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Heckl SM, Schneider C, Kercher L, Behrens HM, Gundlach JP, Bernsmeier A, Schmidt S, Krüger S, Braun F, Günther R, Becker T, Schreiber S, Röcken C. Worse survival of hepatocellular cancer patients with membranous insulin receptor overexpression. Sci Rep 2025; 15:1209. [PMID: 39775131 PMCID: PMC11707270 DOI: 10.1038/s41598-025-85350-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular cancer (HCC) therapy is in need for an ideal companion diagnostic. Preclinical experimental studies have identified the insulin receptor (IR) and its synergistic counterpart, the IGF1 receptor (IGF1R), as relevant in HCC development, and the ligands IGF1 and IGF2 have been found to be elevated in HCC. This study aimed to bridge the gap to the clinical setting and explore whether the IR or the IGF1R would be of prognostic significance and would be associated with clinicopathologic parameters in HCC patients. In our retrospective cohort study located at the University Hospital Schleswig-Holstein, Campus Kiel, Germany, HCC samples of 139 patients were examined for IR and IGF1R expression by immunohistochemistry. A HistoScore was correlated with clinicopathological characteristics and survival. IR overexpression was frequently observed and was associated with clinicopathological parameters and survival. Membranous IR expression was associated with worse tumor specific survival (p = 0.043). Intriguingly, membranous IR expression was associated with worse tumor specific survival (p = 0.017) in the subgroup of patients undergoing sorafenib therapy. IGF1R expression was not associated with survival. In conclusion, our results suggest that membranous IR expression plays a role in HCC prognosis and treatment resistance, inspiring future validation as a potential companion diagnostic in HCC.
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Affiliation(s)
- Steffen Markus Heckl
- Department of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
- Department of Internal Medicine II, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
- Department of Internal Medicine I, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
| | - Carolin Schneider
- Department of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Lukas Kercher
- Department of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Hans-Michael Behrens
- Department of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Jan-Paul Gundlach
- Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Alexander Bernsmeier
- Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Stephan Schmidt
- Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Felix Braun
- Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Rainer Günther
- Department of Internal Medicine I, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Thomas Becker
- Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Stefan Schreiber
- Department of Internal Medicine I, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany
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Rahdan F, Abedi F, Dianat-Moghadam H, Sani MZ, Taghizadeh M, Alizadeh E. Autophagy-based therapy for hepatocellular carcinoma: from standard treatments to combination therapy, oncolytic virotherapy, and targeted nanomedicines. Clin Exp Med 2024; 25:13. [PMID: 39621122 PMCID: PMC11611955 DOI: 10.1007/s10238-024-01527-5] [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: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024]
Abstract
Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abedi
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ma S, Xie F, Wen X, Adzavon YM, Zhao R, Zhao J, Li H, Li Y, Liu J, Liu C, Yi Y, Zhao P, Wang B, Zhao W, Ma X. GSTA1/CTNNB1 axis facilitates sorafenib resistance via suppressing ferroptosis in hepatocellular carcinoma. Pharmacol Res 2024; 210:107490. [PMID: 39510148 DOI: 10.1016/j.phrs.2024.107490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/31/2024] [Accepted: 10/31/2024] [Indexed: 11/15/2024]
Abstract
The emergence of sorafenib resistance has become a predominant impediment and formidable dilemma in the therapeutic approach for hepatocellular carcinoma (HCC). Although the approval of next-generation drugs as alternatives to sorafenib is a significant development, the concurrent use of inhibitors that target additional key molecular pathways remains an effective strategy to mitigate the acquisition of resistance. Here, we identified Glutathione S-Transferase Alpha 1 (GSTA1) as a critical modulator of sorafenib resistance (SR) in hepatocellular carcinoma (HCC) based on our findings from experiments conducted on recurrent liver cancer tissues, xenograft mouse models, organoids, and sorafenib-resistant cells. Elevated GSTA1 levels are strongly associated with adverse clinical prognoses. The knockout of GSTA1 reinstates sorafenib sensitivity, whereas its overexpression attenuates drug efficacy. Mechanistically, GSTA1 enhances the accumulation of lipid peroxides and suppresses ferroptosis by exerting its peroxidase function to regulate the SR. Notably, the upregulation of GSTA1 expression is mediated by the transcription factor CTNNB1 (β-catenin), resulting in the formation of a cytoplasmic complex between GSTA1 and CTNNB1. This complex facilitates the nuclear translocation of CTNNB1, establishing a positive feedback loop. The combined use of GSTA1 and CTNNB1 inhibitors demonstrated synergistic anti-tumour effects through the induction of ferroptosis both in vitro and in vivo. Our findings reveal a novel regulatory role of the GSTA1/CTNNB1 axis in ferroptosis, suggesting that targeting GSTA1 and CTNNB1 could be a promising strategy to circumvent sorafenib resistance in HCC.
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Affiliation(s)
- Shiwen Ma
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China; Key Laboratory of Carcinogenesis and Translational Research/Ministry of Education, Department of Clinical laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Fei Xie
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Xiaohu Wen
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China; Key Laboratory of Carcinogenesis and Translational Research/Ministry of Education, Department of Clinical laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yao Mawulikplimi Adzavon
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Ruping Zhao
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Jinyi Zhao
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Han Li
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Yanqi Li
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Jingtao Liu
- Key Laboratory of Carcinogenesis and Translational Research/Ministry of Education, Department of Clinical laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chen Liu
- Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Yang Yi
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Pengxiang Zhao
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China
| | - Boqing Wang
- Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
| | - Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research/Ministry of Education, Department of Clinical laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Xuemei Ma
- College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China.
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Pathak S, Singh V, Kumar G N, Jayandharan GR. AAV-mediated combination gene therapy of inducible Caspase 9 and miR-199a-5p is therapeutic in hepatocellular carcinoma. Cancer Gene Ther 2024; 31:1796-1803. [PMID: 39385010 DOI: 10.1038/s41417-024-00844-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/11/2024]
Abstract
Advanced-stage hepatocellular carcinoma (HCC) remains an untreatable disease with an overall survival of less than one year. One of the critical molecular mediators contributing to increased resistance to therapy and relapse, is increased hypoxia-inducible factor 1α (HIF-1α) levels, leading to metastasis of tumor cells. Several microRNAs are known to be dysregulated and impact HIF-1α expression in HCC. An in silico analysis demonstrated that hsa-miR-199a-5p is downregulated at various stages of HCC and is known to repress HIF-1α expression. Based on this analysis, we developed a combinatorial suicide gene therapy by employing hepatotropic Adeno-associated virus-based vectors encoding an inducible caspase 9 (iCasp9) and miR-199a. The overexpression of miR-199a-5p alone significantly decreased ( ~ 2-fold vs. Mock treated cells, p < 0.05) HIF-1α mRNA levels, with a concomitant increase in cancer cell cytotoxicity in Huh7 cells in vitro and in xenograft models in vivo. To further enhance the efficacy of gene therapy, we evaluated the synergistic therapeutic effect of AAV8-miR-199a and AAV6-iCasp9 in a xenograft model of HCC. Our data revealed that mice receiving combination suicide gene therapy exhibited reduced expression of HIF-1α ( ~ 4-fold vs. Mock, p < 0.001), with a significant reduction in tumor growth when compared to mock-treated animals. These findings underscore the therapeutic potential of downregulating HIF-1α during suicide gene therapy for HCC.
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Affiliation(s)
- Subhajit Pathak
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India
| | - Vijayata Singh
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India
| | - Narendra Kumar G
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India
| | - Giridhara R Jayandharan
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India.
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Zhao Y, Han S, Zeng Z, Zheng H, Li Y, Wang F, Huang Y, Zhao Y, Zhuo W, Lv G, Wang H, Zhao G, Zhao E, Hu Y, Hu P, Zhao G. Decreased lncRNA HNF4A-AS1 facilitates resistance to sorafenib-induced ferroptosis of hepatocellular carcinoma by reprogramming lipid metabolism. Theranostics 2024; 14:7088-7110. [PMID: 39629121 PMCID: PMC11610135 DOI: 10.7150/thno.99197] [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: 06/01/2024] [Accepted: 10/12/2024] [Indexed: 12/06/2024] Open
Abstract
Background: Resistance to sorafenib remains a major challenge in the systemic therapy of liver cancer. However, the involvement of lipid metabolism-related lncRNAs in this process remains unclear. Methods: Different expression levels of lipid metabolism-related lncRNAs in HCC were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The influence of HNF4A-AS1 on sorafenib response was evaluated through analysis of public biobanks, cell cytotoxicity and colony formation assays. The effect of HNF4A-AS1 on sorafenib-induced ferroptosis was measured using lipid peroxidation, glutathione, malondialdehyde, and ROS levels. Furthermore, bioinformatic analyses and lipidomic profiling were conducted to study HNF4A-AS1 involvement in lipid metabolic reprogramming. Mechanistic experiments, including the luciferase reporter assay, RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and RNA remaining assays, were employed to uncover the downstream targets and regulatory mechanisms of HNF4A-AS1 in sorafenib resistance in HCC. Xenograft and organoid experiments were carried out to assess the impact of HNF4A-AS1 on sorafenib response. Results: Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC. Conclusions: Our results indicated the pivotal role of lipid metabolism-related and liver-specific HNF4A-AS1 in inhibiting sorafenib resistance by promoting ferroptosis and suggesting that HNF4A-AS1 might be a potential target for HCC.
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MESH Headings
- Sorafenib/pharmacology
- Sorafenib/therapeutic use
- Humans
- Ferroptosis/drug effects
- Ferroptosis/genetics
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Drug Resistance, Neoplasm/genetics
- Lipid Metabolism/drug effects
- Lipid Metabolism/genetics
- Animals
- Hepatocyte Nuclear Factor 4/metabolism
- Hepatocyte Nuclear Factor 4/genetics
- Mice
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic/drug effects
- Mice, Nude
- Antineoplastic Agents/pharmacology
- Xenograft Model Antitumor Assays
- Male
- Mice, Inbred BALB C
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Ping Hu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Mahboobnia K, Beveridge DJ, Yeoh GC, Kabir TD, Leedman PJ. MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities. Int J Mol Sci 2024; 25:9393. [PMID: 39273339 PMCID: PMC11395074 DOI: 10.3390/ijms25179393] [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: 07/21/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.
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Affiliation(s)
- Khadijeh Mahboobnia
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - George C Yeoh
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Tasnuva D Kabir
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
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7
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Bartolini D, Stabile AM, Migni A, Gurrado F, Lioci G, De Franco F, Mandarano M, Svegliati-Baroni G, Di Cristina M, Bellezza G, Rende M, Galli F. Subcellular distribution and Nrf2/Keap1-interacting properties of Glutathione S-transferase P in hepatocellular carcinoma. Arch Biochem Biophys 2024; 757:110043. [PMID: 38789086 DOI: 10.1016/j.abb.2024.110043] [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: 04/18/2024] [Revised: 05/20/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
The oncogene and drug metabolism enzyme glutathione S-transferase P (GSTP) is also a GSH-dependent chaperone of signal transduction and transcriptional proteins with key role in liver carcinogenesis. In this study, we explored this role of GSTP in hepatocellular carcinoma (HCC) investigating the possible interaction of this protein with one of its transcription factor and metronome of the cancer cell redox, namely the nuclear factor erythroid 2-related factor 2 (Nrf2). Expression, cellular distribution, and function as glutathionylation factor of GSTP1-1 isoform were investigated in the mouse model of N-nitrosodiethylamine (DEN)-induced HCC and in vitro in human HCC cell lines. The physical and functional interaction of GSTP protein with Nrf2 and Keap1 were investigated by immunoprecipitation and gene manipulation experiments. GSTP protein increased its liver expression, enzymatic activity and nuclear levels during DEN-induced tumor development in mice; protein glutathionylation (PSSG) was increased in the tumor masses. Higher levels and a preferential nuclear localization of GSTP protein were also observed in HepG2 and Huh-7 hepatocarcinoma cells compared to HepaRG non-cancerous cells, along with increased basal and Ebselen-stimulated levels of free GSH and PSSG. GSTP activity inhibition with the GSH analogue EZT induced apoptotic cell death in HCC cells. Hepatic Nrf2 and c-Jun, two transcription factors involved in GSTP expression and GSH biosynthesis, were induced in DEN-HCC compared to control animals; the Nrf2 inhibitory proteins Keap1 and β-TrCP also increased and oligomeric forms of GSTP co-immunoprecipitated with both Nrf2 and Keap1. Nrf2 nuclear translocation and β-TrCP expression also increased in HCC cells, and GSTP transfection in HepaRG cells induced Nrf2 activation. In conclusion, GSTP expression and subcellular distribution are modified in HCC cells and apparently contribute to the GSH-dependent reprogramming of the cellular redox in this type of cancer directly influencing the transcriptional system Nrf2/Keap1.
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Affiliation(s)
- Desirée Bartolini
- Department of Pharmaceutical Sciences, University of Perugia, 06126, Perugia, Italy.
| | - Anna Maria Stabile
- Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy.
| | - Anna Migni
- Department of Pharmaceutical Sciences, University of Perugia, 06126, Perugia, Italy.
| | - Fabio Gurrado
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy.
| | - Gessica Lioci
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy.
| | | | - Martina Mandarano
- Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy
| | - Gianluca Svegliati-Baroni
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy; Obesity Center, Marche Polytechnic University, Ancona, Italy and Liver Injury and Transplant Unit, Ancona, Italy.
| | - Manlio Di Cristina
- Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy.
| | - Guido Bellezza
- Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy.
| | - Mario Rende
- Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy.
| | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, 06126, Perugia, Italy.
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8
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Khilwani H, Stettner S, Sonnabend K, Chen Y, Jain S, Gaba RC. Treatment of Hepatocellular Carcinoma with Combined Transarterial Chemoembolization and Systemic Therapy. Semin Intervent Radiol 2024; 41:309-316. [PMID: 39165657 PMCID: PMC11333115 DOI: 10.1055/s-0044-1787835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Affiliation(s)
- Harsh Khilwani
- University of Illinois College of Medicine, Chicago, Illinois
| | - Sarah Stettner
- University of Illinois College of Medicine, Chicago, Illinois
| | - Kyle Sonnabend
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Yolande Chen
- University of Illinois College of Medicine, Chicago, Illinois
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Shikha Jain
- University of Illinois College of Medicine, Chicago, Illinois
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Ron C. Gaba
- University of Illinois College of Medicine, Chicago, Illinois
- Division of Interventional Radiology, Department of Radiology, University of Illinois at Chicago, Chicago, Illinois
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9
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Sweed D, Gammal SSE, Kilany S, Abdelsattar S, Elhamed SMA. The expression of VEGF and cyclin D1/EGFR in common primary liver carcinomas in Egypt: an immunohistochemical study. Ecancermedicalscience 2023; 17:1641. [PMID: 38414954 PMCID: PMC10898887 DOI: 10.3332/ecancer.2023.1641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Indexed: 02/29/2024] Open
Abstract
Background The most common types of primary malignant liver tumours are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Treatment options for patients who are inoperable/advanced, or recurring are challenging. Cyclin D1, epidermal growth factor (EGFR) and vascular endothelial growth factor (VEGR) are common carcinogenic proteins that have potential therapeutic targets in various cancers. They have been implicated in the development of HCC and CCA. In this study, we aimed to evaluate the oncogenic function expression of cyclin D1, EGFR and VEGF in HCC and CCA of Egyptian patients. This could help to validate their therapeutic potential. Material and methods Tumour cases were selected from 82 cases of primary liver carcinomas, with 58 cases being from HCC and 24 cases from CCA compared to 51 non-tumour adjacent liver cases and 18 from normal liver tissue. The immunohistochemical study of cyclin D1, EGFR and VEGR was conducted. Results Cyclin D1, EGFR and VEGF are overexpressed in HCC and CCA as compared to the control group (p < 0.001). Cyclin D1 was related to well-differentiated grade and early pathologic stage in HCC (p = 0.016 and p = 0.042, respectively). The well-differentiated grade showed significantly higher VEGF levels (p = 0.04). In the CCA group, however, EGFR was strongly related to high tumour size (p = 0.047). EGFR and VEGF were overexpressed in HCC raised in the non-cirrhotic liver compared to those developed in post-hepatitic liver cirrhosis (p = 0.003 and p = 0.014). Conclusion Cyclin D1, EGFR and VEGF shared significant overexpression in HCC and CCA. EGFR and VEGF may play an oncogenic function in the development of HCC in non-cirrhotic liver. Furthermore, cyclin D1 and VEGF may play a good prognostic function in HCC, but EGFR may play a bad prognostic role in CCA.
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Affiliation(s)
- Dina Sweed
- Pathology Department, National Liver Institute, Shebin Elkom, Menofia University, Shebin Elkom 32511, Menoufia, Egypt
- https://orcid.org/0000-0001-6483-5056
| | - Shaymaa Sabry El Gammal
- Pathology Department, National Liver Institute, Shebin Elkom, Menofia University, Shebin Elkom 32511, Menoufia, Egypt
| | - Shimaa Kilany
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Shebin Elkom 32511, Menoufia, Egypt
| | - Shimaa Abdelsattar
- Clinical Biochemistry and Molecular Diagnostics Department, National Liver Institute, Menoufia University, Shebin Elkom 32511, Menoufia, Egypt
| | - Sara Mohamed Abd Elhamed
- Pathology Department, National Liver Institute, Shebin Elkom, Menofia University, Shebin Elkom 32511, Menoufia, Egypt
- https://orcid.org/0000-0003-0526-2627
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10
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Saber S, Hasan AM, Mohammed OA, Saleh LA, Hashish AA, Alamri MMS, Al-Ameer AY, Alfaifi J, Senbel A, Aboregela AM, Khalid TBA, Abdel-Reheim MA, Cavalu S. Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach. Biomed Pharmacother 2023; 164:114918. [PMID: 37216705 DOI: 10.1016/j.biopha.2023.114918] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/24/2023] Open
Abstract
Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.
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Affiliation(s)
- Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.
| | - Alexandru Madalin Hasan
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania.
| | - Osama A Mohammed
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Clinical Pharmacology, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Lobna A Saleh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
| | - Abdullah A Hashish
- Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia; Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | | | - Ahmed Y Al-Ameer
- Department of General Surgery, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Jaber Alfaifi
- Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Ahmed Senbel
- Department of General Surgery, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia; Department of Surgical Oncology, Oncology Center, Faculty of Medicine, Mansoura University, Mansoura 35516 Egypt
| | | | | | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical sciences, College of Pharmacy, Shaqra University, Aldawadmi 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania
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11
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Wang S, Shi JT, Wang XR, Mu HX, Wang XT, Xu KY, Wang QS, Chen SW. 1H-Indazoles derivatives targeting PI3K/AKT/mTOR pathway: Synthesis, anti-tumor effect and molecular mechanism. Bioorg Chem 2023; 133:106412. [PMID: 36773456 DOI: 10.1016/j.bioorg.2023.106412] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/27/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1H-indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC50 values of 0.43-3.88 μM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G2/M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo. Therefore, 3-amino-1H-indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.
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Affiliation(s)
- Shuai Wang
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Jian-Tao Shi
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Xing-Rong Wang
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Hong-Xia Mu
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Xue-Ting Wang
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Kai-Yan Xu
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Qing-Shan Wang
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Shi-Wu Chen
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
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12
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Seydi H, Nouri K, Rezaei N, Tamimi A, Hassan M, Mirzaei H, Vosough M. Autophagy orchestrates resistance in hepatocellular carcinoma cells. Biomed Pharmacother 2023; 161:114487. [PMID: 36963361 DOI: 10.1016/j.biopha.2023.114487] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/26/2023] Open
Abstract
Treatment resistance is one of the major barriers for therapeutic strategies in hepatocellular carcinoma (HCC). Many studies have indicated that chemotherapy and radiotherapy induce autophagy machinery (cell protective autophagy) in HCC cells. In addition, many experiments report a remarkable crosstalk between treatment resistance and autophagy pathways. Thus, autophagy could be one of the key factors enabling tumor cells to hinder induced cell death after medical interventions. Therefore, extensive research on the molecular pathways involved in resistance induction and autophagy have been conducted to achieve the desired therapeutic response. The key molecular pathways related to the therapy resistance are TGF-β, MAPK, NRF2, NF-κB, and non-coding RNAs. In addition, EMT, drug transports, apoptosis evasion, DNA repair, cancer stem cells, and hypoxia could have considerable impact on the hepatoma cell's response to therapies. These mechanisms protect tumor cells against various treatments and many studies have shown that each of them is connected to the molecular pathways of autophagy induction in HCC. Hence, autophagy inhibition may be an effective strategy to improve therapeutic outcome in HCC patients. In this review, we further highlight how autophagy leads to poor response during treatment through a complex molecular network and how it enhances resistance in primary liver cancer. We propose that combinational regimens of approved HCC therapeutic protocols plus autophagy inhibitors may overcome drug resistance in HCC therapy.
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Affiliation(s)
- Homeyra Seydi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Kosar Nouri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Niloufar Rezaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Department of Biotechnology, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Islamic Republic of Iran
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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13
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Huang L, Xu R, Li W, Lv L, Lin C, Yang X, Yao Y, Saw PE, Xu X. Repolarization of macrophages to improve sorafenib sensitivity for combination cancer therapy. Acta Biomater 2023; 162:98-109. [PMID: 36931417 DOI: 10.1016/j.actbio.2023.03.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 02/20/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023]
Abstract
Sorafenib is the first line drug for hepatocellular carcinoma (HCC) therapy. However, HCC patients usually acquire resistance to sorafenib treatment within 6 months. Recent evidences have shown that anticancer drugs with antiangiogenesis effect (e.g., sorafenib) can aggravate the hypoxia microenvironment and promote the infiltration of more tumor-associated macrophages (TAMs) into the tumor tissues. Therefore, repolarization of TAMs phenotype could be expected to not only eliminate the influence of TAMs on sorafenib lethality to HCC cells, but also provide an additional anticancer effect to achieve combination therapy. However, immune side effects remain a great challenge due to the non-specific macrophage repolarization in normal tissues. We herein employed a tumor microenvironment (TME) pH-responsive nanoplatform to concurrently transport sorafenib and modified resiquimod (R848-C16). This nanoparticle (NP) platform is made with a TME pH-responsive methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) copolymer. After intravenous administration, the co-delivery NPs could highly accumulate in the tumor tissues and then respond to the TME pH to detach their surface PEG chains. With this PEG detachment to enhance uptake by TAMs and HCC cells, the co-delivery NPs could combinatorially inhibit HCC tumor growth via sorafenib-mediated lethality to HCC cells and R848-mediated repolarization of TAMs into tumoricidal M1-like macrophages. STATEMENT OF SIGNIFICANCE: Anticancer drugs with antiangiogenesis effect (e.g., sorafenib) can aggravate the hypoxia microenvironment and promote the infiltration of more tumor-associated macrophages (TAMs) into the tumor tissues to restrict the anticancer effect. In this work, we designed and developed a tumor microenvironment (TME) pH-responsive nanoplatform for systemic co-delivery of sorafenib and resiquimod in hepatocellular carcinoma (HCC) therapy. These co-delivery NPs show high tumor accumulation and could respond to the TME pH to enhance uptake by TAMs and HCC cells. With the sorafenib-mediated lethality to HCC cells and R848-mediated repolarization of TAMs, the co-delivery NPs show a combinational inhibition of HCC tumor growth in both xenograft and orthotopic tumor models.
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Affiliation(s)
- Linzhuo Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, PR China
| | - Rui Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, PR China
| | - Weirong Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Li Lv
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, PR China
| | - Chunhao Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, PR China
| | - Xianzhu Yang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China
| | - Yandan Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, PR China.
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, PR China.
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Xiao C, Liu S, Ge G, Jiang H, Wang L, Chen Q, Jin C, Mo J, Li J, Wang K, Zhang Q, Zhou J. Roles of hypoxia-inducible factor in hepatocellular carcinoma under local ablation therapies. Front Pharmacol 2023; 14:1086813. [PMID: 36814489 PMCID: PMC9939531 DOI: 10.3389/fphar.2023.1086813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/18/2023] [Indexed: 02/09/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common digestive malignancies. HCC It ranges as the fifth most common cause of cancer mortality worldwide. While The prognosis of metastatic or advanced HCC is still quite poor. Recently, locoregional treatment, especially local ablation therapies, plays an important role in the treatment of HCC. Radiofrequency ablation (RFA) and high-intensity focused ultrasound (HIFU) ablation are the most common-used methods effective and feasible for treating HCC. However, the molecular mechanisms underlying the actions of ablation in the treatments for HCC and the HCC recurrence after ablation still are poorly understood. Hypoxia-inducible factor (HIF), the key gene switch for adaptive responses to hypoxia, has been found to play an essential role in the rapid aggressive recurrence of HCC after ablation treatment. In this review, we summarized the current evidence of the roles of HIF in the treatment of HCC with ablation. Fifteen relevant studies were included and further analyzed. Among them, three clinical studies suggested that HIF-1α might serve as a crucial role in the RAF treatment of HCC or the local recurrence of HCC after RFA. The remainder included experimental studies demonstrated that HIF-1, 2α might target the different molecules (e.g., BNIP3, CA-IX, and arginase-1) and signaling cascades (e.g., VEGFA/EphA2 pathway), constituting a complex network that promoted HCC invasion and metastasis after ablation. Currently, the inhibitors of HIF have been developed, providing important proof of targeting HIF for the prevention of HCC recurrence after IRFA and HIFU ablation. Further confirmation by prospective clinical and in-depth experimental studies is still warranted to illustrate the effects of HIF in HCC recurrence followed ablation treatment in the future.
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Affiliation(s)
- Chunying Xiao
- Department of Ultrasound, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Sheng Liu
- Department of Hepatobiliary Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ge Ge
- Department of Ultrasound, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Liezhi Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Qi Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Jin Li
- Department of Ultrasound, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
| | - Qianqian Zhang
- Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianyu Zhou
- Department of Ultrasound, Taizhou Central Hospital (Taizhou University, Hospital), Taizhou, Zhejiang, China
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Li X, Yin X, Bao H, Liu C. Circular RNA ITCH increases sorafenib-sensitivity in hepatocellular carcinoma via sequestering miR-20b-5p and modulating the downstream PTEN-PI3K/Akt pathway. Mol Cell Probes 2023; 67:101877. [PMID: 36442661 DOI: 10.1016/j.mcp.2022.101877] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/24/2022] [Accepted: 11/24/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUNDS Sorafenib-resistance leads to poor prognosis and high mortality in advanced hepatocellular carcinoma (HCC), and this study aims to investigate the functional role of a circular RNA ITCH (circITCH) in regulating the sorafenib-resistance of HCC and its underlying mechanisms. METHODS The expression of circITCH in HCC tissues and cell lines were detected by performing quantitative real-time polymerase chain reaction. Sorafenib-resistant HCC cells were transfected with PLCDH-circITCH to upregulate circITCH and intervened with sorafenib, and MTT assay, flow cytometry and transwell assay were used to test the cell viability, apoptosis and migration ability, respectively. The downstream target of circITCH were explored by using bioinformatic analysis, dual luciferase reporter system and Western blot. RESULTS CircITCH was significantly down-regulated in HCC tissues and cell lines, compared with their normal counterparts. Especially, in contrast with the sorafenib-sensitive HCC cells, continuous sorafenib treatment decreased the expression levels of circITCH in the sorafenib-resistant HCC cells. Overexpression of circITCH increased sorafenib-sensitivity, promoted cell apoptosis and reduced cell migration abilities in the sorafenib-resistant HCC cells. Mechanically, circITCH elevated PTEN expression to inactivate the PI3K/Akt signals through negatively regulating miR-20b-5p in HCC, and upregulating miR-20b-5p or inhibiting PTEN abolished the enhancing effect of circITCH overexpression on sorafenib-induced cytotoxicity in sorafenib-resistant HCC cells. CONCLUSION Taken together, this study proves that circITCH enhances sorafenib-sensitivity in sorafenib-resistant HCC cells via regulating the miR-20b-5p/PTEN/PI3K/Akt signaling cascade, which highlights the potential value of circITCH as a target for enhancing the sorafenib-sensitivity in HCC.
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Affiliation(s)
- Xiaodong Li
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
| | - Xuedong Yin
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
| | - Heyi Bao
- Department of General Surgery, Qiqihar First Hospital, Qiqihar, 161005, China.
| | - Chang Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
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16
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Coiled-Coil Domain-Containing Protein 45 Is a Potential Prognostic Biomarker and Is Associated with Immune Cell Enrichment of Hepatocellular Carcinoma. DISEASE MARKERS 2022; 2022:7745315. [PMID: 36618966 PMCID: PMC9815921 DOI: 10.1155/2022/7745315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/31/2022]
Abstract
Objective The role of coiled-coil domain-containing protein 45 (CCDC45) in the development of hepatocellular carcinoma (HCC) has not been reported. The present study is aimed at investigating the expression and prognosis of CCDC45 in HCC and its relevance to immune infiltration. Methods We conducted CCDC45 expression analysis using The Cancer Genome Atlas (TCGA) tumor database, the Human Protein Atlas (HPA) database, and the Tumor Immunological Evaluation Resource (TIMER). We used the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN) database to show the correlation of CCDC45 with clinical features. We examined the prognostic impact of CCDC45 expression levels on HCC patients with the Kaplan-Meier mapper database. Genes coexpressed with CCDC45 and its regulators were also identified using LinkedOmics. The enriched Gene Ontology (GO) categories and associated signaling pathways were estimated using GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Assay (GSEA) pathway data. Correlations between CCDC45 and cancer immune infiltration was analyzed through the TIMER and an integrated repository portal for Tumor-Immune System Interactions (TISIDB) databases. Results The expression of CCDC45 was elevated in HCC tissues compared to adjacent liver tissues, and overexpression of CCDC45 was significantly correlated with tumor stage. Furthermore, HCC patients with CCDC45 overexpression had a shorter overall survival (OS). Functional network analysis indicated that CCDC45 was involved in homologous recombination, spliceosome, and DNA replication. Interestingly, CCDC45 expression was positively correlated with the level of immune cell infiltration. Conclusions CCDC45 is associated with prognosis and immune infiltration of HCC and may be a potential therapeutic target for HCC.
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17
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Lu Q, Wang H, Lei X, Ma Q, Zhao J, Sun W, Guo C, Huang D, Xu Q. LncRNA ALKBH3-AS1 enhances ALKBH3 mRNA stability to promote hepatocellular carcinoma cell proliferation and invasion. J Cell Mol Med 2022; 26:5292-5302. [PMID: 36098205 PMCID: PMC9575106 DOI: 10.1111/jcmm.17558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/22/2022] [Accepted: 09/02/2022] [Indexed: 11/29/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are confirmed as the key regulators of hepatocellular carcinoma (HCC) occurrence and progression, but the role of AlkB homologue 3 antisense RNA 1 (ALKBH3-AS1) in HCC is unclear. We revealed the overexpression of ALKBH3-AS1 in HCC tissues. The upregulated levels of ALKBH3-AS1 were observed in HCC cells. ALKBH3-AS1 was expressed in the nucleus and cytoplasm of HCC cells. The high ALKBH3-AS1 expression was markedly associated with a decreased survival rate of HCC patients. ALKBH3-AS1 knockdown repressed and ALKBH3-AS1 overexpression enhanced HCC cell invasion and proliferation. ALKBH3-AS1 silencing restricted HCC growth in vivo. A significant positive correlation between ALKBH3-AS1 and ALKBH3 mRNA levels was confirmed in HCC specimens. ALKBH3-AS1 silencing reduced ALKBH3 expression by stabilizing its mRNA stability in HCC cells. Notably, the impact of ALKBH3 silencing on HCC cells was similar to that of ALKBH3-AS1 knockdown. ALKBH3 restoration prominently attenuated the suppressive effects resulting from ALKBH3-AS1 silencing in HCCLM3 cells. Hypoxia-inducible factor-1α (HIF-1α) transcriptionally activated ALKBH3-AS1 expression in hypoxic HCC cells. ALKBH3-AS1 knockdown markedly attenuated cell proliferation and invasion in hypoxic Huh7 cells. Collectively, HIF-1α-activated ALKBH3-AS1 exerted an oncogenic role by enhancing ALKBH3 mRNA stability in HCC cells.
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Affiliation(s)
- Qiliang Lu
- Qingdao Medical College, Qingdao University, Qingdao, China.,The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Hao Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | | | - Qiancheng Ma
- Zhejiang University of Technology, Hangzhou, China
| | - Jie Zhao
- Zhejiang University of Technology, Hangzhou, China
| | - Wen Sun
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Cheng Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
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Chen Q, Yang SB, Zhang YW, Han SY, Jia L, Li B, Zhang Y, Zuo S. miR-3682-3p directly targets FOXO3 and stimulates tumor stemness in hepatocellular carcinoma via a positive feedback loop involving FOXO3/PI3K/AKT/c-Myc. World J Stem Cells 2022; 14:539-555. [PMID: 36157524 PMCID: PMC9350627 DOI: 10.4252/wjsc.v14.i7.539] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/24/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) have been implicated in tumorigenesis and tumor recurrence and metastasis are key therapeutic targets in cancer treatment. MicroRNAs display therapeutic potential by controlling the properties of CSCs; however, whether an association exists between miR-3682-3p and CSCs is unknown.
AIM To investigate the mechanism by which miR-3682-3p promotes stemness maintenance in hepatocellular carcinoma (HCC).
METHODS MiR-3682-3p expression in HCC cell lines and 34 pairs of normal and HCC specimens was assayed by quantitative polymerase chain reaction. The functional role of miR-3682-3p was investigated in vitro and in vivo. Dual-luciferase reporter and chromatin immunoprecipitation assays were performed for target assessment, and western blotting was utilized to confirm miR-3682-3p/target relationships.
RESULTS We found that miR-3682-3p plays a key role in HCC pathogenesis by promoting HCC cell stemness. The upregulation of miR-3682-3p enhanced CSC spheroid-forming ability, side population cell fractions, and the expression of CSC factors in HCC cells in vitro and the tumorigenicity of transplanted HCC cells in vivo. Furthermore, silencing miR-3682-3p prolonged the survival of HCC-bearing mice. Mechanistically, we found that miR-3682-3p targets FOXO3 and enables FOXO3/β-catenin interaction, which promotes c-Myc expression through PI3K/AKT; c-Myc, in turn, activates miR-3682-3p, forming a positive feedback loop. Intriguingly, miR-3682-3p expression was induced by hepatitis B virus X protein (HBx) and was involved in HBx-induced tumor stemness-related pathogenesis.
CONCLUSION Our findings reveal a novel mechanism by which miR-3682-3p promotes stemness in HCC stem cells. Silencing miR-3682-3p may represent a novel therapeutic strategy for HCC.
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Affiliation(s)
- Qian Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Si-Bo Yang
- Department of Clinical Medicine, Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Ye-Wei Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Si-Yuan Han
- Department of Infectious Diseases, SSL Central Hospital of Dongguan, Dongguan 523000, Guangdong Province, China
| | - Lei Jia
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Bo Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Yi Zhang
- Department of Hepatobiliary Surgery, Guizhou Provincial People's Hospital, Guiyang 550000, Guizhou Province, China
| | - Shi Zuo
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
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Yan Y, Li H, Yao H, Cheng X. Nanodelivery Systems Delivering Hypoxia-Inducible Factor-1 Alpha Short Interfering RNA and Antisense Oligonucleotide for Cancer Treatment. FRONTIERS IN NANOTECHNOLOGY 2022. [DOI: 10.3389/fnano.2022.932976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Hypoxia-inducible factor (HIF), which plays a crucial role in oxygen homeostasis, contributes to immunosuppression, tumor angiogenesis, multidrug resistance, photodynamic therapy resistance, and metastasis. HIF as a therapeutic target has attracted scientists’ strong academic research interests. Short interfering RNA (siRNA) and antisense oligonucleotide (ASO) are the more promising and broadly utilized methods for oligonucleotide-based therapy. Their physicochemical characteristics such as hydrophilicity, negative charge, and high molecular weight make them impossible to cross the cell membrane. Moreover, siRNA and ASO are subjected to a rapid deterioration in circulation and cannot translocate into nuclear. Delivery of siRNA and ASO to specific gene targets should be realized without off-target gene silencing and affecting the healthy cells. Nanoparticles as vectors for delivery of siRNA and ASO possess great advantages and flourish in academic research. In this review, we summarized and analyzed regulation mechanisms of HIF under hypoxia, the significant role of HIF in promoting tumor progression, and recent academic research on nanoparticle-based delivery of HIF siRNA and ASO for cancer immunotherapy, antiangiogenesis, reversal of multidrug resistance and radioresistance, potentiating photodynamic therapy, inhibiting tumor metastasis and proliferation, and enhancing apoptosis are reviewed in this thesis. Furthermore, we hope to provide some rewarding suggestions and enlightenments for targeting HIF gene therapy.
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DJ-1/FGFR-1 Signaling Pathway Contributes to Sorafenib Resistance in Hepatocellular Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2543220. [PMID: 35770048 PMCID: PMC9236769 DOI: 10.1155/2022/2543220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 05/03/2022] [Accepted: 05/13/2022] [Indexed: 12/26/2022]
Abstract
Sorafenib is the first-line therapeutic regimen targeting against advanced or metastatic stage of hepatocellular carcinoma (HCC). However, HCC patients at these stages will eventually fail sorafenib treatment due to the drug resistance. At present, molecular mechanisms underlying sorafenib resistance are not completely understood. Our past studies have shown that DJ-1 is upregulated in HCC, while DJ-1 knockdown inhibits HCC xenograft-induced tumor growth and regeneration, implying that DJ-1 may be a potential target in for HCC treatment. However, whether DJ-1 plays a regulatory role between tumor cells and vascular endothelial cells and whether DJ-1 contributes to sorafenib resistance in HCC cells are largely unclear. To address these questions, we have performed a series of experiments in the current study, and we found that (1) DJ-1, one of the molecules secreted from HCC cells, promoted angiogenesis and migration of vascular endothelial cells (i.e., ECDHCC-1), by inducing phosphorylation of fibroblast growth factor receptor-1 (FGFR-1), phosphorylation of mTOR, phosphorylation of ERK, and phosphorylation of STAT3; (2) downregulation of FGFR1 inhibited tube formation and migration of ECDHCC-1 cells stimulated by DJ-1; (3) FGFR1 knockdown attenuated the phosphorylation of FGFR1 and impaired the activity of Akt, ERK, and STAT3 signals induced by DJ-1 in ECDHCC-1 cells; (4) knocking down FGFR1 led to the elevated expression of proapoptotic molecules but deceased level of antiapoptotic molecules in sorafenib-resistant HCC cells; and (5) Downregulation of FGFR1 suppressed tumor growth and angiogenesis of sorafenib-resistant HCC cells in vivo. Altogether, our results hinted that DJ-1 plays vital roles in tumor microenvironment in HCC development, and DJ-1/FGFR1 signaling pathway may be a therapeutic target for overcoming sorafenib resistance in treating HCC patients at the late stage.
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Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy. Cancers (Basel) 2022; 14:cancers14051165. [PMID: 35267473 PMCID: PMC8909699 DOI: 10.3390/cancers14051165] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/12/2022] [Accepted: 02/18/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the deadliest human health burdens worldwide. However, the molecular mechanism of HCC development is still not fully understood. Sex determining region Y-related high-mobility group box (SOX) transcription factors not only play pivotal roles in cell fate decisions during development but also participate in the initiation and progression of cancer. Given the significance of SOX factors in cancer and their ‘undruggable’ properties, we summarize the role and molecular mechanism of SOX family members in HCC and the regulatory effect of SOX factors in the tumor immune microenvironment (TIME) of various cancers. For the first time, we analyze the association between the levels of SOX factors and that of immune components in HCC, providing clues to the pivotal role of SOX factors in the TIME of HCC. We also discuss the opportunities and challenges of targeting SOX factors for cancer. Abstract Sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) factors belong to an evolutionarily conserved family of transcription factors that play essential roles in cell fate decisions involving numerous developmental processes. In recent years, the significance of SOX factors in the initiation and progression of cancers has been gradually revealed, and they act as potential therapeutic targets for cancer. However, the research involving SOX factors is still preliminary, given that their effects in some leading-edge fields such as tumor immune microenvironment (TIME) remain obscure. More importantly, as a class of ‘undruggable’ molecules, targeting SOX factors still face considerable challenges in achieving clinical translation. Here, we mainly focus on the roles and regulatory mechanisms of SOX family members in hepatocellular carcinoma (HCC), one of the fatal human health burdens worldwide. We then detail the role of SOX members in remodeling TIME and analyze the association between SOX members and immune components in HCC for the first time. In addition, we emphasize several alternative strategies involved in the translational advances of SOX members in cancer. Finally, we discuss the alternative strategies of targeting SOX family for cancer and propose the opportunities and challenges they face based on the current accumulated studies and our understanding.
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22
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Identification of MAD2L1 as a Potential Biomarker in Hepatocellular Carcinoma via Comprehensive Bioinformatics Analysis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9868022. [PMID: 35132379 PMCID: PMC8817109 DOI: 10.1155/2022/9868022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 01/15/2022] [Indexed: 11/17/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is widely acknowledged as a malignant tumor with rapid progression, high recurrence rate, and poor prognosis. At present, there is a paucity of reliable biomarkers at the clinical level to guide the management of HCC and improve patient outcomes. Our research is aimed at assessing the prognostic value of MAD2L1 in HCC. Methods Four datasets, GSE121248, GSE101685, GSE85598, and GSE62232, were selected from the GEO database to analyze differentially expressed genes (DEGs) between HCC and normal liver tissues. After functional analysis, we constructed a protein-protein interaction network (PPI) for DEGs and identified core genes in this network with high connectivity with other genes. We assessed the relationship between core genes and the pathogenesis and prognosis of HCC. Finally, we explored the gene regulatory signaling mechanisms involved in HCC pathogenesis. Results 145 DEGs were screened from the intersection of the four GEO datasets. MAD2L1 was associated with most genes according to the PPI network and was selected as a candidate gene for further study. Survival analysis suggested that high MAD2L1 expression in HCC correlated with a worse prognosis. In addition, real-time quantitative PCR (RT-qPCR), western blot (WB), and immunohistochemistry (IHC) findings suggested that the expression of MAD2L1 was abnormally increased in HCC tissues and cells compared to paraneoplastic tissues and normal hepatocytes. Conclusion We found that high MAD2L1 expression in HCC was significantly associated with overall patient survival and clinical features. We also explored the potential biological properties of this gene.
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Yuan H, Lu Y, Chan YT, Zhang C, Wang N, Feng Y. The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development. Cancers (Basel) 2021; 13:5700. [PMID: 34830854 PMCID: PMC8616375 DOI: 10.3390/cancers13225700] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/12/2021] [Accepted: 11/12/2021] [Indexed: 12/11/2022] Open
Abstract
Small ubiquitin-like modifier (SUMO) is a highly conserved post-translational modification protein, mainly found in eukaryotes. They are widely expressed in different tissues, including the liver. As an essential post-translational modification, SUMOylation is involved in many necessary regulations in cells. It plays a vital role in DNA repair, transcription regulation, protein stability and cell cycle progression. Increasing shreds of evidence show that SUMOylation is closely related to Hepatocellular carcinoma (HCC). The high expression of SUMOs in the inflammatory hepatic tissue may lead to the carcinogenesis of HCC. At the same time, SUMOs will upregulate the proliferation and survival of HCC, migration, invasion and metastasis of HCC, tumour microenvironment as well as drug resistance. This study reviewed the role of SUMOylation in liver cancer. In addition, it also discussed natural compounds that modulate SUMO and target SUMO drugs in clinical trials. Considering the critical role of SUMO protein in the occurrence of HCC, the drug regulation of SUMOylation may become a potential target for treatment, prognostic monitoring and adjuvant chemotherapy of HCC.
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Affiliation(s)
| | | | | | | | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; (H.Y.); (Y.L.); (Y.-T.C.); (C.Z.)
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; (H.Y.); (Y.L.); (Y.-T.C.); (C.Z.)
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