspective for the treatment of NSCLC.
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Affiliation(s)
- Wei Zhan
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, People's Republic of China
| | - Yuzhe Li
- Department of Clinical Laboratory, The Third Affiliated Hospital of Sun Yat-Sen University, Lingnan Hospital, Guangzhou 510080, People's Republic of China
| | - Xuhui Liu
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, People's Republic of China
| | - Changlong Zheng
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, People's Republic of China
| | - Yongmei Fu
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, People's Republic of China
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Li W, Xue H, Li Y, Li P, Ma F, Liu M, Kong S. ATDC promotes the growth and invasion of hepatocellular carcinoma cells by modulating GSK-3β/Wnt/β-catenin signalling. Clin Exp Pharmacol Physiol 2019; 46:845-853. [PMID: 31168819 DOI: 10.1111/1440-1681.13119] [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] [Received: 03/13/2019] [Revised: 05/26/2019] [Accepted: 06/03/2019] [Indexed: 12/26/2022]
Abstract
Accumulating evidence has suggested that the ataxia telangiectasia group D complementing (ATDC) gene is an emerging cancer-related gene in multiple human cancer types. However, little is known about the role of ATDC in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the expression level, biological function and underlying mechanism of ATDC in HCC. The expression of ATDC in HCC cells was detected by quantitative real-time polymerase chain reaction and western blot analysis. Cell growth was determined by cell counting kit-8 assay and colony formation assay. Cell invasion was assessed by Transwell invasion assay. The activation status of Wnt/β-catenin signalling was evaluated by the luciferase reporter assay. Functional experiments showed that the silencing of ATDC expression significantly suppressed the growth and invasion of HCC cells, whereas the overexpression of ATDC promoted the growth and invasion of HCC cells in vitro. Moreover, we showed that ATDC overexpression promoted the phosphorylation of glycogen synthase kinase (GSK)-3β and resulted in the activation of Wnt/β-catenin signalling. Notably, the inhibition of GSK-3β activity significantly abrogated the tumour suppressive effect of ATDC silencing, while the silencing of β-catenin partially reversed the oncogenic effect of ATDC overexpression. Taken together, these findings reveal an oncogenic role of ATDC in HCC and show that the suppression of ATDC impedes the growth and invasion of HCC cells associated with the inactivation of Wnt/β-catenin signalling. Our study suggests that ATDC may serve as a potential therapeutic target for HCC.
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Affiliation(s)
- Weizhi Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Xue
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yingchao Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Peijie Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fuquan Ma
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengying Liu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuzhen Kong
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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20
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Liang WC, Wong CW, Liang PP, Shi M, Cao Y, Rao ST, Tsui SKW, Waye MMY, Zhang Q, Fu WM, Zhang JF. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol 2019; 20:84. [PMID: 31027518 PMCID: PMC6486691 DOI: 10.1186/s13059-019-1685-4] [Citation(s) in RCA: 360] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 03/29/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Circular RNAs are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. In the current study, we evaluate the function of a novel circRNA derived from the β-catenin gene locus, circβ-catenin. RESULTS Circβ-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circβ-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circβ-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of β-catenin without affecting its mRNA level. We show that circβ-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circβ-catenin produces a novel 370-amino acid β-catenin isoform that uses the start codon as the linear β-catenin mRNA transcript and translation is terminated at a new stop codon created by circularization. We find that this novel isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation, leading to activation of the Wnt pathway. CONCLUSIONS Our findings illustrate a non-canonical function of circRNA in modulating liver cancer cell growth through the Wnt pathway, which can provide novel mechanistic insights into the underlying mechanisms of hepatocellular carcinoma.
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Affiliation(s)
- Wei-Cheng Liang
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, People's Republic of China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China
| | - Cheuk-Wa Wong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China
| | - Pu-Ping Liang
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Mai Shi
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China
| | - Ye Cao
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China
| | - Shi-Tao Rao
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China
| | - Stephen Kwok-Wing Tsui
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China
| | - Mary Miu-Yee Waye
- The Nethersole School of Nursing, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China
| | - Qi Zhang
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Wei-Ming Fu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 511458, People's Republic of China. .,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, People's Republic of China.
| | - Jin-Fang Zhang
- Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China. .,Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China.
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21
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Tripathy A, Thakurela S, Sahu MK, Uthanasingh K, Behera M, Ajay AK, Kumari R. The molecular connection of histopathological heterogeneity in hepatocellular carcinoma: A role of Wnt and Hedgehog signaling pathways. PLoS One 2018; 13:e0208194. [PMID: 30513115 PMCID: PMC6279049 DOI: 10.1371/journal.pone.0208194] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 11/13/2018] [Indexed: 12/21/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is leading cause of cancer-related mortality and is categorized among the most common malignancies around the world. It is a heterogeneous tumor, which shows significant degree of histopathological heterogeneity. Despite the apparent histopathological diversity there has been very little distinct correlation between histopathological features and molecular aberrations particularly when it comes to the expression level of Wnt and Hh pathway molecules. The role of Wnt and Hh pathways in relation to HCC behavior viz. histopathological heterogeneity and aggressiveness is not known. Determining the sequential molecular changes and associated histopathological characteristic during HCC initiation, promotion, and progression would probably lead to a better treatment and prognosis. Methods N-Nitrosodiethylamine (DEN) induced HCC model in male Wistar rats were established to study the expression level of Wnt and Hh pathway molecules during different stages of hepatocarcinogenesis. Their expression levels were checked at mRNA and protein levels at initiation, promotion, and progression stages of HCC. The expression levels of Wnt and Hh pathway molecules were correlated with biospecimens of HCC patients of different stages. Results In the present study we identified the comprehensive change in the expression pattern of Wnt and Hh pathway molecules in DEN induced rodent hepatocarcinogenesis model. Our results demonstrate that β-catenin /CTNNB1 plays important role in tumor initiation and promotion by stimulating tumor cell proliferation. The activated Wnt signaling in early stage of HCC is associated with well-differentiated histological pattern. The Hh activity although activated during the initiation stage but is significantly increased during the early promotion stage of hepatocarcinogenesis. The increased activity of both Wnt & Hh pathways during promotion stage is associated with moderately-differentiated histological pattern and was simultaneously linked with an increased expression of MMP9. Furthermore, our data demonstrated that during the progression stage Wnt pathway is modestly down-regulated but the Hh pathway activity sustained which in turn is associated with aggressive and invasive phenotype and poorly-differentiated histopathology. Conclusion Our data uncovers the grade related expression of Wnt and Hh pathway molecules and the potential utility of these molecular signatures in daily clinical practice is to decide best therapy according to patients characteristic. Additionally, our data offer insight into the interaction between Wnt and Hh pathways which triggers HCC development and progression.
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Affiliation(s)
- Anindita Tripathy
- Disease Biology Lab, KIIT School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Sudhir Thakurela
- Broad Institute of MIT and Harvard, Cambridge, MA, United States of America
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, United States of America
| | - Manoj Kumar Sahu
- Department of Gastroenterology & Hepatobiliary Sciences, IMS & SUM Hospital, Bhubaneswar, India
| | - Kanishka Uthanasingh
- Department of Gastroenterology & Hepatobiliary Sciences, IMS & SUM Hospital, Bhubaneswar, India
| | - Manas Behera
- Department of Gastroenterology & Hepatobiliary Sciences, IMS & SUM Hospital, Bhubaneswar, India
| | - Amrendra Kumar Ajay
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States of America
| | - Ratna Kumari
- Disease Biology Lab, KIIT School of Biotechnology, KIIT University, Bhubaneswar, India
- * E-mail:
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22
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Cheng Z, Lei Z, Yang P, Si A, Xiang D, Zhou J, Hüser N. Long non-coding RNA THOR promotes liver cancer stem cells expansion via β-catenin pathway. Gene 2018; 684:95-103. [PMID: 30359743 DOI: 10.1016/j.gene.2018.10.051] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 10/14/2018] [Accepted: 10/19/2018] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of THOR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of THOR expression in OV6 or EpCAM-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference THOR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found β-catenin as the downstream of THOR in HCC cells. The special β-catenin inhibitor FH535 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between THOR knockdown HCC cells and control cells, which further confirmed that β-catenin was required in THOR promoted liver CSCs expansion. Moreover, interference THOR hepatoma cells were more sensitive to sorafenib treatment, indicates that HCC patients with low THOR expression may benefit from sorafenib treatment. Collectively, THOR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting β-catenin signaling.
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Affiliation(s)
- Zhangjun Cheng
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
| | - Zhengqing Lei
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Pinghua Yang
- Department of Laparoscope, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Anfeng Si
- Department of Surgical Oncology, The Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Daimin Xiang
- National Liver Cancer Science Center, Second Military Medical University, Shanghai, China
| | - Jiahua Zhou
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Norbert Hüser
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich 81675, Germany
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23
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Khalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, Hazle JD, Elsayes KM. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J Hepatocell Carcinoma 2018; 5:61-73. [PMID: 29984212 PMCID: PMC6027703 DOI: 10.2147/jhc.s156701] [Citation(s) in RCA: 163] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and one of the fastest-growing causes of cancer-related mortality in the United States. The molecular basis of HCC carcinogenesis has not been clearly identified. Among the molecular signaling pathways implicated in the pathogenesis of HCC, the Wnt/β-catenin signaling pathway is one of the most frequently activated. A great effort is under way to clearly understand the role of this pathway in the pathogenesis of HCC and its role in the transition from chronic liver diseases, including viral hepatitis, to hepatocellular adenomas (HCAs) and HCCs and its targetability in novel therapies. In this article, we review the role of the β-catenin pathway in hepatocarcinogenesis and progression from chronic inflammation to HCC, the novel potential treatments targeting the pathway and its prognostic role in HCC patients, as well as the imaging features of HCC and their association with aberrant activation of the pathway.
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Affiliation(s)
- Ahmed M Khalaf
- Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David Fuentes
- Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ali I Morshid
- Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,
| | - Mata R Burke
- Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manal Hassan
- Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John D Hazle
- Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Khaled M Elsayes
- Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,
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24
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Schachtschneider KM, Schwind RM, Darfour-Oduro KA, De AK, Rund LA, Singh K, Principe DR, Guzman G, Ray CE, Ozer H, Gaba RC, Schook LB. A validated, transitional and translational porcine model of hepatocellular carcinoma. Oncotarget 2017; 8:63620-63634. [PMID: 28969016 PMCID: PMC5609948 DOI: 10.18632/oncotarget.18872] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 06/05/2017] [Indexed: 12/29/2022] Open
Abstract
Difficult questions are confronting clinicians attempting to improve hepatocellular carcinoma (HCC) outcomes. A large animal model with genetic, anatomical, and physiological similarities to humans is required to transition from mouse models to human clinical trials to address unmet clinical needs. To validate our previously reported inducible porcine cancer model (Oncopig) as a transitional HCC model, Oncopig hepatocyte cultures were transformed using Cre recombinase. The resulting porcine HCC cells (pHCC) expressed oncogenic TP53R167H and KRASG12D, and displayed nuclear pleomorphisms with pale to granular cytoplasm arranged in expanded plates similar to human HCC histopathology. Human HCC transcriptional hallmarks were detected in pHCC cells using RNA-seq, including TERT reactivation, apoptosis evasion, angiogenesis activation, and Wnt signaling activation. Master regulators of gene expression were conserved across Oncopig and 18 human HCC cell lines. pHCC injection into SCID mice resulted in tumors recapitulating human HCC characteristics, including thick trabeculae formation, pseudoacini patterning, and sheets of well-vascularized stroma. Finally, autologous injection of pHCC cells subcutaneously yielded a tumor histologically characterized as Edmondson Steiner (HCC nuclear grade assessment system) grade 2 HCC with trabecular patterning and T-lymphocyte infiltration. These data demonstrate the Oncopig HCC model's utility for improving detection, treatment, and biomarker discovery relevant to human HCC.
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Affiliation(s)
- Kyle M. Schachtschneider
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
- Animal Breeding and Genomics Centre, Wageningen University, Wageningen, The Netherlands
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Regina M. Schwind
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Arun K. De
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
| | - Lauretta A. Rund
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
| | - Kuldeep Singh
- Veterinary Diagnostic Laboratory, University of Illinois, Urbana, IL, USA
| | - Daniel R. Principe
- College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Charles E. Ray
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
- Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL, USA
| | - Howard Ozer
- Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL, USA
| | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Lawrence B. Schook
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
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25
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Perumal N, Perumal M, Kannan A, Subramani K, Halagowder D, Sivasithamparam N. Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells. Exp Cell Res 2017; 355:124-141. [DOI: 10.1016/j.yexcr.2017.03.062] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 03/29/2017] [Accepted: 03/30/2017] [Indexed: 12/12/2022]
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26
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Xiang D, Cheng Z, Liu H, Wang X, Han T, Sun W, Li X, Yang W, Chen C, Xia M, Liu N, Yin S, Jin G, Lee T, Dong L, Hu H, Wang H, Ding J. Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients. Hepatology 2017; 65:1566-1580. [PMID: 28059452 DOI: 10.1002/hep.28919] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 10/16/2016] [Accepted: 10/26/2016] [Indexed: 12/17/2022]
Abstract
UNLABELLED Src-homology 2 domain-containing phosphatase 2 (Shp2) has been reported to play an important role in the maintenance and self-renewal of embryonic and adult stem cells, but its role in cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of Shp2 in both chemoresistant hepatocellular carcinomas (HCCs) and recurrent HCCs from patients. A remarkable increase of Shp2 was detected in sorted epithelial cell adhesion molecule-positive or cluster of differentiation 133-positive liver CSCs and in CSC-enriched hepatoma spheroids from patients. Up-regulated Shp2 facilitated liver CSC expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self-renewal of liver CSCs. Mechanistically, Shp2 dephosphorylated cell division cycle 73 in the cytosol of hepatoma cells, and the dephosphorylated cell division cycle 73 bound β-catenin and facilitated the nuclear translocation of β-catenin, which promoted the dedifferentiation of hepatoma cells. Shp2 increased β-catenin accumulation by inhibiting glycogen synthase kinase 3β-mediated β-catenin degradation in liver CSCs, thereby enhancing the self-renewal of liver CSCs. Blockage of β-catenin abolished the discrepancy in liver CSC proportion and the self-renewal capacity between Shp2-depleted hepatoma cells and control cells, which further confirmed that β-catenin is required in Shp2-promoted liver CSC expansion. More importantly, HCC patients with low Shp2 levels benefited from transcatheter arterial chemoembolization or sorafenib treatment, but patients with high Shp2 expression did not, indicating the significance of Shp2 in personalized HCC therapy. CONCLUSION Shp2 could promote HCC cell dedifferentiation and liver CSC expansion by amplifying β-catenin signaling and may be useful in predicting patient response to chemotherapeutics. (Hepatology 2017;65:1566-1580).
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Affiliation(s)
- Daimin Xiang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.,Nelson Institute of Environmental Medicine, New York University School of Medicine, New York, NY
| | - Zhuo Cheng
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xue Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Tao Han
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.,Department of Oncology, General Hospital of Shenyang Military Region, Shenyang, China
| | - Wen Sun
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Xiaofeng Li
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Wen Yang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Cheng Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Mingyang Xia
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Na Liu
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Shengyong Yin
- Department of General Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Guangzhi Jin
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Terence Lee
- Department of Pathology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong
| | - Liwei Dong
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Heping Hu
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China
| | - Hongyang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Jin Ding
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
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27
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Watany M, Badawi R, Elkhalawany W, Abd-Elsalam S. Study of Dickkopf-1 (DKK-1) Gene Expression in Hepatocellular Carcinoma Patients. J Clin Diagn Res 2017; 11:OC32-OC34. [PMID: 28384913 PMCID: PMC5376795 DOI: 10.7860/jcdr/2017/23095.9450] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 10/19/2016] [Indexed: 01/30/2023]
Abstract
INTRODUCTION Hepatocellular Carcinoma (HCC) is the sixth most common cancer in the world. Dickkopf -1 (DKK-1) protein is a new biomarker used in conjunction with Alpha Fetoprotein (AFP) to differentiate HCC from "non-malignant" liver disease. DKK-1 is an inhibitor of Wnt/β-catenin signaling pathway which is involved in embryogenesis and has been implicated in tumorigenesis in many tissues. AIM To investigate the level of DKK-1 gene expression in the peripheral blood of patients with HCC who had a history of Hepatitis C Virus (HCV) and schistosomal infections. MATERIALS AND METHODS This "cross-sectional" study was carried out in the Tropical Medicine Department of Tanta University Hospital on 50 patients with HCC and 10 healthy volunteers served as control. All patients were tested for HCV antibodies and "anti-schistosomal" antibodies. All groups were tested for DKK-1 gene expression which was measured with quantitative real-time PCR. RESULTS DKK-1 gene was over-expressed in HCC patients than in the control group with mean 3.269±4.762 versus 1.00 in controls (p< 0.005). "Over- expression" of DKK-1 was found in: 8/20 of patients with negative serology for both infections (40%; p<0.001), 7/18 of patients with positive anti-HCV antibodies (38.89%; p<0.001) and 11/12 of patients with positive anti-schistosomal antibodies (91.66%; p<0.001). There was no statistically significant correlation between DKK-1 expression and HCV infection (p=0.139) but there was significant correlation between the gene expression and schistosomal infection (p<0.001). CONCLUSION These data suggest the role of DKK-1 over-expression in HCC development in patients with combined HCV and schistosomal infections and that induction of the Wnt pathway or using DKK-1 antagonist may represent a key advance in the area of genetic prevention of HCC in these "high-risk" patients.
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Affiliation(s)
- Mona Watany
- Department of Clinical Pathology, Tanta University Hospital, Tanta, Egypt
| | - Rehab Badawi
- Department of Tropical Medicine, Tanta University Hospital, Tanta, Egypt
| | - Walaa Elkhalawany
- Department of Tropical Medicine, Tanta University Hospital, Tanta, Egypt
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Lin YT, Chao CCK. Identification of the β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells. Oncotarget 2016; 6:38999-9017. [PMID: 26517516 PMCID: PMC4770752 DOI: 10.18632/oncotarget.5738] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 10/09/2015] [Indexed: 12/24/2022] Open
Abstract
Sorafenib is a kinase inhibitor used as anticancer drug against various human tumors, including advanced hepatocellular carcinoma (HCC). β-Catenin and prothymosin alpha (PTMA) are overexpressed in HCC and other tumors. Previous studies have shown that PTMA expression modulates the response of HCC cells to sorafenib. However, the underlying mechanism of PTMA activity in this context remains unclear. We show here that sorafenib inhibits both β-catenin and PTMA in a dose-dependent manner. Silencing β-catenin reduces PTMA level and sensitizes HCC cells to sorafenib. In contrast, ectopic expression of β-catenin induces PTMA expression and cell resistance to the drug. Sorafenib inhibits PTMA expression at the transcriptional level by inhibiting the β-catenin pathway. Nucleotide deletion analysis of the PTMA gene promoter reveals that a DNA segment lying 1,500–1,600 bp upstream of the PTMA transcription start site represents an AP-1-binding site that is critical for β-catenin modulation of gene transcription in response to sorafenib. In addition, chemical inhibitors that target JNK abrogate β-catenin/AP-1 binding to the endogenous PTMA gene and reduces PTMA transcription and protein expression. Silencing of β-catenin or c-Fos induces similar effects on gene regulation and these are reversed by ectopic expression of β-catenin. Mutations in the PTMA promoter at the predicted β-catenin/AP-1 binding site partly abrogate sorafenib's effects on PTMA transcription. These results indicate that PTMA is induced by the oncoprotein β-catenin and protects HCC cells against sorafenib-induced cell death. The β-catenin/JNK/PTMA axis may thus represent a novel target for chemotherapy against HCC.
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Affiliation(s)
- Yi-Te Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China
| | - Chuck C-K Chao
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China.,Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China
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29
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Li N, Jiang J, Fu J, Yu T, Wang B, Qin W, Xu A, Wu M, Chen Y, Wang H. Targeting interleukin-1 receptor-associated kinase 1 for human hepatocellular carcinoma. J Exp Clin Cancer Res 2016; 35:140. [PMID: 27619757 PMCID: PMC5020546 DOI: 10.1186/s13046-016-0413-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 08/29/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Interleukin-1 receptor associated kinase 1 (IRAK1), as a down-stream of toll-like receptor (TLR) signaling, plays important roles in series of malignancies. However, the role of IRAK1 in hepatocellular carcinoma (HCC) remains little known. METHODS In our study, reverse transcription-PCR (RT-PCR), Western Blot, and immunohistochemical staining were used to assess the mRNA and protein levels of IRAK1 in clinical samples and cell lines. Cell counting assay and flow cytometry were employed to analyze the effect of IRAK1 on cell cycle and apoptosis. Transwell assay was used to study the role of IRAK1 in cell migration. Moreover, subcutaneous xenograft tumor models predict the efficacy of targeting IRAK1 against HCC in vivo. RESULTS IRAK1 was over-expressed in HCC tissues and cell lines. Suppression of IRAK1 by small interference RNA (siRNA) or a pharmaceutical IRAK1/4 inhibitor impeded cell growth, induced apoptosis and lessened HCC xenograft tumor growth. Particularly, IRAK1/4 inhibitor treatment caused G1/S cell cycle arrest and apoptosis, confirming IRAK1 as a new therapeutic target for HCC. CONCLUSION IRAK1 promotes cell proliferation and protects against apoptosis in HCC, and can be a novel target for HCC treatment.
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Affiliation(s)
- Ning Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Jinhua Jiang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
- The First Clinical Medical College, Fujian Medical University, Fuzhou, 350001 Fujian China
| | - Jing Fu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
| | - Ting Yu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
| | - Bibo Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
| | - Wenhao Qin
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
| | - An Xu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
| | - Mengchao Wu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
| | - Yao Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
| | - Hongyang Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, 225 Changhai Road, Shanghai, 200438 People’s Republic of China
- National Center for Liver Cancer, Shanghai, 201805 People’s Republic of China
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Wu J, Lu M, Li Y, Shang YK, Wang SJ, Meng Y, Wang Z, Li ZS, Chen H, Chen ZN, Bian H. Regulation of a TGF-β1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells. Oncogene 2016; 35:5468-5479. [PMID: 27041581 DOI: 10.1038/onc.2016.89] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 01/21/2016] [Accepted: 01/25/2016] [Indexed: 12/17/2022]
Abstract
Cellular plasticity has an important role in the progression of hepatocellular carcinoma (HCC). In this study, the involvement of a TGF-β1-CD147 self-sustaining network in the regulation of the dedifferentiation progress was fully explored in HCC cell lines, hepatocyte-specific basigin/CD147-knockout mice and human HCC tissues. We demonstrated that TGF-β1 stimulation upregulated CD147 expression and mediated the dedifferentiation of HCC cells, whereas all-trans-retinoic acid induced the downregulation of CD147 and promoted differentiation in HCC cells. Overexpression of CD147 induced the dedifferentiation and enhanced the malignancy of HCC cells, and increased the transcriptional expression of TGF-β1 by activating β-catenin. CD147-induced matrix metalloproteinase (MMP) production activated pro-TGF-β1. The activated TGF-β1 signaling subsequently repressed the HNF4α expression via Smad-Snail1 signaling and enhanced the dedifferentiation progress. Hepatocyte-specific basigin/CD147-knockout mice decreased the susceptibility to N-nitrosodiethylamine-induced tumorigenesis by suppressing TGF-β1-CD147 signaling and inhibiting dedifferentiation in hepatocytes during tumor progression. CD147 was positively correlated with TGF-β1 and negatively correlated with HNF4α in human HCC tissues. Positive CD147 staining and lower HNF4α levels in tumor tissues were significantly associated with poor survival of patients with HCC. The overexpression of HNF4α and Smad7 and the deletion of CD147 by lentiviral vectors jointly reprogrammed the expression profile of hepatocyte markers and attenuated malignant properties including proliferation, cell survival and tumor growth of HCC cells. Our results highlight the important role of the TGF-β1-CD147 self-sustaining network in driving HCC development by regulating differentiation plasticity, which provides a strong basis for further investigations of the differentiation therapy of HCC targeting TGF-β1 and CD147.
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Affiliation(s)
- J Wu
- Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Fourth Military Medical University, Xi'an, China
| | - M Lu
- Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Fourth Military Medical University, Xi'an, China
| | - Y Li
- Department of Oncology, PLA 323 Hospital, Xi'an, China
| | - Y-K Shang
- Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Fourth Military Medical University, Xi'an, China
| | - S-J Wang
- Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Fourth Military Medical University, Xi'an, China
| | - Y Meng
- Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Fourth Military Medical University, Xi'an, China
| | - Z Wang
- Department of Pathology, Fourth Military Medical University, Xi'an, China
| | - Z-S Li
- Department of Pathology, Fourth Military Medical University, Xi'an, China
| | - H Chen
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing, China
| | - Z-N Chen
- Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Fourth Military Medical University, Xi'an, China
| | - H Bian
- Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Fourth Military Medical University, Xi'an, China
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31
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Fatima S, Shi X, Lin Z, Chen GQ, Pan XH, Wu JCY, Ho JW, Lee NP, Gao H, Zhang G, Lu A, Bian ZX. 5-Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β-catenin. Mol Oncol 2016; 10:195-212. [PMID: 26474915 PMCID: PMC5528951 DOI: 10.1016/j.molonc.2015.09.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 09/14/2015] [Accepted: 09/15/2015] [Indexed: 12/17/2022] Open
Abstract
5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β-catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signalling by 5-HT. The expression of various 5-HT receptors was studied by quantitative real-time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non-tumour tissues. Receptors 5-HT1D (21/33, 63.6%), 5-HT2B (12/33, 36.4%) and 5-HT7 (15/33, 45.4%) were overexpressed whereas receptors 5-HT2A (17/33, 51.5%) and 5-HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5-HT increased total β-catenin, active β-catenin and decreased phosphorylated β-catenin protein levels in serum deprived HuH-7 and HepG2 cells compared to control cells under serum free medium without 5-HT. Activation of Wnt/β-catenin signalling was evidenced by increased expression of β-catenin downstream target genes, Axin2, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS) by qPCR in serum-deprived HCC cell lines treated with 5-HT. Additionally, biochemical analysis revealed 5-HT disrupted Axin1/β-catenin interaction, a critical step in β-catenin phosphorylation. Increased Wnt/β-catenin activity was attenuated by antagonist of receptor 5-HT7 (SB-258719) in HCC cell lines and patient-derived primary tumour tissues in the presence of 5-HT. SB-258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β-catenin signalling activation by 5-HT and may represent a potential therapeutic target for hepatocarcinogenesis.
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Affiliation(s)
- Sarwat Fatima
- Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region
| | - Xiaoke Shi
- Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region
| | - Zesi Lin
- Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; School of Fundamental Medical Science, University of Chinese Medicine, Guangzhou, China
| | - Guo-qing Chen
- Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, China
| | - Xiao-hua Pan
- Shen Zhen People's Hospital, Shenzhen, 518020, China
| | - Justin Che-Yuen Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region
| | - John W Ho
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Nikki P Lee
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Hengjun Gao
- Institute of Digestive Disease, Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, 200065, China; Shanghai Engineering Center for Molecular Medicine, National Engineering Center for Biochip at Shanghai, Shanghai, 201203, China
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region
| | - Aiping Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China; School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region
| | - Zhao Xiang Bian
- Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
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Waisberg J, Saba GT. Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma. World J Hepatol 2015; 7:2631-2635. [PMID: 26609340 PMCID: PMC4651907 DOI: 10.4254/wjh.v7.i26.2631] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/11/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
The molecular basis of the carcinogenesis of hepatocellular carcinoma (HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-β-catenin. This leads to the activation of β-catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell’s own survival. The disruption of the signaling cascade Wnt-/-β-catenin has shown anticancer properties in HCC’s clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling β-catenin.
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Monga SP. β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. Gastroenterology 2015; 148:1294-310. [PMID: 25747274 PMCID: PMC4494085 DOI: 10.1053/j.gastro.2015.02.056] [Citation(s) in RCA: 391] [Impact Index Per Article: 39.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 02/21/2015] [Accepted: 02/23/2015] [Indexed: 12/11/2022]
Abstract
β-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics.
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Affiliation(s)
- Satdarshan Pal Monga
- Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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Chen J, Liu J, Jin R, Shen J, Liang Y, Ma R, Lin H, Liang X, Yu H, Cai X. Cytoplasmic and/or nuclear expression of β-catenin correlate with poor prognosis and unfavorable clinicopathological factors in hepatocellular carcinoma: a meta-analysis. PLoS One 2014; 9:e111885. [PMID: 25401330 PMCID: PMC4234306 DOI: 10.1371/journal.pone.0111885] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 09/30/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The β-catenin is an important effector in WNT/β-catenin signaling pathway, which exerts a crucial role in the development and progression of hepatocellular carcinoma (HCC). Some researchers have suggested that the overexpression of β-catenin in cytoplasm and/or nucleus was closely correlated to metastasis, poor differentiation and malignant phenotype of HCC while some other researchers hold opposite point. So far, no consensus was obtained on the prognostic and clinicopathological significance of cytoplasmic/nuclear β-catenin overexpression for HCCs. METHODS Systematic strategies were applied to search eligible studies in all available databases. Subgroup analyses, sensitivity analyses and multivariate analysis were performed. In this meta-analysis, we utilized either fixed- or random-effects model to calculate the pooled odds ratios (OR) and its 95% confidence intervals (CI). RESULTS A total of 22 studies containing 2334 cases were enrolled in this meta-analysis. Pooled data suggested that accumulation of β-catenin in cytoplasm and/or nucleus significantly correlated with poor 1-, 3- and 5-year OS and RFS. Moreover, nuclear accumulation combined with cytoplasmic accumulation of β-catenin tended to be associated with dismal metastasis and vascular invasion while cytoplasmic or nuclear expression alone showed no significant effect. Besides, no significant association was observed between cytoplasmic and/or nuclear β-catenin expression and poor differentiation grade, advanced TNM stage, liver cirrhosis, tumor size, tumor encapsulation, AFP and etiologies. Additional subgroup analysis by origin suggested that the prognostic value and clinicopathological significance of cytoplasmic and/or nuclear β-catenin expression was more validated in Asian population. Multivariate analyses of factors showed that cytoplasmic and/or nuclear β-catenin expression, as well as TNM stage, metastasis and tumor size, was an independent risk factors for OS and RFS. CONCLUSIONS Cytoplasmic and/or nuclear accumulation of β-catenin, as an independent prognostic factor, significantly associated with poor prognosis and deeper invasion of HCC, and could serve as a valuable prognostic predictor for HCC.
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Affiliation(s)
- Jiang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Jinghua Liu
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Renan Jin
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiliang Shen
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuelong Liang
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Rui Ma
- Department of Surgery, Zhejiang University Hospital, Hangzhou, Zhejiang, China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Hong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China
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Fatima S, Luk JM, Poon RTP, Lee NP. Dysregulated expression of dickkopfs for potential detection of hepatocellular carcinoma. Expert Rev Mol Diagn 2014; 14:535-48. [PMID: 24809435 DOI: 10.1586/14737159.2014.915747] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The prognosis for hepatocellular carcinoma (HCC) remains dismal due to the lack of diagnostic markers for early detection. This review will discuss the clinical potential of the dickkopf (DKK) family members as diagnostic and/or prognostic markers for HCC. In comparison to serum α-fetoprotein (AFP) level, which remains the gold standard for HCC diagnosis, high serum DKK1 levels have higher diagnostic value for HCC, especially for AFP-negative HCC, and can distinguish HCC from non-malignant chronic liver diseases. Additionally, the combination of serum DKK1 and AFP levels enhances diagnostic accuracy for HCC compared to serum DKK1 or AFP levels alone. Although DKK1 offers potential for its use in HCC diagnosis this review will discuss the challenges facing DKK1 and also shed some light on recent developments on the remaining DKK family members: DKK2, DKK3 and DKK4.
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Affiliation(s)
- Sarwat Fatima
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
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36
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Liu Q, Liu J. Signaling pathways in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2014; 22:59-66. [DOI: 10.11569/wcjd.v22.i1.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma is a complex multistep process involving progressive abnormalities of hepatocellular survival, proliferation, apoptosis and differentiation. Currently, accumulating evidence has demonstrated that the development of hepatocellular carcinoma is closely associated with dysregulation of several signaling pathways. Aberrant activation of these signaling cascades often leads to the over-expression of oncogenes and down-regulation of tumor suppressor genes, thus promoting cell cycle progression and apoptosis evasion. Here, we discuss some signaling pathways in hepatocellular carcinoma.
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Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol 2013; 59:1107-17. [PMID: 23835194 DOI: 10.1016/j.jhep.2013.07.001] [Citation(s) in RCA: 208] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 06/26/2013] [Accepted: 07/02/2013] [Indexed: 12/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. HCC can be cured by radical therapies if early diagnosis is done while the tumor has remained of small size. Unfortunately, diagnosis is commonly late when the tumor has grown and spread. Thus, palliative approaches are usually applied such as transarterial intrahepatic chemoembolization and sorafenib, an anti-angiogenic agent and MAP kinase inhibitor. This latter is the only targeted therapy that has shown significant, although moderate, efficiency in some individuals with advanced HCC. This highlights the need to develop other targeted therapies, and to this goal, to identify more and more pathways as potential targets. The Wnt pathway is a key component of a physiological process involved in embryonic development and tissue homeostasis. Activation of this pathway occurs when a Wnt ligand binds to a Frizzled (FZD) receptor at the cell membrane. Two different Wnt signaling cascades have been identified, called non-canonical and canonical pathways, the latter involving the β-catenin protein. Deregulation of the Wnt pathway is an early event in hepatocarcinogenesis and has been associated with an aggressive HCC phenotype, since it is implicated both in cell survival, proliferation, migration and invasion. Thus, component proteins identified in this pathway are potential candidates of pharmacological intervention. This review focuses on the characteristics and functions of the molecular targets of the Wnt signaling cascade and how they may be manipulated to achieve anti-tumor effects.
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Affiliation(s)
- Floriane Pez
- INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69008 Lyon, France; Université Lyon-1, F-69622 Villeurbanne, France; Centre Léon Bérard, F-69008 Lyon, France
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Molecular functions of thyroid hormones and their clinical significance in liver-related diseases. BIOMED RESEARCH INTERNATIONAL 2013; 2013:601361. [PMID: 23878812 PMCID: PMC3708403 DOI: 10.1155/2013/601361] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 05/14/2013] [Accepted: 05/28/2013] [Indexed: 02/06/2023]
Abstract
Thyroid hormones (THs) are potent mediators of several physiological processes, including embryonic development, cellular differentiation, metabolism, and cell growth. Triiodothyronine (T3) is the most biologically active TH form. Thyroid hormone receptors (TRs) belong to the nuclear receptor superfamily and mediate the biological functions of T3 via transcriptional regulation. TRs generally form heterodimers with the retinoid X receptor (RXR) and regulate target genes upon T3 stimulation. Research over the past few decades has revealed that disruption of cellular TH signaling triggers chronic liver diseases, including alcoholic or nonalcoholic fatty liver disease and hepatocellular carcinoma (HCC). Animal model experiments and epidemiologic studies to date imply close associations between high TH levels and prevention of liver disease. Moreover, several investigations spanning four decades have reported the therapeutic potential of T3 analogs in lowering lipids, preventing chronic liver disease, and as anticancer agents. Thus, elucidating downstream genes/signaling pathways and molecular mechanisms of TH actions is critical for the treatment of significant public health issues. Here, we have reviewed recent studies focusing on the roles of THs and TRs in several disorders, in particular, liver diseases. We also discuss the potential therapeutic applications of THs and underlying molecular mechanisms.
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Hypervascular hepatocellular carcinomas showing hyperintensity on hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging: a possible subtype with mature hepatocyte nature. Jpn J Radiol 2013; 31:480-90. [PMID: 23771695 DOI: 10.1007/s11604-013-0224-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 05/20/2013] [Indexed: 12/21/2022]
Abstract
PURPOSE We evaluated molecular features of hypervascular hepatocellular carcinoma (HCC) that shows iso- or hyperintensity (hyperintense HCC) in the hepatobiliary phase (HB phase) of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI). MATERIALS AND METHODS We investigated 89 surgically resected cases. Patients were divided into two groups according to the signal intensity in the HB phase of EOB-MRI: hyperintense HCCs (n = 18) and hypointense HCCs (n = 71). We performed immunohistochemical staining for uptake transporter of gadoxetic acid: organic anion transporter polypeptides (OATP8); tumor markers: alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II); hepatic stem cell markers: epithelial cell adhesion molecule (EpCAM), cytokeratin 19 (CK19), and neural cell adhesion molecule (NCAM); biliary marker: CK7; hepatocyte marker: hepatocyte paraffin 1 (HepPar1); markers of HCC differentiation: glypican-3; signaling: beta-catenin, and the respective grade was semiquantitatively determined. RESULTS Histopathologically, hyperintense HCCs showed significantly weaker expression of AFP (p < 0.05), PIVKA-II (p < 0.01), EpCAM (p < 0.005), glypican-3 (p < 0.005) relative to the hypointense HCCs, whereas OATP8 (p < 0.0001), HepPar1 (p < 0.05), and beta-catenin (p < 0.001) were overexpressed in hyperintense HCCs compared with hypointense HCCs. CONCLUSION Hyperintense HCC expressed OATP8 and showed a feature of mature hepatocytes with a weak expression of stem cell characteristics immunohistochemically. In addition, this type of HCC demonstrated a weaker expression of the poorer prognosis markers including, AFP, PIVKA-II, EpCAM, CK19, and glypican-3.
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Shen G, Jia H, Tai Q, Li Y, Chen D. miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis 2012; 34:211-9. [PMID: 23087084 DOI: 10.1093/carcin/bgs320] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aberrant activation of the Wnt/β-catenin signal pathway is frequently observed in hepatocellular carcinoma (HCC). β-Catenin is the major cellular effector of Wnt signaling and inactivation of adenomatous polyposis coli (APC) results in nuclear accumulation of β-catenin. Therefore, it was speculated that APC inhibition could play important roles in activating the Wnt/β-catenin pathway and in HCC progression. In this study, we report that miR-106b expression is markedly upregulated in hepatoma cells and hepatoma tissues compared with immortalized normal liver epithelial cells and normal hepatic tissues. Ectopic expression of miR-106b induces the proliferation and anchorage-independent growth of hepatoma cells, whereas inhibition of miR-106b reduced this effect. Furthermore, miR-106b upregulation in hepatoma cells modulated entry into the G(1)/S transitional phase by upregulating cyclin D1 and downregulating APC. Moreover, we demonstrated that miR-106b downregulates APC expression by directly targeting the 3'-untranslated region of APC messenger RNA. Taken together, our results suggest that miR-106b plays an important role in promoting the proliferation of human hepatoma cells and presents a novel mechanism of micro RNA-mediated direct suppression of APC expression in cancer cells.
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Affiliation(s)
- Gang Shen
- Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, China
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Hernández S, Venegas M, Brahm J, Villanueva RA. The viral transactivator HBx protein exhibits a high potential for regulation via phosphorylation through an evolutionarily conserved mechanism. Infect Agent Cancer 2012; 7:27. [PMID: 23079056 PMCID: PMC3533737 DOI: 10.1186/1750-9378-7-27] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2012] [Accepted: 09/20/2012] [Indexed: 12/30/2022] Open
Abstract
UNLABELLED BACKGROUND Hepatitis B virus (HBV) encodes an oncogenic factor, HBx, which is a multifunctional protein that can induce dysfunctional regulation of signaling pathways, transcription, and cell cycle progression, among other processes, through interactions with target host factors. The subcellular localization of HBx is both cytoplasmic and nuclear. This dynamic distribution of HBx could be essential to the multiple roles of the protein at different stages during HBV infection. Transactivational functions of HBx may be exerted both in the nucleus, via interaction with host DNA-binding proteins, and in the cytoplasm, via signaling pathways. Although there have been many studies describing different pathways altered by HBx, and its innumerable binding partners, the molecular mechanism that regulates its different roles has been difficult to elucidate. METHODS In the current study, we took a bioinformatics approach to investigate whether the viral protein HBx might be regulated via phosphorylation by an evolutionarily conserved mechanism. RESULTS We found that the phylogenetically conserved residues Ser25 and Ser41 (both within the negative regulatory domain), and Thr81 (in the transactivation domain) are predicted to be phosphorylated. By molecular 3D modeling of HBx, we further show these residues are all predicted to be exposed on the surface of the protein, making them easily accesible to these types of modifications. Furthermore, we have also identified Yin Yang sites that might have the potential to be phosphorylated and O-β-GlcNAc interplay at the same residues. CONCLUSIONS Thus, we propose that the different roles of HBx displayed in different subcellular locations might be regulated by an evolutionarily conserved mechanism of posttranslational modification, via phosphorylation.
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Affiliation(s)
- Sergio Hernández
- Laboratorio de Virus Hepatitis, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Avda. República 217, 3er piso, Santiago 8370146, Chile
| | - Mauricio Venegas
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Avda. Santos Dumont 999, Independencia, Santiago 8340457, Chile
| | - Javier Brahm
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Avda. Santos Dumont 999, Independencia, Santiago 8340457, Chile
| | - Rodrigo A Villanueva
- Laboratorio de Virus Hepatitis, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Avda. República 217, 3er piso, Santiago 8370146, Chile
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Zhang ZQ, Li DL, Chen SH, Jiang Y, Cheng BQ, Fan JJ, Ma M. Correlation between β-catenin expression and recurrence and metastasis of primary hepatocellular carcinoma in patients after surgery. Shijie Huaren Xiaohua Zazhi 2012; 20:1662-1666. [DOI: 10.11569/wcjd.v20.i18.1662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the expression of β-catenin in hepatocellular carcinoma and to analyze its correlation with recurrence and metastasis of primary hepatocellular carcinoma in patients after surgery.
METHODS: Immunohistochemistry was used to detect the expression of β-catenin in tumor samples and matched tumor-adjacent tissue samples taken form patients who had recurrence and/or metastasis within one year after surgery for primary hepatocellular carcinoma and those had no recurrence or metastasis. The correlation between β-catenin expression and the clinicopathological characteristics of primary hepatocellular carcinoma was analyzed.
RESULTS: β-catenin was mainly distributed on the membrane of cells in tumor-adjacent tissue. The rate of aberrant expression of β-catenin was significantly higher in tumor tissue than in tumor-adjacent tissue (60% vs 15%, χ2 = 17.28, P < 0.001). There was no significant difference in the expression of β-catenin in tumor-adjacent normal tissue between patients with and without cirrhosis (χ2 = 0.388, P = 0.533). The rate of aberrant expression of β-catenin was significantly higher in primary hepatocellular carcinoma with recurrence and/or metastasis than in that without recurrence or metastasis (80.0% vs 40%, χ2 = 6.667, P = 0.010). Aberrant expression of β-catenin was not correlated with age, liver cirrhosis, tumor size or differentiation, but was associated with the recurrence and metastasis of primary hepatocellular carcinoma.
CONCLUSION: Aberrant expression of β-catenin is associated with the development, recurrence metastasis of primary hepatocellular carcinoma and may be used as a useful prognostic parameter to predict overall survival.
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King TD, Zhang W, Suto MJ, Li Y. Frizzled7 as an emerging target for cancer therapy. Cell Signal 2012; 24:846-51. [PMID: 22182510 PMCID: PMC3268941 DOI: 10.1016/j.cellsig.2011.12.009] [Citation(s) in RCA: 109] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 12/04/2011] [Indexed: 02/09/2023]
Abstract
Wnt proteins are secreted glycoproteins that bind to the N-terminal extra-cellular cysteine-rich domain of the Frizzled (Fzd) receptor family. The Fzd receptors can respond to Wnt proteins in the presence of Wnt co-receptors to activate the canonical and non-canonical Wnt pathways. Recent studies indicated that, among the Fzd family, Fzd7 is the Wnt receptor most commonly upregulated in a variety of cancers including colorectal cancer, hepatocellular carcinoma and triple negative breast cancer. Fzd7 plays an important role in stem cell biology and cancer development and progression. In addition, it has been demonstrated that siRNA knockdown of Fzd7, the anti-Fzd7 antibody or the extracellular peptide of Fzd7 (soluble Fzd7 peptide) displayed anti-cancer activity in vitro and in vivo mainly due to the inhibition of the canonical Wnt signaling pathway. Furthermore, pharmacological inhibition of Fzd7 by small interfering peptides or a small molecule inhibitor suppressed β-catenin-dependent tumor cell growth. Therefore, targeted inhibition of Fzd7 represents a rational and promising new approach for cancer therapy.
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Affiliation(s)
- Taj D. King
- Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
| | - Wei Zhang
- Department of Medicinal Chemistry, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
| | - Mark J. Suto
- Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
- Department of Medicinal Chemistry, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
| | - Yonghe Li
- Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
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Wang H, Wen W. Biomarkers of Hepatocellular Carcinoma. PRIMARY LIVER CANCER 2012:79-154. [DOI: 10.1007/978-3-642-28702-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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45
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Fatima S, Lee NP, Luk JM. Dickkopfs and Wnt/β-catenin signalling in liver cancer. World J Clin Oncol 2011; 2:311-25. [PMID: 21876852 PMCID: PMC3163259 DOI: 10.5306/wjco.v2.i8.311] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Revised: 07/07/2011] [Accepted: 07/14/2011] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the fifth and seventh most common cause of cancer in men and women, respectively. Wnt/β-catenin signalling has emerged as a critical player in both the development of normal liver as well as an oncogenic driver in hepatocellular carcinoma (HCC). Based on the current understanding, this article summarizes the possible mechanisms for the aberrant activation of this pathway with specific focus on HCC. Furthermore, we will discuss the role of dickkopfs (DKKs) in regulating Wnt/β-catenin signalling, which is poorly understood and understudied. DKKs are a family of secreted proteins that comprise at least four members, namely DKK1-DKK4, which act as inhibitors of Wnt/β-catenin signalling. Nevertheless, not all members antagonize Wnt/β-catenin signalling. Their functional significance in hepatocarcinogenesis remains to be further characterized for which these studies should provide new insights into the regulatory role of DKKs in Wnt/β-catenin signalling in hepatic carcinogenesis. Because of the important oncogenic roles, there are an increasing number of therapeutic molecules targeting β-catenin and the Wnt/β-catenin pathway for potential therapy of HCC.
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Affiliation(s)
- Sarwat Fatima
- Sarwat Fatima, Nikki P Lee, Department of Surgery, The University of Hong Kong, Hong Kong, China
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Dong LW, Yang GZ, Pan YF, Chen Y, Tan YX, Dai RY, Ren YB, Fu J, Wang HY. The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling. Cell Res 2011; 21:1248-61. [PMID: 21691299 DOI: 10.1038/cr.2011.103] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
p28(GANK) (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28(GANK) mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate β-catenin, whether p28(GANK) is involved in the regulation of β-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28(GANK) expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28(GANK) expression subsequently enhanced the transcription activity of β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28(GANK)-mediated activation of β-catenin. p28(GANK) overexpression also reduced E-cadherin protein levels, leading to increased release of free β-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28(GANK) resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28(GANK), and a correlation between p28(GANK) overexpression and c-Myc, cyclin D1 and β-catenin activation in primary human HCC. Together, these results suggest that p28(GANK) expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.
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Affiliation(s)
- Li-wei Dong
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
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Shanbhogue AK, Prasad SR, Takahashi N, Vikram R, Sahani DV. Recent advances in cytogenetics and molecular biology of adult hepatocellular tumors: implications for imaging and management. Radiology 2011; 258:673-93. [PMID: 21339346 DOI: 10.1148/radiol.10100376] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Focal nodular hyperplasia (FNH), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) compose hepatocellular neoplasms that occur in adults. These tumors demonstrate characteristic epidemiologic and histopathologic features and clinical and imaging manifestations. HCAs are monoclonal neoplasms characterized by increased predilection to hemorrhage or rupture and occasional transformation to HCC. On the other hand, FNH is a polyclonal tumorlike lesion that occurs in response to increased perfusion and has an indolent clinical course. Up to 90% of HCCs occur in the setting of cirrhosis. Chronic viral hepatitis (hepatitis B and hepatitis C) infection and metabolic syndrome are major risk factors that can induce HCCs in nonfibrotic liver. Recent advances in pathology and genetics have led to better understanding of the histogenesis, natural history, and molecular events that determine specific oncologic pathways used by these neoplasms. HCAs are now believed to result from specific genetic mutations involving TCF1 (transcription factor 1 gene), IL6ST (interleukin 6 signal transducer gene), and CTNNB1 (β catenin-1 gene); FNHs are characterized by an "imbalance" of angiopoietin. While the β catenin signaling pathway is associated with well- and moderately differentiated HCCs, mutations involving p53 (tumor protein 53 gene), MMP14 (matrix metalloproteinase 14 gene), and RhoC (Ras homolog gene family, member C) are associated with larger tumor size, higher tumor grade with resultant shortened tumor-free survival, and poor prognosis. Fibrolamellar carcinoma (FLC), a unique HCC subtype, exhibits genomic homogeneity that partly explains its better overall prognosis. On the basis of recent study results involving cytogenetics and oncologic pathways of HCCs, novel drugs that act against molecular targets are being developed. Indeed, sorafenib (a multikinase inhibitor) is currently being used in the successful treatment of patients with advanced HCC. Characterization of genetic abnormalities and genotype-phenotype correlations in adult hepatocellular tumors provides better understanding of tumor pathology and biology, imaging findings, prognosis, and response to molecular therapeutics.
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Affiliation(s)
- Alampady K Shanbhogue
- Department of Radiology, University of Texas Health Science Center-San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA
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Choi SS, Omenetti A, Syn WK, Diehl AM. The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol 2011; 43:238-44. [PMID: 21056686 PMCID: PMC3022074 DOI: 10.1016/j.biocel.2010.10.015] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2009] [Revised: 09/14/2010] [Accepted: 10/28/2010] [Indexed: 12/13/2022]
Abstract
Repair of adult liver, like many tissues, involves the coordinated response of a number of different cell types. In adult livers, fibroblastic cells, ductular cells, inflammatory cells, and progenitor cells contribute to this process. Our studies demonstrate that the fates of such cells are dictated, at least in part, by Hedgehog, a fetal morphogenic pathway that was once thought to be active mainly during embryogenesis. Studies of injured adult human and rodent livers demonstrate that injury-related activation of the Hedgehog pathway modulates several important aspects of repair, including the growth of hepatic progenitor populations, hepatic accumulation of myofibroblasts, repair-related inflammatory responses, vascular remodeling, liver fibrosis and hepatocarcinogenesis. These findings identify the Hedgehog pathway as a potentially important target for biomarker development and therapeutic manipulation, and emphasize the need for further research to advance knowledge about how this pathway is regulated by and interacts with other signals that regulate adult liver repair.
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Affiliation(s)
- Steve S. Choi
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
- Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, NC
| | - Alessia Omenetti
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
| | - Wing-Kin Syn
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
| | - Anna Mae Diehl
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
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Nejak-Bowen KN, Monga SPS. Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin Cancer Biol 2011; 21:44-58. [PMID: 21182948 PMCID: PMC3050081 DOI: 10.1016/j.semcancer.2010.12.010] [Citation(s) in RCA: 204] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 12/09/2010] [Accepted: 12/14/2010] [Indexed: 12/19/2022]
Abstract
Among the adult organs, liver is unique for its ability to regenerate. A concerted signaling cascade enables optimum initiation of the regeneration process following insults brought about by surgery or a toxicant. Additionally, there exists a cellular redundancy, whereby a transiently amplifying progenitor population appears and expands to ensure regeneration, when differentiated cells of the liver are unable to proliferate in both experimental and clinical scenarios. One such pathway of relevance in these phenomena is Wnt/β-catenin signaling, which is activated relatively early during regeneration mostly through post-translational modifications. Once activated, β-catenin signaling drives the expression of target genes that are critical for cell cycle progression and contribute to initiation of the regeneration process. The role and regulation of Wnt/β-catenin signaling is now documented in rats, mice, zebrafish and patients. More recently, a regenerative advantage of the livers in β-catenin overexpressing mice was reported, as was also the case after exogenous Wnt-1 delivery to the liver paving the way for assessing means to stimulate the pathway for therapeutics in liver failure. β-Catenin is also pertinent in hepatic oval cell activation and differentiation. However, aberrant activation of the Wnt/β-catenin signaling is reported in a significant subset of hepatocellular cancers (HCC). While many mechanisms of such activation have been reported, the most functional means of aberrant and sustained activation is through mutations in the β-catenin gene or in AXIN1/2, which encodes for a scaffolding protein critical for β-catenin degradation. Intriguingly, in experimental models hepatic overexpression of normal or mutant β-catenin is insufficient for tumorigenesis. In fact β-catenin loss promoted chemical carcinogenesis in the liver due to alternate mechanisms. Since most HCC occur in the backdrop of chronic hepatic injury, where hepatic regeneration is necessary for maintenance of liver function, but at the same time serves as the basis of dysplastic changes, this Promethean attribute exhibits a Jekyll and Hyde behavior that makes distinguishing good regeneration from bad regeneration essential for targeting selective molecular pathways as personalized medicine becomes a norm in clinical practice. Could β-catenin signaling be one such pathway that may be redundant in regeneration and indispensible in HCC in a subset of cases?
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50
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Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling. Cancer Lett 2011; 300:162-72. [DOI: 10.1016/j.canlet.2010.09.018] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Revised: 09/28/2010] [Accepted: 09/28/2010] [Indexed: 12/17/2022]
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