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Davis E, Ermi AG, Sarkar D. Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH): A Promising Molecular Marker and Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:1375. [PMID: 40282551 PMCID: PMC12025727 DOI: 10.3390/cancers17081375] [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: 03/10/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule.
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Affiliation(s)
- Eva Davis
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Ali Gawi Ermi
- Department of Cellular, Molecular and Genetic Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Department of Cellular, Molecular and Genetic Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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2
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Yang SM, Hu TH, Wu JC, Yi LN, Kuo HM, Kung ML, Chu TH, Huang ST, Huang CC, Kao YH, Lin YW, Tai MH. Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation. J Transl Med 2025; 105:104127. [PMID: 40081662 DOI: 10.1016/j.labinv.2025.104127] [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: 07/08/2024] [Revised: 01/28/2025] [Accepted: 03/05/2025] [Indexed: 03/16/2025] Open
Abstract
Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. In this study, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent nontumor tissue, were analyzed for expression of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The Cancer Genome Atlas cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in patients with HCC. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated alpha-fetoprotein, and poor survival and recurrent outcomes in the liver cancer cohort. HDGF knockout mice exhibited decreased liver C-tail--phosphorylated PTEN (p-PTEN) levels and increased PTEN expression. Furthermore, an in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, whereas knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of phosphatidylinositol 3,4,5-trisphosphate. Blockade of HDGF and casein kinase 2 signaling using anti-HDGF and a casein kinase 2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for patients with HCC.
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Affiliation(s)
- Shih-Ming Yang
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jian-Ching Wu
- National Sun Yat-Sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Li-Na Yi
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hsiao-Mei Kuo
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Tian-Huei Chu
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Shih-Tsung Huang
- National Sun Yat-Sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ying-Hsien Kao
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
| | - Yu-Wei Lin
- Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
| | - Ming-Hong Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
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Lv J, Wang Y, Lv J, Zheng C, Zhang X, Wan L, Zhang J, Liu F, Zhang H. Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment. Cell Death Dis 2025; 16:42. [PMID: 39863613 PMCID: PMC11762308 DOI: 10.1038/s41419-025-07332-6] [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: 05/03/2024] [Revised: 12/10/2024] [Accepted: 01/07/2025] [Indexed: 01/30/2025]
Abstract
TSC2, a suppressor of mTOR, is inactivated in up to 20% of HBV-associated liver cancer. This subtype of liver cancer is associated with aggressive behavior and early recurrence after hepatectomy. Being the first targeted regimen for advanced liver cancer, sorafenib has limited efficacy in HBV-positive patients. In this study, we observed that mTOR-activated cells, due to the loss of either TSC2 or PTEN, were insensitive to the treatment of sorafenib. Mechanistically, HSP70 enhanced the interaction between active mTOR-potentiated CREB1 and CREBBP to boost the transcription of the antioxidant response regulator SESN3. In return, elevated SESN3 enhanced cellular antioxidant capacity and rendered cells resistant to sorafenib. Pifithrin-μ, an HSP70 inhibitor, synergized with sorafenib in the induction of ferroptosis in mTOR-activated liver cancer cells and suppression of TSC2-deficient hepatocarcinogenesis. Our findings highlight the pivotal role of the mTOR-CREB1-SESN3 axis in sorafenib resistance of liver cancer and pave the way for combining pifithrin-μ and sorafenib for the treatment of mTOR-activated liver cancer.
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Affiliation(s)
- Jiarui Lv
- Department of Organ Transplantation and Hepatobiliary Surgery, Key Laboratory of Organ Transplantation of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanan Wang
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiacheng Lv
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Cuiting Zheng
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Zhang
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiology, State Key Laboratory of Complex, Severe and Rare Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College and Peking Union Medical College Hospital, Beijing, China
| | - Linyan Wan
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Gastroenterology, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
| | - Jiayang Zhang
- Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China
| | - Fangming Liu
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongbing Zhang
- Department of Organ Transplantation and Hepatobiliary Surgery, Key Laboratory of Organ Transplantation of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Cao D, Wang YN, Sun CY, Li H, Ren G, Zhou YF, Zhang MY, Wang SC, Mai SJ, Wang HY. MAF1 inhibits hepatocarcinogenesis by fostering an immunostimulatory tumor microenvironment. J Immunother Cancer 2025; 13:e009656. [PMID: 39800372 PMCID: PMC11749189 DOI: 10.1136/jitc-2024-009656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 12/06/2024] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND The biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in HCC is crucial for developing novel immunotherapy strategies and enhancing clinical responses to treatment for patients with HCC. METHODS Mice were subjected to hydrodynamic tail vein injections of transposon vectors to overexpress AKT/NRas, or c-Myc, with or without wild-type (WT) or mutant-activated (-4A) MAF1, or short-hairpin MAF1 (shMAF1). Liver tissues and tumors were harvested and analyzed using histology, immunohistochemistry, immunoblotting, quantitative reverse-transcription PCR, and flow cytometry. MAF1 was overexpressed or knocked down in HCC cells via lentiviral transfection. Cell lines were analyzed using RNA sequencing, immunoblotting, dual luciferase reporter, and chromatin precipitation assays. RESULTS Both MAF1-WT and MAF1-4A proteins significantly inhibit hepatocarcinogenesis in mice, with the mutant form exhibiting a stronger suppressive effect. Although MAF1 knockdown alone does not induce abnormalities in the mouse liver, it accelerates c-Myc-induced carcinogenesis. Our results provide the first in vivo evidence that MAF1 plays a tumor suppressor role by activating PTEN to suppress the AKT-mammalian target of rapamycin signaling pathway during hepatocarcinogenesis in physiologically relevant tumor models. More importantly, we found that MAF1 not only enhances the intratumoral infiltration of CD8+ T cells by increasing CXCL10 secretion but also enhances their functional activity by inhibiting PDL1 transcription in mouse liver cancer, which were confirmed in human HCC or in vitro experiments. Furthermore, PDL1 overexpression accelerates mouse hepatocarcinogenesis by antagonizing the tumor-suppressive role of MAF1. CONCLUSIONS Our study uncovers a novel anti-tumor immunity of MAF1 in hepatocarcinogenesis and human HCC. These findings suggest that the stimulated MAF1 could potentially improve immunotherapy in combination with immune checkpoint inhibitors in HCC patients, especially in those with an absence of T cells in HCC tissues.
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Affiliation(s)
- Di Cao
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yue-Ning Wang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chao-Yue Sun
- College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, China
| | - Haojiang Li
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ge Ren
- Department of Health Technology and Informatics, Hong Kong Polytechnic University University Learning Hub, Kowloon, Hong Kong
| | - Yu-Feng Zhou
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuo-Cheng Wang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shi-Juan Mai
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Jia Y, Xu X, Liu Y, Shen H, Sun S, Sun G. Effect of calcium concentration on metastasis of hepatocellular carcinoma cells cultured in alginate gel beads. Colloids Surf B Biointerfaces 2025; 245:114201. [PMID: 39255748 DOI: 10.1016/j.colsurfb.2024.114201] [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: 07/11/2024] [Revised: 08/28/2024] [Accepted: 08/31/2024] [Indexed: 09/12/2024]
Abstract
Changes in sodium alginate and calcium ion concentrations have a considerable impact on the structural properties of calcium alginate gel (ALG) beads, consequently influencing the biological characteristics of the cells encapsulated within them. This study aimed to examine the effects of calcium on the metastatic potential of hepatocellular carcinoma (HCC) cells encapsulated in ALG beads. The results showed that the invasion ability of HCC cells significantly increased when they were encapsulated in beads prepared with a calcium concentration of 200 mM compared to those prepared with a calcium concentration of 50 mM. Furthermore, the expression levels of genes related to metastasis were significantly elevated in ALG beads prepared with a calcium concentration of 200 mM. Specifically, the expression of activated matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and urokinase-type plasminogen activator system proteins was found to be high. Conversely, the expression of phosphatase and tensin homolog deleted on chromosome 10 was observed to be significantly reduced. These findings indicate that manipulating the calcium ion concentration during the fabrication of ALG beads enables the generation of three-dimensional HCC cells with varying metastatic capacities. This model offers a valuable tool for investigating the mechanisms underlying liver cancer metastasis and screening potential therapeutic drugs.
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Affiliation(s)
- Yunbo Jia
- Innovative Engineering Technology Research Center for Cell Therapy, Shengjing Hospital of China Medical University, Shenyang, China; Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaoxi Xu
- Laboratory of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Yang Liu
- Innovative Engineering Technology Research Center for Cell Therapy, Shengjing Hospital of China Medical University, Shenyang, China; Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China; Laboratory of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Hongfei Shen
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Siyu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Guangwei Sun
- Innovative Engineering Technology Research Center for Cell Therapy, Shengjing Hospital of China Medical University, Shenyang, China; Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China; Laboratory of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
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Che L, Stevenson CK, Plas DR, Wang J, Du C. BRUCE liver-deficiency potentiates MASLD/MASH in PTEN liver-deficient background by impairment of mitochondrial metabolism in hepatocytes and activation of STAT3 signaling in hepatic stellate cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.13.611500. [PMID: 39314445 PMCID: PMC11419131 DOI: 10.1101/2024.09.13.611500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common liver disease, affecting up to 25% of people worldwide, featuring excessive fat accumulation in hepatocytes. Its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is a serious disease with hepatic inflammation and fibrosis, increasing the need for liver transplants. However, the pathogenic mechanism of MASLD and MASH is not fully understood. We reported that BRUCE ( BIRC6) is a liver cancer suppressor and is downregulated in MASLD/MASH patient liver specimens, though the functional role of BRUCE in MASLD/MASH remains to be elucidated. To this end, we generated liver-specific double KO (DKO) mice of BRUCE and PTEN, a major tumor suppressor and MASLD/MASH suppressor. By comparing liver histopathology among 2-3-month-old mice, there were no signs of MASLD or MASH in BRUCE liver-KO mice and only onset of steatosis in PTEN liver-KO mice. Interestingly, DKO mice had developed robust hepatic steatosis with inflammation and fibrosis. Further analysis of mitochondrial function with primary hepatocytes found moderate reduction of mitochondrial respiration, ATP production and fatty acid oxidation in BRUCE KO and the greatest reduction in DKO hepatocytes. Moreover, aberrant activation of pro-fibrotic STAT3 signaling was found in hepatic stellate cells (HSCs) in DKO mice which was prevented by administered STAT3-specific inhibitor (TTI-101). Collectively, the data demonstrates by maintaining mitochondrial metabolism BRUCE works in concert with PTEN to suppress the pro-fibrogenic STAT3 activation in HSCs and consequentially prevent MASLD/MASH. The findings highlight BRUCE being a new co-suppressor of MASLD/MASH.
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Hussain MS, Moglad E, Afzal M, Gupta G, Hassan Almalki W, Kazmi I, Alzarea SI, Kukreti N, Gupta S, Kumar D, Chellappan DK, Singh SK, Dua K. Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives. Pathol Res Pract 2024; 258:155303. [PMID: 38728793 DOI: 10.1016/j.prp.2024.155303] [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: 03/04/2024] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 05/12/2024]
Abstract
Hepatocellular carcinoma (HCC) is among the primary reasons for fatalities caused by cancer globally, highlighting the need for comprehensive knowledge of its molecular aetiology to develop successful treatment approaches. The PI3K/Akt system is essential in the course of HCC, rendering it an intriguing candidate for treatment. Non-coding RNAs (ncRNAs), such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are important mediators of the PI3K/Akt network in HCC. The article delves into the complex regulatory functions of ncRNAs in influencing the PI3K/Akt system in HCC. The study explores how lncRNAs, miRNAs, and circRNAs impact the expression as well as the function of the PI3K/Akt network, either supporting or preventing HCC growth. Additionally, treatment strategies focusing on ncRNAs in HCC are examined, such as antisense oligonucleotide-based methods, RNA interference, and small molecule inhibitor technologies. Emphasizing the necessity of ensuring safety and effectiveness in clinical settings, limitations, and future approaches in using ncRNAs as therapies for HCC are underlined. The present study offers useful insights into the complex regulation system of ncRNAs and the PI3K/Akt cascade in HCC, suggesting possible opportunities for developing innovative treatment approaches to address this lethal tumor.
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Affiliation(s)
- Md Sadique Hussain
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan 302017, India
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Gaurav Gupta
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Saurabh Gupta
- Chameli Devi Institute of Pharmacy, Department of Pharmacology, Khandwa Road, Village Umrikheda, Near Toll Booth, Indore, Madhya Pradesh 452020, India
| | - Dinesh Kumar
- School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; School of Medical and Life Sciences, Sunway University, 47500 Sunway City, Malaysia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
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You X, Dou L, Tan M, Xiong X, Sun Y. SHOC2 plays an oncogenic or tumor-suppressive role by differentially targeting the MAPK and mTORC1 signals in liver cancer. LIFE MEDICINE 2024; 3:lnae023. [PMID: 39871893 PMCID: PMC11749279 DOI: 10.1093/lifemedi/lnae023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 05/21/2024] [Indexed: 01/29/2025]
Abstract
SHOC2 is a scaffold protein that activates the RAS-MAPK signal. Our recent study showed that SHOC2 is also a negative regulator of the mTORC1 signal in lung cancer cells. Whether and how SHOC2 differentially regulates the RAS-MAPK vs. the mTORC1 signals in liver cancer remains unknown. Here, we showed that S HOC2 is overexpressed in human liver cancer tissues, and SHOC2 overexpression promotes the growth and survival of liver cancer cells via activation of the RAS-MAPK signal, although the mTORC1 signal is inactivated. SHOC2 knockdown suppresses the growth of liver cancer cells mainly through inactivating the RAS-MAPK signal. Thus, in the cell culture models, SHOC2 regulation of growth is dependent of the RAS-MAPK but not the mTORC1 signal. Interestingly, in a mouse liver cancer model induced by diethylnitrosamine (DEN)-high-fat diet (HFD), hepatocyte-specific Shoc2 deletion inactivates the Ras-Mapk signal but has no effect in liver tumorigenesis. However, in the Pten loss-induced liver cancer model, Shoc2 deletion further activates mTorc1 without affecting the Ras-Mapk signal and promotes liver tumorigenesis. Collectively, it appears that SHOC2 could act as either an oncogene (via activating the MAPK signal) or a tumor suppressor (via inactivating the mTORC1 signal) in the manner dependent of the dominancy of the MAPK vs. mTORC1 signals.
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Affiliation(s)
- Xiahong You
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
- Cancer Center of Zhejiang University, Hangzhou 310029, China
| | - Longyu Dou
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
- Cancer Center of Zhejiang University, Hangzhou 310029, China
| | - Mingjia Tan
- Department of Radiation Oncology, University of Michigan, Ann Arbor MI 48109, United States
| | - Xiufang Xiong
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
- Cancer Center of Zhejiang University, Hangzhou 310029, China
| | - Yi Sun
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
- Cancer Center of Zhejiang University, Hangzhou 310029, China
- Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou 310029, China
- Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, China
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9
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Huang F, Zhao N, Cai P, Hou M, Yang S, Zheng B, Ma Q, Jiang J, Gai X, Mao Y, Wang L, Hu Z, Zha X, Liu F, Zhang H. Active AKT2 stimulation of SREBP1/SCD1-mediated lipid metabolism boosts hepatosteatosis and cancer. Transl Res 2024; 268:51-62. [PMID: 38244769 DOI: 10.1016/j.trsl.2024.01.005] [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: 08/08/2023] [Revised: 01/14/2024] [Accepted: 01/17/2024] [Indexed: 01/22/2024]
Abstract
Due to soared obesity population worldwide, hepatosteatosis is becoming a major risk factor for hepatocellular carcinoma (HCC). Undertaken molecular events during the progression of steatosis to liver cancer are thus under intensive investigation. In this study, we demonstrated that high-fat diet potentiated mouse liver AKT2. Hepatic AKT2 hyperactivation through gain-of-function mutation of Akt2 (Akt2E17K) caused spontaneous hepatosteatosis, injury, inflammation, fibrosis, and eventually HCC in mice. AKT2 activation also exacerbated lipopolysaccharide and D-galactosamine hydrochloride-induced injury/inflammation and N-Nitrosodiethylamine (DEN)-induced HCC. A positive correlation between AKT2 activity and SCD1 expression was observed in human HCC samples. Activated AKT2 enhanced the production of monounsaturated fatty acid which was dependent on SREBP1 upregulation of SCD1. Blockage of active SREBP1 and ablation of SCD1 reduced steatosis, inflammation, and tumor burden in DEN-treated Akt2E17K mice. Therefore, AKT2 activation is crucial for the development of steatosis-associated HCC which can be treated with blockage of AKT2-SREBP1-SCD1 signaling cascade.
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Affiliation(s)
- Fuqiang Huang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Na Zhao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Blood Transfusion, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
| | - Pei Cai
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengjie Hou
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuhui Yang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bohao Zheng
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian Ma
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Jingpeng Jiang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaochen Gai
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Lianmei Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhongdong Hu
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaojun Zha
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Fangming Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Hongbing Zhang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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10
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Huang F, Guo J, Zhao N, Hou M, Gai X, Yang S, Cai P, Wang Y, Ma Q, Zhao Q, Li L, Yang H, Jing Y, Jin D, Hu Z, Zha X, Wang H, Mao Y, Liu F, Zhang H. PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1. J Transl Med 2024; 22:254. [PMID: 38459588 PMCID: PMC10924424 DOI: 10.1186/s12967-024-04976-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 02/10/2024] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis. METHODS HBV-positive human liver cancer tissues were checked for PTEN expression. Transgenic HBV, Alb-Cre and Ptenfl/fl mice were inter-crossed to generate WT, HBV, Pten-/- and HBV; Pten-/- mice. Immunoblotting, histological analysis and qRT-PCR were used to study these livers. Gp73-/- mice were then mated with HBV; Pten-/- mice to illustrate the role of hepatic tumor biomarker golgi membrane protein 73 (GP73)/ golgi membrane protein 1 (GOLM1) in hepatic oncogenesis. RESULTS Pten deletion and HBV transgene synergistically aggravated liver injury, inflammation, fibrosis and development of mixed hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). GP73 was augmented in HBV; Pten-/- livers. Knockout of GP73 blunted the synergistic effect of deficient Pten and transgenic HBV on liver injury, inflammation, fibrosis and cancer development. CONCLUSIONS This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.
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Affiliation(s)
- Fuqiang Huang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Jing Guo
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Na Zhao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
- Department of Blood Transfusion, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Mengjie Hou
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Xiaochen Gai
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Shuhui Yang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Pei Cai
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Yanan Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Qian Ma
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Qi Zhao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Li Li
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yanling Jing
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China
| | - Di Jin
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhongdong Hu
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaojun Zha
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Hongyang Wang
- International Co-Operation Laboratory On Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Fangming Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China.
| | - Hongbing Zhang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China.
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11
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Jiang Z, Shi B, Zhang Y, Yu T, Cheng Y, Zhu J, Zhang G, Zhong M, Hu S, Ma X. CREB3L4 promotes hepatocellular carcinoma progression and decreases sorafenib chemosensitivity by promoting RHEB-mTORC1 signaling pathway. iScience 2024; 27:108843. [PMID: 38303702 PMCID: PMC10831937 DOI: 10.1016/j.isci.2024.108843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 11/09/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024] Open
Abstract
This study was designed to explore the roles of CREB3L4 in the pathogenesis and drug resistance of hepatocellular carcinoma (HCC). The proliferation of HCC lines was determined in the presence of CREB3L4 over-expression and silencing. Chromatin immunoprecipitation (ChIP) assay and dual-luciferase reporter assay were performed to screen the potential target of CREB3L4 on mTORC1. Xenografted tumor model was established to define the regulatory effects of CREB3L4 in the tumorigenesis. Then we evaluated the roles of CREB3L4 in chemosensitivity to sorafenib treatment. CREB3L4 significantly induced the HCC cell proliferation by modulating the activation of mTROC1-S6K1 signaling pathway via binding with RHEB promoter. Moreover, CREB3L4 dramatically inhibited the chemosensitivity to sorafenib treatment via up-regulating RHEB-mTORC1 signaling. CREB3L4 promoted HCC progression and decreased its chemosensitivity to sorafenib through up-regulating RHEB-mTORC1 signaling pathway, indicating a potential treatment strategy for HCC through targeting CREB3L4.
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Affiliation(s)
- Zhengchen Jiang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou 310022, China
| | - Bowen Shi
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250014, China
| | - Yun Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Tianming Yu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250014, China
| | - Yang Cheng
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250014, China
| | - Jiankang Zhu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Guangyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Sanyuan Hu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Xiaomin Ma
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
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12
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Tian LY, Smit DJ, Popova NV, Horn S, Velasquez LN, Huber S, Jücker M. All Three AKT Isoforms Can Upregulate Oxygen Metabolism and Lactate Production in Human Hepatocellular Carcinoma Cell Lines. Int J Mol Sci 2024; 25:2168. [PMID: 38396845 PMCID: PMC10889766 DOI: 10.3390/ijms25042168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is related to risk factors such as viral hepatitis, alcohol intake, and non-alcoholic fatty liver disease (NAFLD). The constitutive activation of the PI3K/AKT signaling pathway is common in HCC and has essential involvement in tumor progression. The serine/threonine kinase AKT has several downstream substrates, which have been implicated in the regulation of cellular metabolism. However, the contribution of each of the three AKT isoforms, i.e., AKT1, AKT2 and AKT3, to HCC metabolism has not been comprehensively investigated. In this study, we analyzed the functional role of AKT1, AKT2 and AKT3 in HCC metabolism. The overexpression of activated AKT1, AKT2 and AKT3 isoforms in the human HCC cell lines Hep3B and Huh7 resulted in higher oxygen consumption rate (OCR), ATP production, maximal respiration and spare respiratory capacity in comparison to vector-transduced cells. Vice versa, lentiviral vector-mediated knockdowns of each AKT isoform reduced OCR in both cell lines. Reduced OCR rates observed in the three AKT isoform knockdowns were associated with reduced extracellular acidification rates (ECAR) and reduced lactate production in both analyzed cell lines. Mechanistically, the downregulation of OCR by AKT isoform knockdowns correlated with an increased phosphorylation of the pyruvate dehydrogenase on Ser232, which negatively regulates the activity of this crucial gatekeeper of mitochondrial respiration. In summary, our data indicate that each of the three AKT isoforms is able to upregulate OCR, ECAR and lactate production independently of each other in human HCC cells through the regulation of the pyruvate dehydrogenase.
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Affiliation(s)
- Ling-Yu Tian
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; (L.-Y.T.); (D.J.S.); (N.V.P.)
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing 100044, China
| | - Daniel J. Smit
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; (L.-Y.T.); (D.J.S.); (N.V.P.)
| | - Nadezhda V. Popova
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; (L.-Y.T.); (D.J.S.); (N.V.P.)
| | - Stefan Horn
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Lis Noelia Velasquez
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.N.V.); (S.H.)
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.N.V.); (S.H.)
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; (L.-Y.T.); (D.J.S.); (N.V.P.)
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13
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Li YM, He HW, Zhang N. Targeting Protein Phosphatases for the Treatment of Chronic Liver Disease. Curr Drug Targets 2024; 25:171-189. [PMID: 38213163 DOI: 10.2174/0113894501278886231221092522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 01/13/2024]
Abstract
There exists a huge number of patients suffering from chronic liver disease worldwide. As a disease with high incidence and mortality worldwide, strengthening the research on the pathogenesis of chronic liver disease and the development of novel drugs is an important issue related to the health of all human beings. Phosphorylation modification of proteins plays a crucial role in cellular signal transduction, and phosphatases are involved in the development of liver diseases. Therefore, this article summarized the important role of protein phosphatases in chronic liver disease with the aim of facilitating the development of drugs targeting protein phosphatases for the treatment of chronic liver disease.
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Affiliation(s)
- Yi-Ming Li
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Hong-Wei He
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Na Zhang
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
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14
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Bartosh UI, Dome AS, Zhukova NV, Karitskaya PE, Stepanov GA. CRISPR/Cas9 as a New Antiviral Strategy for Treating Hepatitis Viral Infections. Int J Mol Sci 2023; 25:334. [PMID: 38203503 PMCID: PMC10779197 DOI: 10.3390/ijms25010334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatitis is an inflammatory liver disease primarily caused by hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV) viruses. The chronic forms of hepatitis resulting from HBV and HCV infections can progress to cirrhosis or hepatocellular carcinoma (HCC), while acute hepatitis can lead to acute liver failure, sometimes resulting in fatality. Viral hepatitis was responsible for over 1 million reported deaths annually. The treatment of hepatitis caused by viral infections currently involves the use of interferon-α (IFN-α), nucleoside inhibitors, and reverse transcriptase inhibitors (for HBV). However, these methods do not always lead to a complete cure for viral infections, and chronic forms of the disease pose significant treatment challenges. These facts underscore the urgent need to explore novel drug developments for the treatment of viral hepatitis. The discovery of the CRISPR/Cas9 system and the subsequent development of various modifications of this system have represented a groundbreaking advance in the quest for innovative strategies in the treatment of viral infections. This technology enables the targeted disruption of specific regions of the genome of infectious agents or the direct manipulation of cellular factors involved in viral replication by introducing a double-strand DNA break, which is targeted by guide RNA (spacer). This review provides a comprehensive summary of our current knowledge regarding the application of the CRISPR/Cas system in the regulation of viral infections caused by HAV, HBV, and HCV. It also highlights new strategies for drug development aimed at addressing both acute and chronic forms of viral hepatitis.
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Affiliation(s)
| | | | | | | | - Grigory A. Stepanov
- The Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk 630090, Russia; (U.I.B.); (A.S.D.); (N.V.Z.); (P.E.K.)
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15
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Yang S, Ruan X, Hu B, Tu J, Cai H. lncRNA SNHG9 enhances liver cancer stem cell self-renewal and tumorigenicity by negatively regulating PTEN expression via recruiting EZH2. Cell Tissue Res 2023; 394:441-453. [PMID: 37851112 DOI: 10.1007/s00441-023-03834-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 09/28/2023] [Indexed: 10/19/2023]
Abstract
Liver cancer stem cell (CSC) self-renewal and tumorigenesis are important causes of hepatocellular carcinoma (HCC) recurrence. We purposed to investigate the function of long noncoding RNA small nucleolar RNA host gene 9 (SNHG9) in liver CSC self-renewal and tumorigenesis in this study. Flow cytometry was carried out to separate CD133+ Populations and CD133- Populations from HCC cell lines. A combination of CD133+ cells and Matrigel matrix was subcutaneously injected to create the NOD-SCID mouse xenograft tumor model. Colony formation test and spheroids formation assay were carried out to clarify the impact of SNHG9 on the self-renewal of liver CSCs. RNA immunoprecipitation, RNA-pull down, and chromatin immunoprecipitation were performed on CD133+ cells to elucidate the mechanism of SNHG9 regulating PTEN expression. We found that SNHG9 was highly expressed in HCC clinical samples, HCC cells, and CD133+ cells. In vitro, interference with SNHG9 prevented the formation of colonies and spheroids in liver CSC cells and primary HCC cells. In vivo, interference with SNHG9 reduced the tumor volume and weight. SNHG9 could bind to EZH2, and SNHG9 interference suppressed EZH2 recruitment and H3K27me3 levels in the PTEN promoter region. In addition, SNHG9 inhibition promoted PTEN expression while having little impact on EZH2 levels. Interference with SNHG9 inhibited liver CSC self-renewal and tumorigenesis by up-regulating PTEN levels. In conclusion, by binding to EZH2, SNHG9 down-regulated PTEN levels, promoting liver CSC self-renewal and tumor formation, and exacerbating HCC progression.
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Affiliation(s)
- Shouzhang Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China
| | - Xiaojiao Ruan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Bingren Hu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China
| | - Jinfu Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China
| | - Huajie Cai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China.
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16
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Peixoto ÁS, Moreno MF, Castro É, Perandini LA, Belchior T, Oliveira TE, Vieira TS, Gilio GR, Tomazelli CA, Leonardi BF, Ortiz-Silva M, Silva Junior LP, Moretti EH, Steiner AA, Festuccia WT. Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning. J Physiol Biochem 2023; 79:731-743. [PMID: 37405670 DOI: 10.1007/s13105-023-00970-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 06/23/2023] [Indexed: 07/06/2023]
Abstract
Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.
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Affiliation(s)
- Álbert S Peixoto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Mayara F Moreno
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Érique Castro
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Luiz A Perandini
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Thiago Belchior
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Tiago E Oliveira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Thayna S Vieira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Gustavo R Gilio
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Caroline A Tomazelli
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Bianca F Leonardi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Milene Ortiz-Silva
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Luciano P Silva Junior
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil
| | - Eduardo H Moretti
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Alexandre A Steiner
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - William T Festuccia
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil.
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17
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Brodaczewska K, Majewska A, Filipiak-Duliban A, Kieda C. Pten knockout affects drug resistance differently in melanoma and kidney cancer. Pharmacol Rep 2023; 75:1187-1199. [PMID: 37673853 PMCID: PMC10539195 DOI: 10.1007/s43440-023-00523-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/12/2023] [Accepted: 08/22/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND PTEN is a tumor suppressor that is often mutated and nonfunctional in many types of cancer. The high heterogeneity of PTEN function between tumor types makes new Pten knockout models necessary to assess its impact on cancer progression and/or treatment outcomes. METHODS We aimed to show the effect of CRISPR/Cas9-mediated Pten knockout on murine melanoma (B16 F10) and kidney cancer (Renca) cells. We evaluated the effect of PTEN deregulation on tumor progression in vivo and in vitro, as well as on the effectiveness of drug treatment in vitro. In addition, we studied the molecular changes induced by Pten knockout. RESULTS In both models, Pten mutation did not cause significant changes in cell proliferation in vitro or in vivo. Cells with Pten knockout differed in sensitivity to cisplatin treatment: in B16 F10 cells, the lack of PTEN induced sensitivity and, in Renca cells, resistance to drug treatment. Accumulation of pAKT was observed in both cell lines, but only Renca cells showed upregulation of the p53 level after Pten knockout. PTEN deregulation also varied in the way that it altered PAI-1 secretion in the tested models, showing a decrease in PAI-1 in B16 F10 Pten/KO and an increase in Renca Pten/KO cells. In kidney cancer cells, Pten knockout caused changes in epithelial to mesenchymal transition marker expression, with downregulation of E-cadherin and upregulation of Snail, Mmp9, and Acta2 (α-SMA). CONCLUSIONS The results confirmed heterogenous cell responses to PTEN loss, which may lead to a better understanding of the role of PTEN in particular types of tumors and points to PTEN as a therapeutic target for personalized medicine.
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Affiliation(s)
- Klaudia Brodaczewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland.
| | - Aleksandra Majewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland
- Postgraduate School of Molecular Medicine (Medical University of Warsaw), Żwirki I Wigury 61, 02-091, Warsaw, Poland
| | - Aleksandra Filipiak-Duliban
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland
- Postgraduate School of Molecular Medicine (Medical University of Warsaw), Żwirki I Wigury 61, 02-091, Warsaw, Poland
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland
- Center for Molecular Biophysics UPR 4301, CNRS, 45071, Orleans, France
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18
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Zheng C, Snow BE, Elia AJ, Nechanitzky R, Dominguez-Brauer C, Liu S, Tong Y, Cox MA, Focaccia E, Wakeham AC, Haight J, Tobin C, Hodgson K, Gill KT, Ma W, Berger T, Heikenwälder M, Saunders ME, Fortin J, Leung SY, Mak TW. Tumor-specific cholinergic CD4 + T lymphocytes guide immunosurveillance of hepatocellular carcinoma. NATURE CANCER 2023; 4:1437-1454. [PMID: 37640929 PMCID: PMC10597839 DOI: 10.1038/s43018-023-00624-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 07/26/2023] [Indexed: 08/31/2023]
Abstract
Cholinergic nerves are involved in tumor progression and dissemination. In contrast to other visceral tissues, cholinergic innervation in the hepatic parenchyma is poorly detected. It remains unclear whether there is any form of cholinergic regulation of liver cancer. Here, we show that cholinergic T cells curtail the development of liver cancer by supporting antitumor immune responses. In a mouse multihit model of hepatocellular carcinoma (HCC), we observed activation of the adaptive immune response and induction of two populations of CD4+ T cells expressing choline acetyltransferase (ChAT), including regulatory T cells and dysfunctional PD-1+ T cells. Tumor antigens drove the clonal expansion of these cholinergic T cells in HCC. Genetic ablation of Chat in T cells led to an increased prevalence of preneoplastic cells and exacerbated liver cancer due to compromised antitumor immunity. Mechanistically, the cholinergic activity intrinsic in T cells constrained Ca2+-NFAT signaling induced by T cell antigen receptor engagement. Without this cholinergic modulation, hyperactivated CD25+ T regulatory cells and dysregulated PD-1+ T cells impaired HCC immunosurveillance. Our results unveil a previously unappreciated role for cholinergic T cells in liver cancer immunobiology.
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Affiliation(s)
- Chunxing Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
| | - Bryan E Snow
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Andrew J Elia
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Robert Nechanitzky
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | | | - Shaofeng Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Yin Tong
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Maureen A Cox
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Enrico Focaccia
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrew C Wakeham
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jillian Haight
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Chantal Tobin
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Kelsey Hodgson
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Kyle T Gill
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Wei Ma
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Thorsten Berger
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- The M3 Research Center, Medical Faculty Tübingen, Tübingen, Germany
| | - Mary E Saunders
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jerome Fortin
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Suet Yi Leung
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Tak W Mak
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China.
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.
- Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
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19
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Chakraborty S, Karmakar S, Basu M, Kal S, Ghosh MK. The E3 ubiquitin ligase CHIP drives monoubiquitylation-mediated nuclear import of the tumor suppressor PTEN. J Cell Sci 2023; 136:jcs260950. [PMID: 37676120 DOI: 10.1242/jcs.260950] [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: 01/10/2023] [Accepted: 08/04/2023] [Indexed: 09/08/2023] Open
Abstract
Monoubiquitylation is a principal mechanism driving nuclear translocation of the protein PTEN (phosphatase and tensin homolog deleted on chromosome ten). In this study, we describe a novel mechanism wherein the protein CHIP (C-terminus of Hsc70-interacting protein) mediates PTEN monoubiquitylation, leading to its nuclear import. Western blot analysis revealed a rise in both nuclear and total cellular PTEN levels under monoubiquitylation-promoting conditions, an effect that was abrogated by silencing CHIP expression. We established time-point kinetics of CHIP-mediated nuclear translocation of PTEN using immunocytochemistry and identified a role of karyopherin α1 (KPNA1) in facilitating nuclear transport of monoubiquitylated PTEN. We further established a direct interaction between CHIP and PTEN inside the nucleus, with CHIP participating in either polyubiquitylation or monoubiquitylation of nuclear PTEN. Finally, we showed that oxidative stress enhanced CHIP-mediated nuclear import of PTEN, which resulted in increased apoptosis, and decreased cell viability and proliferation, whereas CHIP knockdown counteracted these effects. To the best of our knowledge, this is the first report elucidating non-canonical roles for CHIP on PTEN, which we establish here as a nuclear interacting partner of CHIP.
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Affiliation(s)
- Shrabastee Chakraborty
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata 700091 and 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Subhajit Karmakar
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata 700091 and 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, South 24 Parganas 743372, India
| | - Satadeepa Kal
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata 700091 and 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Mrinal K Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata 700091 and 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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20
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Engel BJ, Paolillo V, Uddin MN, Gonzales KA, McGinnis KM, Sutton MN, Patnana M, Grindel BJ, Gores GJ, Piwnica-Worms D, Beretta L, Pisaneschi F, Gammon ST, Millward SW. Gender Differences in a Mouse Model of Hepatocellular Carcinoma Revealed Using Multi-Modal Imaging. Cancers (Basel) 2023; 15:3787. [PMID: 37568603 PMCID: PMC10417617 DOI: 10.3390/cancers15153787] [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: 05/12/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 08/13/2023] Open
Abstract
The worldwide incidence of hepatocellular carcinoma (HCC) continues to rise, in part due to poor diet, limited exercise, and alcohol abuse. Numerous studies have suggested that the loss or mutation of PTEN plays a critical role in HCC tumorigenesis through the activation of the PI3K/Akt signaling axis. The homozygous knockout of PTEN in the livers of mice results in the accumulation of fat (steatosis), inflammation, fibrosis, and eventually progression to HCC. This phenotype bears a striking similarity to non-alcoholic steatohepatitis (NASH) which is thought to occupy an intermediate stage between non-alcoholic fatty liver disease (NAFLD), fibrosis, and HCC. The molecular and physiological phenotypes that manifest during the transition to HCC suggest that molecular imaging could provide a non-invasive screening platform to identify the hallmarks of HCC initiation prior to the presentation of clinical disease. We have carried out longitudinal imaging studies on the liver-specific PTEN knockout mouse model using CT, MRI, and multi-tracer PET to interrogate liver size, steatosis, inflammation, and apoptosis. In male PTEN knockout mice, significant steatosis was observed as early as 3 months using both magnetic resonance spectroscopy (MRS) and computed tomography (CT). Enhanced uptake of the apoptosis tracer 18F-TBD was also observed in the livers of male PTEN homozygous knockout mice between 3 and 4 months of age relative to heterozygous knockout controls. Liver uptake of the inflammation tracer [18F]4FN remained relatively low and constant over 7 months in male PTEN homozygous knockout mice, suggesting the suppression of high-energy ROS/RNS with PTEN deletion relative to heterozygous males where the [18F]4FN liver uptake was elevated at early and late time points. All male PTEN homozygous mice developed HCC lesions by month 10. In contrast to the male cohort, only 20% (2 out of 10) of female PTEN homozygous knockout mice developed HCC lesions by month 10. Steatosis was significantly less pronounced in the female PTEN homozygous knockout mice relative to males and could not accurately predict the eventual occurrence of HCC. As with the males, the [18F]4FN uptake in female PTEN homozygous knockout mice was low and constant throughout the time course. The liver uptake of 18F-TBD at 3 and 4.5 months was higher in the two female PTEN knockout mice that would eventually develop HCC and was the most predictive imaging biomarker for HCC in the female cohort. These studies demonstrate the diagnostic and prognostic role of multi-modal imaging in HCC mouse models and provide compelling evidence that disease progression in the PTEN knockout model is highly dependent on gender.
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Affiliation(s)
- Brian J. Engel
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vincenzo Paolillo
- Cyclotron Radiochemistry Facility, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Md. Nasir Uddin
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kristyn A. Gonzales
- Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kathryn M. McGinnis
- Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Margie N. Sutton
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Madhavi Patnana
- Department of Abdominal Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Brian J. Grindel
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | | | - David Piwnica-Worms
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Federica Pisaneschi
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM) at the University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Seth T. Gammon
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Steven W. Millward
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
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21
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Todeschini L, Cristin L, Martinino A, Mattia A, Agnes S, Giovinazzo F. The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma. Curr Oncol 2023; 30:5574-5592. [PMID: 37366904 DOI: 10.3390/curroncol30060421] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.
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Affiliation(s)
- Letizia Todeschini
- Faculty of Medicine and Surgery, University of Verona, 37134 Verona, Italy
| | - Luca Cristin
- Faculty of Medicine and Surgery, University of Verona, 37134 Verona, Italy
| | | | - Amelia Mattia
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Salvatore Agnes
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Giovinazzo
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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22
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1407-1424. [DOI: 10.3748/wjg.v29.i10.1407] [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: 03/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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23
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1551-1568. [PMID: 36970588 PMCID: PMC10037251 DOI: 10.3748/wjg.v29.i10.1551] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/08/2023] [Accepted: 02/22/2023] [Indexed: 03/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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24
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Gromowski T, Lukacs-Kornek V, Cisowski J. Current view of liver cancer cell-of-origin and proposed mechanisms precluding its proper determination. Cancer Cell Int 2023; 23:3. [PMID: 36609378 PMCID: PMC9824961 DOI: 10.1186/s12935-022-02843-0] [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: 09/01/2022] [Accepted: 12/30/2022] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.
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Affiliation(s)
- Tomasz Gromowski
- grid.5522.00000 0001 2162 9631Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Veronika Lukacs-Kornek
- grid.10388.320000 0001 2240 3300Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Jaroslaw Cisowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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25
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Nguyen Huu T, Park J, Zhang Y, Duong Thanh H, Park I, Choi JM, Yoon HJ, Park SC, Woo HA, Lee SR. The Role of Oxidative Inactivation of Phosphatase PTEN and TCPTP in Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12010120. [PMID: 36670982 PMCID: PMC9854873 DOI: 10.3390/antiox12010120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent worldwide. Despite the different etiologies, their spectra and histological feature are similar, from simple steatosis to more advanced stages such as steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Studies including peroxiredoxin knockout models revealed that oxidative stress is crucial in these diseases, which present as consequences of redox imbalance. Protein tyrosine phosphatases (PTPs) are a superfamily of enzymes that are major targets of reactive oxygen species (ROS) because of an oxidation-susceptible nucleophilic cysteine in their active site. Herein, we review the oxidative inactivation of two tumor suppressor PTPs, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and T-cell protein tyrosine phosphatase (TCPTP), and their contribution to the pathogenicity of ALD and NAFLD, respectively. This review might provide a better understanding of the pathogenic mechanisms of these diseases and help develop new therapeutic strategies to treat fatty liver disease.
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Affiliation(s)
- Thang Nguyen Huu
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
| | - Jiyoung Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Ying Zhang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Hien Duong Thanh
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
- Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Iha Park
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Jin Myung Choi
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Hyun Joong Yoon
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Sang Chul Park
- The Future Life and Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju 61469, Republic of Korea
| | - Hyun Ae Woo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Seung-Rock Lee
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Correspondence: ; Tel.: +82-61-379-2775; Fax: +82-61-379-2782
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Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:14117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Chao X, Williams SN, Ding WX. Role of mechanistic target of rapamycin in autophagy and alcohol-associated liver disease. Am J Physiol Cell Physiol 2022; 323:C1100-C1111. [PMID: 36062877 PMCID: PMC9550572 DOI: 10.1152/ajpcell.00281.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/26/2022] [Accepted: 08/26/2022] [Indexed: 11/22/2022]
Abstract
Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase and a cellular sensor for nutrient and energy status, which is critical in regulating cell metabolism and growth by governing the anabolic (protein and lipid synthesis) and catabolic process (autophagy). Alcohol-associated liver disease (ALD) is a major chronic liver disease worldwide that carries a huge financial burden. The spectrum of the pathogenesis of ALD includes steatosis, fibrosis, inflammation, ductular reaction, and eventual hepatocellular carcinoma, which is closely associated with metabolic changes that are regulated by mTOR. In this review, we summarized recent progress of alcohol consumption on the changes of mTORC1 and mTORC2 activity, the potential mechanisms and possible impact of the mTORC1 changes on autophagy in ALD. We also discussed the potential beneficial effects and limitations of targeting mTORC1 against ALD.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Sha Neisha Williams
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
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Probiotics suppress nonalcoholic steatohepatitis and carcinogenesis progression in hepatocyte-specific PTEN knockout mice. Sci Rep 2022; 12:16206. [PMID: 36171333 PMCID: PMC9519992 DOI: 10.1038/s41598-022-20296-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 09/12/2022] [Indexed: 11/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a hepatic characteristic of metabolic syndrome, received significant attention in clinical settings. The multiple-hit theory is one of the proposed mechanisms of NAFLD, and gut dysbiosis is considered a hit. Thus, controlling gut microbiota is a potential target in the management of NAFLD, and probiotics can be used as a treatment agent for NAFLD. The current study aimed to investigate the efficacy of probiotics against nonalcoholic steatohepatitis in a hepatocyte-specific PTEN knockout mouse model that mimics the characteristics of human NAFLD. Probiotics were administered to male knockout mice for 8 or 40 weeks. Next, we assessed hepatic inflammation, fibrosis, carcinogenesis, and oxidative stress. Probiotics were found to reduce serum transaminase levels, NAFLD activity score, and the gene expression of pro-inflammatory cytokines. In addition, they decreased liver fibrosis grade, which was examined via Sirius red staining, gene expression of fibrotic markers, and hydroxyproline. Furthermore, probiotics suppressed the number of liver tumors, particular in HCC. Probiotics reduced oxidative stresses, including glutathione levels, and anti-oxidative stress marker, which may be an underlying mechanism for their beneficial effects. In conclusion, probiotics treatment had beneficial effects against NAFLD and carcinogenesis in hepatocyte-specific PTEN knockout mice.
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Tu WL, Chih YC, Shih YT, Yu YR, You LR, Chen CM. Context-specific roles of diphthamide deficiency in hepatocellular carcinogenesis. J Pathol 2022; 258:149-163. [PMID: 35781884 DOI: 10.1002/path.5986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/13/2022] [Accepted: 07/01/2022] [Indexed: 11/07/2022]
Abstract
Diphthamide biosynthesis protein 1 (DPH1) is biochemically involved in the first step of diphthamide biosynthesis, a post-translational modification of eukaryotic elongation factor 2 (EEF2). Earlier studies showed that DPH1, also known as ovarian cancer-associated gene 1 (OVCA1), is involved in ovarian carcinogenesis. However, the role of DPH1 in hepatocellular carcinoma (HCC) remains unclear. To investigate the impact of DPH1 in hepatocellular carcinogenesis, we have performed data mining from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. We found that reduced DPH1 levels were associated with advanced stages and poor survival of patients with HCC. Also, we generated hepatocyte-specific Dph1 deficient mice and showed that diphthamide deficient EEF2 resulted in a reduced translation elongation rate in the hepatocytes and let to mild liver damage with fatty accumulation. After N-diethylnitrosamine (DEN) -induced acute liver injury, p53-mediated pericentral hepatocyte death was increased, and compensatory proliferation was reduced in Dph1-deficient mice. Consistent with these effects, Dph1 deficiency decreased the incidence of DEN-induced pericentral-derived HCC and revealed a protective effect against p53 loss. In contrast, Dph1 deficiency combined with Trp53- or Trp53/Pten-deficient hepatocytes led to increased tumor loads associated with KRT19 (K19)-positive periportal-like cell expansion in mice. Further gene set enrichment analysis also revealed that HCC patients with lower levels of DPH1 and TP53 expression had enriched gene-sets related to the cell cycle and K19-upregulated HCC. Additionally, liver tumor organoids obtained from 6-month-old Pten/Trp53/Dph1-triple-mutant mice had a higher frequency of organoid re-initiation cells and higher proliferative index compared with those of the Pten/Trp53-double-mutant. Pten/Trp53/Dph1-triple-mutant liver tumor organoids showed expression of genes associated with stem/progenitor phenotypes, including Krt19 and Prominin-1 (Cd133) progenitor markers, combined with low hepatocyte-expressed fibrinogen genes. These findings indicate that diphthamide deficiency differentially regulates hepatocellular carcinogenesis, which inhibits pericentral hepatocytes-derived tumor and promotes periportal progenitors-associated liver tumors. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Wei-Ling Tu
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Yu-Chan Chih
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Ya-Tung Shih
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Yi-Ru Yu
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Li-Ru You
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Ming Chen
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Karanam G, Arumugam MK. Potential anticancer effects of cyclo(-Pro-Tyr) against N-diethyl nitrosamine induced hepatocellular carcinoma in mouse through PI3K/AKT signaling. ENVIRONMENTAL TOXICOLOGY 2022; 37:256-269. [PMID: 34726822 DOI: 10.1002/tox.23395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 10/22/2021] [Indexed: 06/13/2023]
Abstract
The oceans are considered as magnificent source of bioactive metabolites, of which marine sponges associated organisms are being the most effective producers of various bioactive molecules. We previously reported that cyclo(-Pro-Tyr) (CPT), a dipeptide from marine sponge Callyspongia fistularis associated Bacillus pumilus AMK1 bacteria for its anti-proliferative activity through down regulating PI3K signaling and inducing mitochondrial mediated apoptosis in HepG2 cells. Further we emphasize to study the role of CPT against hepatocellular carcinoma (HCC) induced by N-diethylnitrosamine (DEN) in male swiss albino mice in vivo. In this study, HCC was induced by the administration of DEN (75 mg/kg b.wt) dissolved in saline once/week for 3 weeks, then 100 mg/kg b.wt for another successive 3 weeks and observed for 18 weeks. CPT (100 mg/kg b.wt) treatment was started after 14 weeks of DEN induction. The obtained results demonstrated that CPT altered DEN induced oxidative stress by decreasing serum SGOT and SGPT followed increment in the antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. This was accompanied by decreased accumulation of glycoconjugates and argyophilic nucleolar organizing regions in the treatment groups. Further, CPT significantly reduced the levels of phospho-PI3Kinase p85 and phospho-AKT and upregulation of PTEN compared with DEN induced group. Besides this, decreased expression of Bcl-2 and increased expression of Bax, Caspase 3, and p53 was observed in CPT treated mice. Therefore, the anticancer mechanism of CPT against DEN induced HCC may be associated with the regulation of the PI3K/AKT signaling pathway, which ultimately stimulates apoptosis.
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Affiliation(s)
- Gayathri Karanam
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Madan Kumar Arumugam
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
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31
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Zuo Z, Yu Y, Ren B, Liu S, Nelson J, Wang Z, Tao J, Pradhan‐Sundd T, Bhargava R, Michalopoulos G, Chen Q, Zhang J, Ma D, Pennathur A, Luketich J, Satdarshan Monga P, Nalesnik M, Luo J. Oncogenic Activity of Solute Carrier Family 45 Member 2 and Alpha-Methylacyl-Coenzyme A Racemase Gene Fusion Is Mediated by Mitogen-Activated Protein Kinase. Hepatol Commun 2022; 6:209-222. [PMID: 34505419 PMCID: PMC8710797 DOI: 10.1002/hep4.1724] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/23/2021] [Accepted: 02/28/2021] [Indexed: 11/09/2022] Open
Abstract
Chromosome rearrangement is one of the hallmarks of human malignancies. Gene fusion is one of the consequences of chromosome rearrangements. In this report, we show that gene fusion between solute carrier family 45 member 2 (SLC45A2) and alpha-methylacyl-coenzyme A racemase (AMACR) occurs in eight different types of human malignancies, with frequencies ranging from 45% to 97%. The chimeric protein is translocated to the lysosomal membrane and activates the extracellular signal-regulated kinase signaling cascade. The fusion protein promotes cell growth, accelerates migration, resists serum starvation-induced cell death, and is essential for cancer growth in mouse xenograft cancer models. Introduction of SLC45A2-AMACR into the mouse liver using a sleeping beauty transposon system and somatic knockout of phosphatase and TENsin homolog (Pten) generated spontaneous liver cancers within a short period. Conclusion: The gene fusion between SLC45A2 and AMACR may be a driving event for human liver cancer development.
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Affiliation(s)
- Ze‐Hua Zuo
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Yan‐Ping Yu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Bao‐Guo Ren
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Silvia Liu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Joel Nelson
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Zhou Wang
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Junyan Tao
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | | | - Rohit Bhargava
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - George Michalopoulos
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Qi Chen
- Department of PharmacologyToxicology, and TherapeuticsUniversity of KansasKansas CityKSUSA
| | - Jun Zhang
- Department of MedicineUniversity of IowaIowa CityIAUSA
- Present address:
Department of MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Deqin Ma
- Department of PathologyUniversity of IowaIowa CityIAUSA
| | - Arjun Pennathur
- Thoracic SurgeryUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - James Luketich
- Thoracic SurgeryUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Paul Satdarshan Monga
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Michael Nalesnik
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Jian‐Hua Luo
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
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Zhai S, Zhang H, Chen R, Wu J, Ai D, Tao S, Cai Y, Zhang JQ, Wang L. Design, synthesis and biological evaluation of novel hybrids targeting mTOR and HDACs for potential treatment of hepatocellular carcinoma. Eur J Med Chem 2021; 225:113824. [PMID: 34509167 DOI: 10.1016/j.ejmech.2021.113824] [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: 06/18/2021] [Revised: 08/19/2021] [Accepted: 08/28/2021] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major contributor to global cancer incidence and mortality. Many pathways are involved in the development of HCC and various proteins including mTOR and HDACs have been identified as potential drug targets for HCC treatment. In the present study, two series of novel hybrid molecules targeting mTOR and HDACs were designed and synthesized based on parent inhibitors (MLN0128 and PP121 for mTOR, SAHA for HDACs) by using a fusion-type molecular hybridization strategy. In vitro antiproliferative assays demonstrated that these novel hybrids with suitable linker lengths exhibited broad cytotoxicity against various cancer cell lines, with significant activity against HepG2 cells. Notably, DI06, an MLN0128-based hybrid, exhibited antiproliferative activity against HepG2 cells with an IC50 value of 1.61 μM, which was comparable to those of both parent drugs (MLN0128, IC50 = 2.13 μM and SAHA, IC50 = 2.26 μM). In vitro enzyme inhibition assays indicated that DI06, DI07 and DI17 (PP121-based hybrid) exhibited nanomolar inhibitory activity against mTOR kinase and HDACs (e.g., HDAC1, HDAC2, HDAC3, HADC6 and HADC8). Cellular studies and western blot analyses uncovered that in HepG2 cells, DI06 and DI17 induced cell apoptosis by targeting mTOR and HDACs, blocked the cell cycle at the G0/G1 phase and suppressed cell migration. The potential binding modes of the hybrids (DI06 and DI17) with mTOR and HDACs were investigated by molecular docking. DI06 displayed better stability in rat liver microsomes than DI07 and DI17. Collectively, DI06 as a novel mTOR and HDACs inhibitor presented here warrants further investigation as a potential treatment of HCC.
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Affiliation(s)
- Shiyang Zhai
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Huimin Zhang
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Rui Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Jiangxia Wu
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Daiqiao Ai
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Shunming Tao
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Yike Cai
- Center for Certification and Evaluation, Guangdong Drug Administration, Guangzhou, 510080, China
| | - Ji-Quan Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Ling Wang
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China.
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Liu Z, Sun J, Li C, Xu L, Liu J. MKL1 regulates hepatocellular carcinoma cell proliferation, migration and apoptosis via the COMPASS complex and NF-κB signaling. BMC Cancer 2021; 21:1184. [PMID: 34742274 PMCID: PMC8571910 DOI: 10.1186/s12885-021-08185-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 04/14/2021] [Indexed: 12/18/2022] Open
Abstract
Background Histone modification plays essential roles in hepatocellular carcinoma (HCC) pathogenesis, but the regulatory mechanisms remain poorly understood. In this study, we aimed to analyze the roles of Megakaryoblastic leukemia 1 (MKL1) and its regulation of COMPASS (complex of proteins associated with Set1) in HCC cells. Methods MKL1 expression in clinical tissues and cell lines were detected by bioinformatics, qRT-PCR and western blot. MKL1 expression in HCC cells were silenced with siRNA, followed by cell proliferation evaluation via Edu staining and colony formation, migration and invasion using the Transwell system, and apoptosis by Hoechst staining. HCC cell tumorigenesis was assessed by cancer cell line-based xenograft model, combined with H&E staining and IHC assays. Results MKL1 expression was elevated in HCC cells and clinical tissues which was correlated with poor prognosis. MKL1 silencing significantly repressed proliferation, migration, invasion and colony formation but enhanced apoptosis in HepG2 and Huh-7 cells. MKL1 silencing also inhibited COMPASS components and p65 protein expression in HepG2 and Huh-7 cells. HepG2 cell tumorigenesis in nude mice was severely impaired by MKL1 knockdown, resulted into suppressed Ki67 expression and cell proliferation. Conclusion MKL1 promotes HCC pathogenesis by regulating hepatic cell proliferation, migration and apoptosis via the COMPASS complex and NF-κB signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08185-w.
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Affiliation(s)
- Zhao Liu
- Department of Hepatobiliary and Pancreatic Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jiuzheng Sun
- Department of Hepatobiliary and Pancreatic Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanzhi Li
- Department of Hepatobiliary and Pancreatic Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liyou Xu
- Department of Hepatobiliary and Pancreatic Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. .,Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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34
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Liu HY, Pedros C, Kong KF, Canonigo-Balancio AJ, Xue W, Altman A. Leveraging the Treg-intrinsic CTLA4-PKCη signaling pathway for cancer immunotherapy. J Immunother Cancer 2021; 9:jitc-2021-002792. [PMID: 34588224 PMCID: PMC8483050 DOI: 10.1136/jitc-2021-002792] [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] [Accepted: 09/03/2021] [Indexed: 12/03/2022] Open
Abstract
Background Our previous studies revealed a critical role of a novel CTLA4-protein kinase C-eta (PKCη) signaling axis in mediating the suppressive activity of regulatory T cells (Tregs) in antitumor immunity. These studies have employed adoptive transfer of germline PKCη-deficient (Prkch−/−) Tregs into Prkch+/+ mice prior to tumor implantation. Here, we extended these findings into a biologically and clinically more relevant context. Methods We have analyzed the role of PKCη in antitumor immunity and the tumor microenvironment (TME) in intact tumor-bearing mice with Treg-specific or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. In addition to measuring tumor growth, we analyzed the phenotype and functional attributes of tumor-infiltrating immune cells, particularly Tregs and dendritic cells (DCs). Results Using two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found, first, that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16–F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive TME, indicated by increased numbers and function of tumor-infiltrating CD8+ effector T cells and elevated expression of the costimulatory ligand CD86 on intratumoral DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth or the abundance and functionality of CD8+ effector T cells, consistent with findings that Prkch−/− CD8+ T cells proliferated normally in response to in vitro polyclonal or specific antigen stimulation. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Fms-like tyrosine kinase 3 ligand (Flt3L)-expressing B16–F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies. Conclusion These findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat patients with cancer, especially when combined with adjuvant therapies.
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Affiliation(s)
- Hsin-Yu Liu
- La Jolla Institute for Immunology, La Jolla, California, USA
| | - Christophe Pedros
- La Jolla Institute for Immunology, La Jolla, California, USA.,CERTIS, San Diego, California, USA
| | - Kok-Fai Kong
- La Jolla Institute for Immunology, La Jolla, California, USA
| | | | - Wen Xue
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Amnon Altman
- La Jolla Institute for Immunology, La Jolla, California, USA
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35
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Zhu H, Liu X. Advances of Tumorigenesis, Diagnosis at Early Stage, and Cellular Immunotherapy in Gastrointestinal Malignancies. Front Oncol 2021; 11:666340. [PMID: 34434889 PMCID: PMC8381364 DOI: 10.3389/fonc.2021.666340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/19/2021] [Indexed: 01/10/2023] Open
Abstract
Globally, in 2018, 4.8 million new patients have a diagnosis of gastrointestinal (GI) cancers, while 3.4 million people died of such disorders. GI malignancies are tightly relevant to 26% of the world-wide cancer incidence and occupies 35% of all cancer-associated deaths. In this article, we principally investigated molecular and cellular mechanisms of tumorigenesis in five major GI cancers occurring at esophagus, stomach, liver, pancreas, and colorectal region that illustrate high morbidity in Eastern and Western countries. Moreover, through this investigation, we not only emphasize importance of the tumor microenvironment in development and treatment of malignant tumors but also identify significance of M2PK, miRNAs, ctDNAs, circRNAs, and CTCs in early detection of GI cancers, as well as systematically evaluate contribution of personalized precision medicine including cellular immunotherapy, new antigen and vaccine therapy, and oncolytic virotherapy in treatment of GI cancers.
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Affiliation(s)
- Haipeng Zhu
- Precision and Personalized Cancer Treatment Center, Division of Cancer Diagnosis & Therapy, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China.,Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical College, Xinxiang, China
| | - Xiaojun Liu
- Division of Cellular & Biomedical Science, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China
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Luo J, Lu C, Feng M, Dai L, Wang M, Qiu Y, Zheng H, Liu Y, Li L, Tang B, Xu C, Wang Y, Yang X. Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish. J Exp Clin Cancer Res 2021; 40:262. [PMID: 34416907 PMCID: PMC8377946 DOI: 10.1186/s13046-021-02061-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/05/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. METHODS We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. RESULTS We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. CONCLUSION Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.
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Affiliation(s)
- Juanjuan Luo
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
- Shantou University Medical College, Shantou, China
| | - Chunjiao Lu
- Shantou University Medical College, Shantou, China
| | - Meilan Feng
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Lu Dai
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Maya Wang
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Yang Qiu
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Huilu Zheng
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Yao Liu
- Shantou University Medical College, Shantou, China
| | - Li Li
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Key Laboratory of Aquatic Science of Chongqing, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China
| | - Bo Tang
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chuan Xu
- Integrative Cancer Center & Cancer Clinical Research Center, Cancer Center, Sichuan Cancer Hospital & Institute Sichuan, School of Medicine University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Yajun Wang
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China.
| | - Xiaojun Yang
- Shantou University Medical College, Shantou, China.
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Jeoung NH, Jeong JY, Kang BS. Cryptotanshinone Prevents the Binding of S6K1 to mTOR/Raptor Leading to the Suppression of mTORC1-S6K1 Signaling Activity and Neoplastic Cell Transformation. J Cancer Prev 2021; 26:145-152. [PMID: 34258253 PMCID: PMC8249204 DOI: 10.15430/jcp.2021.26.2.145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 01/07/2023] Open
Abstract
Cryptotanshinone is known for its inhibitory activity against tumorigenesis in various human cancer cells. However, exact mechanisms underlying the anticancer effects of cryptotanshinone are not fully elucidated. Here, we propose a plausible molecular mechanism, wherein cryptotanshinone represses rapamycin-sensitive mTORC1/S6K1 mediated cancer cell growth and cell transformation. We investigated the various effects of cryptotanshinone on the mTORC1/S6K1 axis, which is associated with the regulation of cell growth in response to nutritional and growth factor signals. We found that cryptotanshinone specifically inhibited the mTORC1-mediated phosphorylation of S6K1, which consequently suppressed the clonogenicity of SK-Hep1 cells and the neoplastic transformation of JB6 Cl41 cells induced by insulin-like growth factor-1. Finally, we observed that cryptotanshinone prevented S6K1 from binding to the Raptor/mTOR complex, rather than regulating mTOR and its upstream pathway. Overall, our findings provide a novel mechanism underlying anti-cancer effects cryptotanshinone targeting mTORC1 signaling, contributing to the development of anticancer agents involving metabolic cancer treatment.
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Affiliation(s)
- Nam Ho Jeoung
- Bio-Medical Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea.,Department of Pharmaceutical Engineering, Daegu Catholic University, Gyeongsan, Korea
| | - Ji Yun Jeong
- Bio-Medical Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea.,Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Gumi, Korea
| | - Bong Seok Kang
- Bio-Medical Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea
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Peruhova M, Peshevska-Sekulovska M, Panayotova G, Velikova T. Foremost Concepts in Mechanisms of De Novo Post-Liver Transplantation Malignancy. GASTROENTEROLOGY INSIGHTS 2021; 12:283-292. [DOI: 10.3390/gastroent12030025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
In liver transplant patients, solid tumors and post-transplant lymphoproliferative disorders (PTLD) have emerged as significant long-term mortality causes. Additionally, it is assumed that de novo malignancy (DNM) after liver transplantation (LT) is the second-leading cause of death after cardiovascular complications. Well-established risk factors for PTLD and solid tumors are calcineurin inhibitors (CNIs), tacrolimus (TAC), and cyclosporine, the cornerstones of all immunosuppressive (IS) therapies used after LT. The loss of immunocompetence facilitated by the host immune system due to prolonged IS therapy leads to cancer development, including in LT patients. Hindering DNA repair mechanisms, promoting tumor cell invasiveness, and hampering apoptosis are critical events in tumorigenesis and tumor growth in LT patients resulting from IS administration. This paper aims to overview the refined mechanisms of IS-induced tumorigenesis after LT and the loss of immunocompetence facilitated by the host immune system due to prolonged IS therapy. In addition, we also discuss in detail the mechanisms of action in different types of IS regimen used after LT, and their putative effect on DNM.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Lozenetz, 1 Kozyak str., 1407 Sofia, Bulgaria
| | | | - Gabriela Panayotova
- Department of Gastroenterology, University Hospital Lozenetz, 1 Kozyak str., 1407 Sofia, Bulgaria
| | - Tsvetelina Velikova
- Department of Clinical Immunology, Medical Faculty, University Hospital Lozenetz, Sofia University, St. Kliment Ohridski, 1407 Sofia, Bulgaria
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Banerjee I, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1): A key driver of hepatocellular carcinoma (HCC). Adv Cancer Res 2021; 152:329-381. [PMID: 34353442 DOI: 10.1016/bs.acr.2021.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
An array of human cancers, including hepatocellular carcinoma (HCC), overexpress the oncogene Astrocyte elevated gene-1 (AEG-1). It is now firmly established that AEG-1 is a key driver of carcinogenesis, and enhanced expression of AEG-1 is a marker of poor prognosis in cancer patients. In-depth studies have revealed that AEG-1 positively regulates different hallmarks of HCC progression including growth and proliferation, angiogenesis, invasion, migration, metastasis and resistance to therapeutic intervention. By interacting with a plethora of proteins as well as mRNAs, AEG-1 regulates gene expression at transcriptional, post-transcriptional, and translational levels, and modulates numerous pro-tumorigenic and tumor-suppressive signal transduction pathways. Even though extensive research over the last two decades using various in vitro and in vivo models has established the pivotal role of AEG-1 in HCC, effective targeting of AEG-1 as a therapeutic intervention for HCC is yet to be achieved in the clinic. Targeted delivery of AEG-1 small interfering ribonucleic acid (siRNA) has demonstrated desired therapeutic effects in mouse models of HCC. Peptidomimetic inhibitors based on protein-protein interaction studies has also been developed recently. Continuous unraveling of novel mechanisms in the regulation of HCC by AEG-1 will generate valuable knowledge facilitating development of specific AEG-1 inhibitory strategies. The present review describes the current status of AEG-1 in HCC gleaned from patient-focused and bench-top studies as well as transgenic and knockout mouse models. We also address the challenges that need to be overcome and discuss future perspectives on this exciting molecule to transform it from bench to bedside.
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Affiliation(s)
- Indranil Banerjee
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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Liu Z, Sun J, Wang X, Cao Z. MicroRNA-129-5p promotes proliferation and metastasis of hepatocellular carcinoma by regulating the BMP2 gene. Exp Ther Med 2021; 21:257. [PMID: 33603864 DOI: 10.3892/etm.2021.9688] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 11/26/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor that poses a serious threat to human health. Due to its occult onset and rapid development, HCC is a challenge to diagnose early and effectively treat, and thus patients with HCC often have an unfavorable prognosis. MicroRNA (miR)-129 and its target gene play an important role in the regulation of various diseases. Therefore, the aim of the present study was to investigate the role and mechanism of action for miR-129-5p in the development of HCC. Quantitative results of clinical samples analyzed using reverse transcription-quantitative PCR suggested that miR-129-5p had a significantly lower expression level in tumoral tissues compared with corresponding peritumoral tissues. Overexpression of miR-129-5p in HCC cells was performed using a transfection technique, followed by MTT, Transwell, invasion and wound healing assays to detect the effect of miR-129-5p on the cell cytotoxicity and metastasis of liver cancer in vitro. The downstream target gene of miR-129-5p, bone morphogenetic protein 2 (BMP2), was determined using a luciferase reporter assay. Overexpression of miR-129-5p played a vital role in decreasing cytotoxicity and promoting metastasis of HCC, which may be attributed to its inhibitory effect on the expression of its target gene, BMP2. In clinical samples, miR-129-5p expression levels were found to be negatively correlated with BMP2 and closely associated with HCC metastasis and infiltration. Collectively, the results suggested that miR-129-5p may contribute to proliferation and metastasis of HCC through its target gene, BMP2, and thus may be a potential novel therapeutic target for the treatment of HCC.
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Affiliation(s)
- Zengyao Liu
- Department of Intervention, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jiefei Sun
- Interventional Catheter Therapy Section Office, Zhaodong Renmin Hospital, Zhaodong, Heilongjiang 151100, P.R. China
| | - Xiaochun Wang
- Department of Nursing, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhenyuan Cao
- Department of Intervention, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2020; 13:ph13120432. [PMID: 33260729 PMCID: PMC7760785 DOI: 10.3390/ph13120432] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
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Chao X, Qian H, Wang S, Fulte S, Ding WX. Autophagy and liver cancer. Clin Mol Hepatol 2020; 26:606-617. [PMID: 33053934 PMCID: PMC7641568 DOI: 10.3350/cmh.2020.0169] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 07/31/2020] [Accepted: 08/01/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Xiao Y, Gong Q, Wang W, Liu F, Kong Q, Pan F, Zhang X, Yu C, Hu S, Fan F, Li S, Liu Y. The combination of Biochanin A and SB590885 potentiates the inhibition of tumour progression in hepatocellular carcinoma. Cancer Cell Int 2020; 20:371. [PMID: 32774165 PMCID: PMC7405455 DOI: 10.1186/s12935-020-01463-w] [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: 03/07/2020] [Accepted: 07/29/2020] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most aggressive and frequently diagnosed malignancy of the liver. Despite aggressive therapy, life expectancy of many patients in these cases is extended by only a few months. Hepatocellular carcinoma (HCC) has a particularly poor prognosis and would greatly benefit from more effective therapies. Methods The CCK-8 assay and colony formation assays were used to test the cell proliferation and viability. The effects of combination Biochanin A and SB590885 on apoptosis and cell cycle arrest of HCC cells were analysed by flow cytometry. The expression of ERK MAPK and PI3K/AKT/mTOR signalling as well as apoptosis and cell cycle-related proteins in HCC cells were tested by western blotting. The HCC cell xenograft model was established to test the tumor proliferation. Serum and plasma were tested for liver and kidney safety markers (ALP, ALT, AST, total bilirubin, creatinine, urea nitrogen) by using SpectraMax i3X. Results The combination of natural product Biochanin A with the BRAF inhibitor SB590885 synergistically suppressed proliferation, and promoted cell cycle arrest and apoptosis in vitro. Furthermore, we demonstrated that the combination of Biochanin A and SB590885 led to increased impairment of proliferation and HCC tumour inhibition through disrupting of the ERK MAPK and the PI3K/AKT pathways in vitro. The volumes tumors and the weights of tumours were significantly reduced by the combination treatment compared to the control or single treatments in vivo. In addition, we found that there was no significant hepatorenal toxicity with the drug combination, as indicated by the hepatorenal toxicity test. Conclusion The results identify an effective combination therapy for the most aggressive form of HCC and provide the possibility of therapeutic improvement for patients with advanced HCC.
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Affiliation(s)
- Yi Xiao
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Department of Biochemistry and Molecular Biology, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Qiang Gong
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Wenhong Wang
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Fang Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China
| | - Qinghong Kong
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Feng Pan
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Xiaoke Zhang
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Changyan Yu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Shanshan Hu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Good Clinical Practice Center, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000 China
| | - Fang Fan
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Department of Biochemistry and Molecular Biology, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China
| | - Sanhua Li
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
| | - Yun Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Department of Biochemistry and Molecular Biology, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000 China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000 China
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Molecular Mechanisms Regulating Obesity-Associated Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12051290. [PMID: 32443737 PMCID: PMC7281233 DOI: 10.3390/cancers12051290] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/14/2020] [Accepted: 05/17/2020] [Indexed: 02/07/2023] Open
Abstract
Obesity is a global, intractable issue, altering inflammatory and stress response pathways, and promoting tissue adiposity and tumorigenesis. Visceral fat accumulation is correlated with primary tumor recurrence, poor prognosis and chemotherapeutic resistance. Accumulating evidence highlights a close association between obesity and an increased incidence of hepatocellular carcinoma (HCC). Obesity drives HCC, and obesity-associated tumorigenesis develops via nonalcoholic fatty liver (NAFL), progressing to nonalcoholic steatohepatitis (NASH) and ultimately to HCC. The better molecular elucidation and proteogenomic characterization of obesity-associated HCC might eventually open up potential therapeutic avenues. The mechanisms relating obesity and HCC are correlated with adipose tissue remodeling, alteration in the gut microbiome, genetic factors, ER stress, oxidative stress and epigenetic changes. During obesity-related hepatocarcinogenesis, adipokine secretion is dysregulated and the nuclear factor erythroid 2 related factor 1 (Nrf-1), nuclear factor kappa B (NF-κB), mammalian target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are activated. This review captures the present trends allied with the molecular mechanisms involved in obesity-associated hepatic tumorigenesis, showcasing next generation molecular therapeutic strategies and their mechanisms for the successful treatment of HCC.
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The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors. Cell Death Dis 2020; 11:333. [PMID: 32382012 PMCID: PMC7206028 DOI: 10.1038/s41419-020-2536-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
Autophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not unclear. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1), which was released from autophagy-deficient hepatocytes. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis. We found that in liver-specific autophagy-deficient (Atg7ΔHep) mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of Hmgb1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. However, RAGE expression was only found on ductual cells and Kupffer’s cells but not on hepatoctyes, suggesting that HMGB1 might promote hepatic tumor growth through a paracrine mode, which altered the tumor microenvironment. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potentially important role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.
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46
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Yuan P, Zheng A, Tang Q. Tripartite motif protein 25 is associated with epirubicin resistance in hepatocellular carcinoma cells via regulating PTEN/AKT pathway. Cell Biol Int 2020; 44:1503-1513. [PMID: 32196840 DOI: 10.1002/cbin.11346] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 03/01/2020] [Accepted: 03/19/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Peng Yuan
- Department of Interventional TherapyThe People's Hospital of JianhuJianhu 224700 Jiangsu P. R. China
| | - Aidong Zheng
- Department of Intensive MedicineThe People's Hospital of JianhuJianhu 224700 Jiangsu P. R. China
| | - Qing Tang
- Department of OncologyThe People's Hospital of Funing County in Yancheng CityYancheng 224400 Jiangsu P. R. China
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Genome-wide CRISPR knockout screens identify ADAMTSL3 and PTEN genes as suppressors of HCC proliferation and metastasis, respectively. J Cancer Res Clin Oncol 2020; 146:1509-1521. [PMID: 32266537 DOI: 10.1007/s00432-020-03207-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/31/2020] [Indexed: 01/03/2023]
Abstract
PURPOSE It is important for hepatocellular carcinoma (HCC) treatment that the targets related to its progression are identified. Clustered regularly interspaced short palindromic repeat (CRISPR)-associated nuclease 9 (Cas9)-based genetic screening is a powerful tool for identifying genes with loss-of-function mutations that are critical for tumour growth and metastasis. METHODS We transduced the human SMMC7721 HCC cell line expressing Cas9 with a human genome-scale CRISPR-Cas9 knockout (GeCKO) lentiviral library A (hGeCKOa) of 65,383 single-guide RNAs (sgRNAs) targeting 19,050 human genes; we then subcutaneously transplanted the transduced cells into nude mice. RESULTS The transduced cells were found to proliferate and metastasize faster than the untransduced cells. Through next-generation sequencing, the genes potentially related to HCC proliferation and metastasis were identified. The sgRNAs targeting the ADAMTSL3 and PTEN genes appeared twice on the list of genes related to HCC proliferation and metastasis, respectively. Analysis based on the data mining of Oncomine revealed that the ADAMTSL3 and PTEN genes were expressed at lower levels in HCC cells than they were in normal liver cells, indicating their tumour-suppressive roles. Downregulation of ADAMTSL3 and PTEN displayed poor overall survival (OS) and predicted poor relapse-free survival (RFS), further supporting their tumour-suppressive roles. Moreover, knocking out either the ADAMTSL3 or PTEN genes promoted either the proliferation or metastasis of HCC cells, respectively. CONCLUSIONS Using both in vitro and in vivo approaches, we described the profound role of the ADAMTSL3 and PTEN genes. This study indicates novel candidate targets for use in HCC treatment and therapy.
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Ferrín G, Guerrero M, Amado V, Rodríguez-Perálvarez M, De la Mata M. Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:1266. [PMID: 32070029 PMCID: PMC7072933 DOI: 10.3390/ijms21041266] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.
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Affiliation(s)
- Gustavo Ferrín
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
| | - Marta Guerrero
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Víctor Amado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Manuel Rodríguez-Perálvarez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Manuel De la Mata
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
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Sun HX, Yang ZF, Tang WG, Ke AW, Liu WR, Li Y, Gao C, Hu B, Fu PY, Yu MC, Gao BW, Shi YH, Fan J, Xu Y. MicroRNA-19a-3p regulates cell growth through modulation of the PIK3IP1-AKT pathway in hepatocellular carcinoma. J Cancer 2020; 11:2476-2484. [PMID: 32201518 PMCID: PMC7066004 DOI: 10.7150/jca.37748] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023] Open
Abstract
There are some controversies about the involvement of microRNA (miR)-19a-3p in hepatocellular carcinoma (HCC) biology, even though many studies have shown that it plays an important role in cancer. In this study, we found that miR-19a-3p is usually overexpressed in HCC tissues compared with corresponding peritumorous tissues, and its expression was associated with tumor size and poor overall survival. MiR-19a-3p promoted cell proliferation significantly, and more cells were found in the S phase. In vivo, miR-19a-3p promoted liver tumor growth, and more HCC cells were found in the active cell cycle. Sequencing and bioinformatics analysis predicted that PIK3IP1 is a likely target gene of miR-19a-3p, and we next confirmed it by luciferase and rescue assays. Altogether, our data showed an important role of PIK3IP1 downregulation by miR-19a-3p in HCC progression, and the miR-19a-3p-PIK3IP1-AKT pathway may be a potential therapeutic target.
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Affiliation(s)
- Hai-Xiang Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Wei-Guo Tang
- Minhang Hospital, Fudan University; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 200032, China
| | - Ai-Wu Ke
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Wei-ren Liu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Yan Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Chao Gao
- Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Bo Hu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Pei-Yao Fu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Min-Cheng Yu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Bo-Wen Gao
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Ying-hong Shi
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yang Xu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
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Stem Cell Therapy for Hepatocellular Carcinoma: Future Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1237:97-119. [PMID: 31728916 DOI: 10.1007/5584_2019_441] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer and results in a high mortality rate worldwide. Unfortunately, most cases of HCC are diagnosed in an advanced stage, resulting in a poor prognosis and ineffective treatment. HCC is often resistant to both radiotherapy and chemotherapy, resulting in a high recurrence rate. Although the use of stem cells is evolving into a potentially effective approach for the treatment of cancer, few studies on stem cell therapy in HCC have been published. The administration of stem cells from bone marrow, adipose tissue, the amnion, and the umbilical cord to experimental animal models of HCC has not yielded consistent responses. However, it is possible to induce the apoptosis of cancer cells, repress angiogenesis, and cause tumor regression by administration of genetically modified stem cells. New alternative approaches to cancer therapy, such as the use of stem cell derivatives, exosomes or stem cell extracts, have been proposed. In this review, we highlight these experimental approaches for the use of stem cells as a vehicle for local drug delivery.
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