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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [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: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Karimi Jirandehi A, Asgari R, Keshavarz Shahbaz S, Rezaei N. Nanomedicine marvels: crafting the future of cancer therapy with innovative statin nano-formulation strategies. NANOSCALE ADVANCES 2024:d4na00808a. [PMID: 39478996 PMCID: PMC11515941 DOI: 10.1039/d4na00808a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 10/11/2024] [Indexed: 11/02/2024]
Abstract
Statins, traditionally used for managing hyperlipidemia and cardiovascular diseases, have garnered significant interest for their potential anti-cancer properties. Research indicates that statins can inhibit critical processes in cancer development, such as apoptosis, angiogenesis, and metastasis. Despite their promising anti-cancer effects, the clinical application of statins in oncology has been hampered by their inherent low solubility and bioavailability. These pharmacokinetic challenges can be effectively addressed through the use of nano-based drug delivery systems. Nano-formulations enhance the delivery and therapeutic efficacy of statins by improving their solubility, stability, and targeting ability, thus maximizing their concentration within the tumor microenvironment and minimizing systemic side effects. This review delves into the potential of nanoparticles as carriers for statins in cancer therapy. It explores the mechanisms by which statins exert their anti-cancer effects, such as through the inhibition of the mevalonate pathway, modulation of immune responses, and induction of apoptosis. Furthermore, the review examines the development of various statin-loaded nano-formulations, highlighting their advantages over conventional formulations. The novelty of this review lies in its focus on recent advancements in nanoformulations that enhance statin delivery to the tumor microenvironment. By discussing the current advancements and prospects of statin nano-formulations, this review aims to provide a comprehensive understanding of how these innovative strategies can improve cancer treatment outcomes and enhance the quality of life for patients. The integration of nanotechnology with statin therapy offers a novel approach to overcoming existing therapeutic limitations and paving the way for more effective and safer cancer treatments.
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Affiliation(s)
- Ashkan Karimi Jirandehi
- Student Research Committee, School of Medicine, Qazvin University of Medical Sciences Qazvin Iran
- USERN Office, Qazvin University of Medical Science Qazvin Iran
| | - Reza Asgari
- Student Research Committee, School of Medicine, Qazvin University of Medical Sciences Qazvin Iran
- USERN Office, Qazvin University of Medical Science Qazvin Iran
| | - Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Noncommunicable Disease, Qazvin University of Medical Sciences Qazvin Iran
- USERN Office, Qazvin University of Medical Science Qazvin Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science Tehran Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN) Tehran Iran
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Liu J, Fu J, Fu P, Liu M, Liu Z, Song B. Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway. Cancer Cell Int 2024; 24:224. [PMID: 38943199 PMCID: PMC11214206 DOI: 10.1186/s12935-024-03416-z] [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: 10/17/2023] [Accepted: 06/22/2024] [Indexed: 07/01/2024] Open
Abstract
BACKGROUND Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated. METHODS Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model. RESULTS PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway. CONCLUSION Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.
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Affiliation(s)
- Jie Liu
- Cancer Center, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Jialei Fu
- Shandong Academy of Chinese Medicine, Jinan, China
| | - Ping Fu
- Department of Chemotherapy, Jinan Zhangqiu District People's Hospital, Jinan, China
| | - Menghan Liu
- Clinical Medical College, Shandong First Medical University, Jinan, China
| | - Zining Liu
- Department of Nuclear Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, The Third Affiliated Hospital of Shandong First Medical University, Jinan, China.
| | - Bao Song
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
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Pham N, Benhammou JN. Statins in Chronic Liver Disease: Review of the Literature and Future Role. Semin Liver Dis 2024; 44:191-208. [PMID: 38701856 DOI: 10.1055/a-2319-0694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.
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Affiliation(s)
- Nguyen Pham
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jihane N Benhammou
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
- Veterans Affairs Greater Los Angeles, Los Angeles, California
- Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, California
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Olaoba OT, Yang M, Adelusi TI, Maidens T, Kimchi ET, Staveley-O’Carroll KF, Li G. Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:1470. [PMID: 38672552 PMCID: PMC11048089 DOI: 10.3390/cancers16081470] [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: 02/17/2024] [Revised: 04/05/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.
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Affiliation(s)
- Olamide T. Olaoba
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, USA
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
| | - Temitope I. Adelusi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
| | - Tessa Maidens
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
| | - Eric T. Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, USA
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
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Fang XH, Wang CE, Deng J, Qi XS. Statins for treatment of fatty liver disease: Recent advances. Shijie Huaren Xiaohua Zazhi 2023; 31:659-665. [DOI: 10.11569/wcjd.v31.i16.659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/28/2023] Open
Affiliation(s)
- Xiao-Hui Fang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Cai-E Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Jiao Deng
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xing-Shun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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Saito Y, Yin D, Kubota N, Wang X, Filliol A, Remotti H, Nair A, Fazlollahi L, Hoshida Y, Tabas I, Wangensteen KJ, Schwabe RF. A Therapeutically Targetable TAZ-TEAD2 Pathway Drives the Growth of Hepatocellular Carcinoma via ANLN and KIF23. Gastroenterology 2023; 164:1279-1292. [PMID: 36894036 PMCID: PMC10335360 DOI: 10.1053/j.gastro.2023.02.043] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 01/24/2023] [Accepted: 02/14/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND & AIMS Despite recent progress, long-term survival remains low for hepatocellular carcinoma (HCC). The most effective HCC therapies target the tumor immune microenvironment (TIME), and there are almost no therapies that directly target tumor cells. Here, we investigated the regulation and function of tumor cell-expressed Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HCC. METHODS HCC was induced in mice by Sleeping Beauty-mediated expression of MET, CTNNB1-S45Y, or TAZ-S89A, or by diethylnitrosamine plus CCl4. Hepatocellular TAZ and YAP were deleted in floxed mice via adeno-associated virus serotype 8-mediated expression of Cre. TAZ target genes were identified from RNA sequencing, confirmed by chromatin immunoprecipitation, and evaluated in a clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen. TEA domain transcription factors (TEADs), anillin (ANLN), Kif23, and programmed cell death protein ligand 1 were knocked down by guide RNAs in dead clustered regularly interspaced short palindromic repeats-associated protein 9 (dCas9) knock-in mice. RESULTS YAP and TAZ were up-regulated in murine and human HCC, but only deletion of TAZ consistently decreased HCC growth and mortality. Conversely, overexpression of activated TAZ was sufficient to trigger HCC. TAZ expression in HCC was regulated by cholesterol synthesis, as demonstrated by pharmacologic or genetic inhibition of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), farnesyl pyrophosphate synthase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1), or sterol regulatory element-binding protein 2 (SREBP2). TAZ- and MET/CTNNB1-S45Y-driven HCC required the expression of TEAD2 and, to a lesser extent, TEAD4. Accordingly, TEAD2 displayed the most profound effect on survival in patients with HCC. TAZ and TEAD2 promoted HCC via increased tumor cell proliferation, mediated by TAZ target genes ANLN and kinesin family member 23 (KIF23). Therapeutic targeting of HCC, using pan-TEAD inhibitors or the combination of a statin with sorafenib or anti-programmed cell death protein 1, decreased tumor growth. CONCLUSIONS Our results suggest the cholesterol-TAZ-TEAD2-ANLN/KIF23 pathway as a mediator of HCC proliferation and tumor cell-intrinsic therapeutic target that could be synergistically combined with TIME-targeted therapies.
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Affiliation(s)
- Yoshinobu Saito
- Department of Medicine, Columbia University, New York, New York.
| | - Dingzi Yin
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Mayo Clinic, Rochester, Minnesota
| | - Naoto Kubota
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Xiaobo Wang
- Department of Medicine, Columbia University, New York, New York
| | - Aveline Filliol
- Department of Medicine, Columbia University, New York, New York
| | - Helen Remotti
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Ajay Nair
- Department of Medicine, Columbia University, New York, New York
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ira Tabas
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Institute of Human Nutrition, New York, New York
| | - Kirk J Wangensteen
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Mayo Clinic, Rochester, Minnesota.
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, New York, New York.
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Zhang J, Fu S, Liu D, Wang Y, Tan Y. Statin can reduce the risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2023; 35:353-358. [PMID: 36719824 DOI: 10.1097/meg.0000000000002517] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Currently, nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and liver-related mortality worldwide. Hepatocellular carcinoma (HCC) is a fatal complication in patients with NAFLD. However, whether statins can reduce the risk of HCC in patients with NAFLD remains controversial. We aimed to determine the relationship between statin use and HCC occurrence among patients with NAFLD. We independently retrieved related studies from PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrial.gov (from 1 January 2000 to 27 February 2022). The main outcome was the development of HCC. A fixed-effects model was used to merge odds ratio (OR) in the meta-analysis. Five studies involving 684 363 patients were included. The results of the meta-analysis suggested a significantly lower risk of HCC among statin users with NAFLD [OR = 0.59; 95% confidence interval (CI), 0.39-0.89; I2 = 87.90%]. Additionally, a lower risk of HCC was observed among patients with NAFLD aged less than 65 years (OR = 0.59; 95% CI, 0.46-0.77; I2 = 20.50%). Statins can reduce the risk of HCC in patients aged less than 65 years with NAFLD.
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Affiliation(s)
- Jie Zhang
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Shifeng Fu
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Deliang Liu
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Yongjun Wang
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Yuyong Tan
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University
- Research Center of Digestive Disease, Central South University, Changsha, China
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Wang Y, Chen H, Yu J, Kang W, To KF. Recent insight into the role and therapeutic potential of YAP/TAZ in gastrointestinal cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188787. [PMID: 36041574 DOI: 10.1016/j.bbcan.2022.188787] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/25/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022]
Abstract
With the rapid development of cancer treatment, gastrointestinal (GI) cancers are still the most prevalent malignancies with high morbidity and mortality worldwide. Dysregulation of the Hippo signaling pathway has been recognized to play a critical role during cancer development and adopted for monitoring disease progression and therapy response. Despite the well-documented tumor proliferation and metastasis, recent efforts in two core Hippo components, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), have identified as the driving forces behind cancer metabolism, stemness, tumor immunity, and therapy resistance. Understanding the molecular mechanisms by which YAP/TAZ facilitates the tumorigenesis and progression of GI cancer, and identifying novel therapeutic strategies for targeting YAP/TAZ are crucial to GI cancer treatment and prevention. In this study, we summarize the latest findings on the function and regulatory mechanisms of YAP/TAZ in GI cancers, and highlight the translational significance of targeting YAP/TAZ for cancer therapies.
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Affiliation(s)
- Yifei Wang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Huarong Chen
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
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10
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Mranda GM, Xiang ZP, Liu JJ, Wei T, Ding Y. Advances in prognostic and therapeutic targets for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The hippo signaling pathway. Front Oncol 2022; 12:937957. [PMID: 36033517 PMCID: PMC9411807 DOI: 10.3389/fonc.2022.937957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/13/2022] [Indexed: 01/07/2023] Open
Abstract
Primary liver cancer is the sixth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related death. The majority of the primary liver cancer cases are hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Worldwide, there is an increasing incidence of primary liver cancer cases due to multiple risk factors ranging from parasites and viruses to metabolic diseases and lifestyles. Often, patients are diagnosed at advanced stages, depriving them of surgical curability benefits. Moreover, the efficacy of the available chemotherapeutics is limited in advanced stages. Furthermore, tumor metastases and recurrence make primary liver cancer management exceptionally challenging. Thus, exploring the molecular mechanisms for the development and progression of primary liver cancer is critical in improving diagnostic, treatment, prognostication, and surveillance modalities. These mechanisms facilitate the discovery of specific targets that are critical for novel and more efficient treatments. Consequently, the Hippo signaling pathway executing a pivotal role in organogenesis, hemostasis, and regeneration of tissues, regulates liver cells proliferation, and apoptosis. Cell polarity or adhesion molecules and cellular metabolic status are some of the biological activators of the pathway. Thus, understanding the mechanisms exhibited by the Hippo pathway is critical to the development of novel targeted therapies. This study reviews the advances in identifying therapeutic targets and prognostic markers of the Hippo pathway for primary liver cancer in the past six years.
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Patel KK, Kashfi K. Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs. Biochem Pharmacol 2022; 196:114654. [PMID: 34129857 PMCID: PMC8665945 DOI: 10.1016/j.bcp.2021.114654] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 02/03/2023]
Abstract
Cholesterol is an amphipathic sterol molecule that is vital for maintaining normal physiological homeostasis. It is a relatively complicated molecule with 27 carbons whose synthesis starts with 2-carbon units. This in itself signifies the importance of this molecule. Cholesterol serves as a precursor for vitamin D, bile acids, and hormones, including estrogens, androgens, progestogens, and corticosteroids. Although essential, high cholesterol levels are associated with cardiovascular and kidney diseases and cancer initiation, progression, and metastasis. Although there are some contrary reports, current literature suggests a positive association between serum cholesterol levels and the risk and extent of cancer development. In this review, we first present a brief overview of cholesterol biosynthesis and its transport, then elucidate the role of cholesterol in the progression of some cancers. Suggested mechanisms for cholesterol-mediated cancer progression are plentiful and include the activation of oncogenic signaling pathways and the induction of oxidative stress, among others. The specific roles of the lipoprotein molecules, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), in this pathogenesis, are also reviewed. Finally, we hone on the potential role of some cholesterol-lowering medications in cancer.
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Affiliation(s)
- Kush K Patel
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA; Graduate Program in Biology, City University of New York Graduate Center, NY, USA.
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12
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Khajeh E, Moghadam AD, Eslami P, Ali-Hasan-Al-Saegh S, Ramouz A, Shafiei S, Ghamarnejad O, Dezfouli SA, Rupp C, Springfeld C, Carvalho C, Probst P, Mousavizadeh SM, Mehrabi A. Statin use is associated with the reduction in hepatocellular carcinoma recurrence after liver surgery. BMC Cancer 2022; 22:91. [PMID: 35062904 PMCID: PMC8781082 DOI: 10.1186/s12885-022-09192-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) is the sixth most common form of cancer worldwide. Although surgical treatments have an acceptable cure rate, tumor recurrence is still a challenging issue. In this meta-analysis, we investigated whether statins prevent HCC recurrence following liver surgery.
Methods
PubMed, Web of Science, EMBASE and Cochrane Central were searched. The Outcome of interest was the HCC recurrence after hepatic surgery. Pooled estimates were represented as hazard ratios (HRs) and odds ratios (ORs) using a random-effects model. Summary effect measures are presented together with their corresponding 95% confidence intervals (CI). The certainty of evidence was evaluated using the Grades of Research, Assessment, Development and Evaluation (GRADE) approach.
Results
The literature search retrieved 1362 studies excluding duplicates. Nine retrospective studies including 44,219 patients (2243 in the statin group and 41,976 in the non-statin group) were included in the qualitative analysis. Patients who received statins had a lower rate of recurrence after liver surgery (HR: 0.53; 95% CI: 0.44–0.63; p < 0.001). Moreover, Statins decreased the recurrence 1 year after surgery (OR: 0.27; 95% CI: 0.16–0.47; P < 0.001), 3 years after surgery (OR: 0.22; 95% CI: 0.15–0.33; P < 0.001), and 5 years after surgery (OR: 0.28; 95% CI: 0.19–0.42; P < 0.001). The certainty of evidence for the outcomes was moderate.
Conclusion
Statins increase the disease-free survival of patients with HCC after liver surgery. These drugs seem to have chemoprevention effects that decrease the probability of HCC recurrence after liver transplantation or liver resection.
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13
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Uemura N, Hayashi H, Baba H. Statin as a therapeutic agent in gastroenterological cancer. World J Gastrointest Oncol 2022; 14:110-123. [PMID: 35116106 PMCID: PMC8790423 DOI: 10.4251/wjgo.v14.i1.110] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/19/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and are widely used as an effective and safe approach handle hypercholesterolemia. The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression. Multiple studies have indicated that statins improve patient prognosis in various carcinomas. Basic research on the mechanisms underlying the antitumor effects of statins is underway. The development of new anti-cancer drugs is progressing, but increasing medical costs from drug development have become a major obstacle. Readily available, inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment. Identifying the cancer patients that may benefit from statins is key to improved patient treatment. This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.
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Affiliation(s)
- Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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14
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Tang HX, Yi FZ, Huang ZS, Huang GL. Role of Hippo signaling pathway in occurrence, development, and treatment of primary hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2022; 30:34-42. [DOI: 10.11569/wcjd.v30.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The Hippo signal transduction pathway, first discovered in drosophila, is a highly conserved signaling pathway that inhibits cell growth. Its core molecules include Hpo, Sav, Wts, Mats, and downstream effector factor YAP/TAZ. Corresponding homologous analogs in humans are STE20 protein-like kinase 1/2, Salvatore family 1, large tumor suppressor gene 1/2 kinase, and MOB kinase activator 1A/1B. Inactivation of this pathway promotes the survival, proliferation, invasive migration, and metastasis of cancer cells. This process can be seen in liver cancer, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, melanoma, glioma, and other cancers, which can lead to the occurrence of resistance to chemotherapy, radiotherapy, or immunotherapy. This paper aims to review the role of the Hippo signaling pathway in the occurrence, development, and treatment of liver cancer, in order to provide reference for new targeted therapies for liver cancer.
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Affiliation(s)
- Hui-Xian Tang
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Fu-Zhen Yi
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Zan-Song Huang
- Department of Gastroenter-ology, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China,Guangxi Clinical Research Center for Hepatobiliary Diseases, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Gui-Liu Huang
- Department of Gastroenter-ology, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
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15
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Ishikawa T, Osaki T, Sugiura A, Tashiro J, Warita T, Hosaka YZ, Warita K. Atorvastatin preferentially inhibits the growth of high ZEB-expressing canine cancer cells. Vet Comp Oncol 2021; 20:313-323. [PMID: 34657361 DOI: 10.1111/vco.12778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/03/2021] [Accepted: 10/13/2021] [Indexed: 11/30/2022]
Abstract
The epithelial-to-mesenchymal transition (EMT) is fundamental in cancer progression and contributes to the acquisition of malignant properties. The statin class of cholesterol-lowering drugs exhibits pleiotropic anticancer effects in vitro and in vivo, and many epidemiologic studies have reported a correlation between statin use and reduced cancer mortality. We have shown previously that sensitivity to the anti-proliferative effect of statins varies among human cancer cells and statins are more effective against mesenchymal-like cells than epithelial-like ones in human cancers. There have only been few reports on the application of statins to cancer therapy in veterinary medicine, and differences in statin sensitivity among canine cancer cells have not been examined. In this study, we aimed to clarify the correlation between sensitivity to atorvastatin and epithelial/mesenchymal states in 11 canine cancer cell lines derived from mammary gland, squamous cell carcinoma, lung, and melanoma. Sensitivity to atorvastatin varied among canine cancer cells, with IC50 values ranging from 5.92 to 71.5 μM at 48 h, which were higher than the plasma concentrations clinically achieved with statin therapy. Atorvastatin preferentially attenuated the proliferation of mesenchymal-like cells. In particular, highly statin-sensitive cells were characterized by aberrant expression of the ZEB family of EMT-inducing transcription factors. However, ZEB2 silencing in highly sensitive cells did not induce resistance to atorvastatin. Taken together, these results suggest that high expression of ZEB is a characteristic of highly statin-sensitive cells and could be a molecular marker for predicting whether cancers are sensitive to statins, though ZEB itself does not confer statin sensitivity.
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Affiliation(s)
- Takuro Ishikawa
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Tomohiro Osaki
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Akihiro Sugiura
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Jiro Tashiro
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Tomoko Warita
- Department of Biomedical Sciences, School of Biological and Environmental Science, Kwansei Gakuin University, Hyogo, Japan
| | - Yoshinao Z Hosaka
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Katsuhiko Warita
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
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16
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Hayashi H, Uemura N, Zhao L, Matsumura K, Sato H, Shiraishi Y, Baba H. Biological Significance of YAP/TAZ in Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 11:700315. [PMID: 34395269 PMCID: PMC8358930 DOI: 10.3389/fonc.2021.700315] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer. Despite major advances in defining the molecular mutations driving PDAC, this disease remains universally lethal with an overall 5-year survival rate of only about 7–8%. Genetic alterations in PDAC are exemplified by four critical genes (KRAS, TP53, CDKN2A, and SMAD4) that are frequently mutated. Among these, KRAS mutation ranges from 88% to 100% in several studies. Hippo signaling is an evolutionarily conserved network that plays a key role in normal organ development and tissue regeneration. Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2. Interestingly, pancreas-specific MST1/2 double knockout mice have been reported to display a decreased pancreas mass. Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while the Hippo transducers Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are identified as oncogenes. By dephosphorylation, YAP and TAZ accumulate in the nucleus and interact with transcription factors such as TEA domain transcription factor-1, 2, 3, and 4. Dysregulation of Hippo signaling and activation of YAP/TAZ have been recognized in a variety of human solid cancers, including PDAC. Recent studies have elucidated that YAP/TAZ play a crucial role in the induction of acinar-to-ductal metaplasia, an initial step in the progression to PDAC, in genetically engineered mouse models. YAP and TAZ also play a key role in the development of PDAC by both KRAS-dependent and KRAS-independent bypass mechanisms. YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.
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Affiliation(s)
- Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Liu Zhao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroki Sato
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuta Shiraishi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
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17
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Alhakamy NA, Badr-Eldin SM, Aldawsari HM, Alfarsi A, Neamatallah T, Okbazghi SZ, Fahmy UA, Ahmad OA, Eid BG, Mahdi WA, Alghaith AF, Alshehri S, Md S. Fluvastatin-Loaded Emulsomes Exhibit Improved Cytotoxic and Apoptosis in Prostate Cancer Cells. AAPS PharmSciTech 2021; 22:177. [PMID: 34128106 DOI: 10.1208/s12249-021-02021-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/19/2021] [Indexed: 12/26/2022] Open
Abstract
Fluvastatin (FLV) is known to inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), which is over-expressed in various cancers. FLV has been reported to decrease cancer development and metastasis. However, because of low bioavailability, extensive first-pass metabolism and short half-life of FLV (1.2 h), it is not appropriate for clinical application. Therefore, FLV-loaded emulsomes were formulated and optimized using Box-Behnken experimental design to achieve higher efficiency of formulation. Antitumor activity of optimized FLV-loaded emulsomes was evaluated in prostate cancer cells using cell cytotoxicity, apoptotic activity, cell cycle analysis, and enzyme-linked immunosorbent assay. The FLV-loaded emulsomes exhibited a monodispersed size distribution with a mean particle size less than 100 nm as measured by zetasizer. The entrapment efficiency was found to be 93.74% with controlled drug release profile. FLV-EMLs showed a significant inhibitory effect on the viability of PC3 cells when compared to the free FLV (P < 0.0025). Furthermore, FLV-EMLs showed significant arrest in G2/M and increase in percentage of apoptotic cells as compared to free FLV. FLV-EMLs were more effective than free FLV in reducing mitochondrial membrane potential and increase in caspase-3 activity. These results suggesting that FLV-EMLs caused cell cycle arrest which clarifies its significant antiproliferative effect compared to the free drug. Therefore, optimized FLV-EMLs may be an effective carrier for FLV in prostate cancer treatment.
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18
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Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms. Cancer Lett 2021; 510:1-12. [PMID: 33857528 DOI: 10.1016/j.canlet.2021.03.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/21/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022]
Abstract
Proliferating cancer cells exhibit metabolic alterations and specific nutritional needs for adapting to their rapid growth. These changes include using aerobic glycolysis, lipid metabolic disorder, and irregular protein degradation. It may be useful to target metabolic abnormalities for cancer chemoprevention. Epidemiological and mechanism-related studies have indicated that many FDA-approved anti-metabolic drugs decrease tumor risk, inhibit tumor growth, or enhance the effect of chemotherapeutic drugs. Drugs targeting nutrient metabolism have fewer side effects with long-term use compared to chemotherapeutic drugs. The characteristics of these drugs make them promising candidates for cancer chemoprevention. Here, we summarize recent discoveries of the chemo-preventive effects of drugs targeting nutrient metabolic pathways and discuss future applications and challenges. Understanding the effects and mechanisms of anti-metabolic drugs in cancer has important implications for exploring strategies for cancer chemoprevention.
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19
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He Y, Cui X, Lin Y, Wang Y, Wu D, Fang Y. Using Elevated Cholesterol Synthesis as a Prognostic Marker in Wilms' Tumor: A Bioinformatic Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8826286. [PMID: 33628817 PMCID: PMC7886595 DOI: 10.1155/2021/8826286] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/20/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Wilms tumor is the most common renal malignancy of children. Identifying factors that could predict the prognosis of patients with Wilms tumor is clinically meaningful. Many studies found tumors with elevated cholesterol synthesis that are featured with dismal prognosis. Even in some clinical trials, people with excessive dietary cholesterol intake and high plasma low-density lipoprotein levels are observed to have increased risk for cancer. However, the role of cholesterol biosynthesis in Wilms tumor has not yet been well clarified. METHODS RNA sequencing transcriptome data and all corresponding clinicopathological information used in our study were downloaded from the TARGET database. High-throughput sequencing (Fragments Per Kilobase of transcript per Million fragments mapped) data sets of 130 tumor samples and 6 normal samples were obtained for further analysis. RESULTS Wilms tumor samples with higher activity of cholesterol synthesis are characterized with worse overall survival (P < 0.05). In addition, Wilms tumor samples with mitigated activity of cholesterol synthesis are featured with better dendritic cell (DC) function and cytolytic activity (P < 0.05). Furthermore, we constructed a prognosis model based on differential expressed cholesterol synthesis-related genes (DECSG), which could predict the OS of patients with Wilms tumor accurately. KEGG and GO analysis of differential expressed genes between tumor samples with high and low cholesterol synthesis indicated that DECSGs are highly enriched in "mitosis nuclear division," "nuclear division," "chromosome segregation," "cell cycle," "Spliceosome," and "RNA transport." CONCLUSIONS In conclusion, our study reported increased cholesterol synthesis in Wilms tumor predicts a worse prognosis and mitigated cytolytic activity, DC function, and MHC I signature in the tumor microenvironment. We also constructed a prognosis model for predicting the OS of patients with good accuracy, which is promising in clinical translation. Future studies should focus on the detailed mechanism that caused increasing cholesterol which promotes tumor progression and undermines patients' survival.
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Affiliation(s)
- Yuanbin He
- Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Xu Cui
- Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Yu Lin
- Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Yunjin Wang
- Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Dianming Wu
- Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
| | - Yifan Fang
- Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
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20
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Zeng R, Dong J. The Hippo Signaling Pathway in Drug Resistance in Cancer. Cancers (Basel) 2021; 13:cancers13020318. [PMID: 33467099 PMCID: PMC7830227 DOI: 10.3390/cancers13020318] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Although great breakthroughs have been made in cancer treatment following the development of targeted therapy and immune therapy, resistance against anti-cancer drugs remains one of the most challenging conundrums. Considerable effort has been made to discover the underlying mechanisms through which malignant tumor cells acquire or develop resistance to anti-cancer treatment. The Hippo signaling pathway appears to play an important role in this process. This review focuses on how components in the human Hippo signaling pathway contribute to drug resistance in a variety of cancer types. This article also summarizes current pharmacological interventions that are able to target the Hippo signaling pathway and serve as potential anti-cancer therapeutics. Abstract Chemotherapy represents one of the most efficacious strategies to treat cancer patients, bringing advantageous changes at least temporarily even to those patients with incurable malignancies. However, most patients respond poorly after a certain number of cycles of treatment due to the development of drug resistance. Resistance to drugs administrated to cancer patients greatly limits the benefits that patients can achieve and continues to be a severe clinical difficulty. Among the mechanisms which have been uncovered to mediate anti-cancer drug resistance, the Hippo signaling pathway is gaining increasing attention due to the remarkable oncogenic activities of its components (for example, YAP and TAZ) and their druggable properties. This review will highlight current understanding of how the Hippo signaling pathway regulates anti-cancer drug resistance in tumor cells, and currently available pharmacological interventions targeting the Hippo pathway to eradicate malignant cells and potentially treat cancer patients.
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Affiliation(s)
| | - Jixin Dong
- Correspondence: ; Tel.: +1-402-559-5596; Fax: +1-402-559-4651
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21
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Abstract
Metastasis is the most complex and deadly event. Tumor-stromal interface is a place where invasion of tumor cells in the form of single-cell or collective migration occurs, with the latter being less common but more efficient. Initiation of metastasis relies on the tumor cell cross-talking with stromal cells and taking an epithelial-mesenchymal transition (EMT) in single cells, and a hybrid EMT in collective migratory cells. Stromal cross-talking along with an abnormal leaky vasculature facilitate intravasation of tumor cells, here the cells are called circulating tumor cells (CTCs). Tumor cells isolated from the primary tumor exploit several mechanisms to maintain their survival including rewiring metabolic demands to use sources available within the new environments, avoiding anoikis cell death when cells are detached from extracellular matrix (ECM), adopting flow mechanic by acquiring platelet shielding and immunosuppression by negating the activity of suppressor immune cells, such as natural killer (NK) cells. CTCs will adhere to the interstituim of the secondary organ/s, within which the newly arrived disseminative tumor cells (DTCs) undergo either dormancy or proliferation. Metastatic outgrowth is under the influence of several factors, such as the activity of macrophages, impaired autophagy and secondary site inflammatory events. Metastasis can be targeted by multiple ways, such as repressing the promoters of pre-metastatic niche (PMN) formation, suppressing environmental contributors, such as hypoxia, oxidative and metabolic stressors, and targeting signaling and cell types that take major contribution to the whole process. These strategies can be used in adjuvant with other therapeutics, such as immunotherapy.
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Affiliation(s)
- Jamal Majidpoor
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Keywan Mortezaee
- Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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22
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Samji P, Rajendran MK, Warrier VP, Ganesh A, Devarajan K. Regulation of Hippo signaling pathway in cancer: A MicroRNA perspective. Cell Signal 2020; 78:109858. [PMID: 33253912 DOI: 10.1016/j.cellsig.2020.109858] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 11/22/2020] [Accepted: 11/24/2020] [Indexed: 12/11/2022]
Abstract
Recent studies have suggested that Hippo signaling is not only involved in controlling organ size in Drosophila but can also regulate cell proliferation, tissue homeostasis, differentiation, apoptosis and regeneration. Any dysregulation of Hippo signaling, especially the hyper activation of its downstream effectors YAP/TAZ, can lead to uncontrolled cell proliferation and malignant transformation. In majority of cancers, expression of YAP/TAZ is extremely high and this increased expression of YAP/TAZ has been shown to be an independent predictor of prognosis and indicator of increased cell proliferation, metastasis and poor survival. In this review, we have summarized the most recent findings about the cross talk of Hippo signaling pathway with other signaling pathways and its regulation by different miRNAs in various cancer types. Recent evidence has suggested that Hippo pathway is also involved in mediating the resistance of different cancer cells to chemotherapeutic drugs and in a few cancer types, this is brought about by regulating miRNAs. Therefore, the delineation of the underlying mechanisms regulating the chemotherapeutic resistance might help in developing better treatment options. This review has attempted to provide an overview of different drugs/options which can be utilized to target oncogenic YAP/TAZ proteins for therapeutic interventions.
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Affiliation(s)
- Priyanka Samji
- Cancer Biology Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, Chennai, India.
| | - Manoj K Rajendran
- Cancer Biology Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, Chennai, India
| | - Vidya P Warrier
- Cancer Biology Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, Chennai, India
| | - Akshayaa Ganesh
- Cancer Biology Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, Chennai, India
| | - Karunagaran Devarajan
- Cancer Biology Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, Chennai, India
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23
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Simon TG, Chan AT. Lifestyle and Environmental Approaches for the Primary Prevention of Hepatocellular Carcinoma. Clin Liver Dis 2020; 24:549-576. [PMID: 33012445 PMCID: PMC7536356 DOI: 10.1016/j.cld.2020.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Patients with chronic liver disease are at increased risk of developing hepatocellular carcinoma (HCC). Most patients diagnosed with HCC have limited treatment options and a poor overall prognosis, with a 5-year survival less than 15%. Preventing the development of HCC represents the most important strategy. However, current guidelines lack specific recommendations for primary prevention. Lifestyle factors may be central in the pathogenesis of HCC, and primary prevention strategies focused on lifestyle modification could represent an important approach to the prevention of HCC. Both experimental and epidemiologic studies have identified promising chemopreventive agents for the primary prevention of HCC.
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Affiliation(s)
- Tracey G. Simon
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - Andrew T. Chan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA,Broad Institute, Boston MA,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston MA
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Bisso A, Filipuzzi M, Gamarra Figueroa GP, Brumana G, Biagioni F, Doni M, Ceccotti G, Tanaskovic N, Morelli MJ, Pendino V, Chiacchiera F, Pasini D, Olivero D, Campaner S, Sabò A, Amati B. Cooperation Between MYC and β-Catenin in Liver Tumorigenesis Requires Yap/Taz. Hepatology 2020; 72:1430-1443. [PMID: 31965581 DOI: 10.1002/hep.31120] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/20/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. APPROACH AND RESULTS We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or loss of APC - adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis. CONCLUSIONS Myc and β-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.
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Affiliation(s)
- Andrea Bisso
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
| | | | | | - Giulia Brumana
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Francesca Biagioni
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Mirko Doni
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
| | | | | | - Marco Jacopo Morelli
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Vera Pendino
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Fulvio Chiacchiera
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy.,Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy
| | - Diego Pasini
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy.,Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Stefano Campaner
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Arianna Sabò
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
| | - Bruno Amati
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
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25
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Liu Y, Wang X, Yang Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin Mol Hepatol 2020; 26:742-750. [PMID: 32981290 PMCID: PMC7641559 DOI: 10.3350/cmh.2020.0178] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 09/10/2020] [Indexed: 12/21/2022] Open
Abstract
Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.
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Affiliation(s)
- Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Xiaohui Wang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.,Harvard Stem Cell Institute, Boston, MA, USA.,Program in Gastrointestinal Malignancies, Dana-Farber/Harvard Cancer Center, Boston, MA, USA
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26
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Xue L, Qi H, Zhang H, Ding L, Huang Q, Zhao D, Wu BJ, Li X. Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy. Front Oncol 2020; 10:1510. [PMID: 32974183 PMCID: PMC7472741 DOI: 10.3389/fonc.2020.01510] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/14/2020] [Indexed: 12/14/2022] Open
Abstract
Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.
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Affiliation(s)
- Linyuan Xue
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Hongyu Qi
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - He Zhang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Lu Ding
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Qingxia Huang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Daqing Zhao
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Boyang Jason Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, United States
| | - Xiangyan Li
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
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27
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Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J, Meng Q, Yu X, Shi S. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol 2020; 13:110. [PMID: 32778143 PMCID: PMC7418434 DOI: 10.1186/s13045-020-00946-7] [Citation(s) in RCA: 826] [Impact Index Per Article: 165.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.
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Affiliation(s)
- Rong Tang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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Al-Wahaibi LH, Al-Saleem MSM, Ahmed OAA, Fahmy UA, Alhakamy NA, Eid BG, Abdel-Naim AB, Abdel-Mageed WM, AlRasheed MM, Shazly GA. RETRACTED: Optimized Conjugation of Fluvastatin to HIV-1 TAT Displays Enhanced Pro-Apoptotic Activity in HepG2 Cells. Int J Mol Sci 2020; 21:E4138. [PMID: 32531976 PMCID: PMC7312570 DOI: 10.3390/ijms21114138] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/06/2020] [Accepted: 06/07/2020] [Indexed: 12/15/2022] Open
Abstract
Accumulating evidence indicates that statins reduce the risk of different cancers and inhibit the proliferation of liver cancer cells. This study aims to explore whether the electrostatic conjugation of optimized fluvastatin (FLV) to human immunodeficiency virus type 1 (HIV-1) trans-activator transcription peptide (TAT) would enhance the anti-proliferative activity against HepG2 cells. FLV-TAT conjugation was optimized to achieve the lowest size with highest zeta potential. Nine formulae were constructed, using a factorial design with three factors-FLV concentration, TAT concentration, and pH of the medium-while the responses were zeta potential and size. The optimized formula showed a particle size of 199.24 nm and 29.14 mV zeta potential. Data indicates that conjugation of FLV to TAT (optimized formula) significantly enhances anti-proliferative activity and uptake by HepG2 cells when compared to raw FLV. Flow cytometry showed significant accumulation of cells in the pre-G phase, which highlights higher apoptotic activity. Annexin V staining indicated a significant increase in total cell death in early and late apoptosis. This was confirmed by significantly elevated caspase 3 in cells exposed to FLV-TAT preparation. In conclusion, the FLV-TAT optimized formula exhibited improved anti-proliferative action against HepG2. This is partially attributed to the enhanced apoptotic effects and cellular uptake of FLV.
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Affiliation(s)
- Lamya H. Al-Wahaibi
- Department of Chemistry, Science College, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia; (L.H.A.-W.); (M.S.M.A.-S.)
| | - Muneera S. M. Al-Saleem
- Department of Chemistry, Science College, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia; (L.H.A.-W.); (M.S.M.A.-S.)
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (U.A.F.); (N.A.A.)
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (U.A.F.); (N.A.A.)
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (U.A.F.); (N.A.A.)
| | - Basma G. Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Ashraf B. Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Wael M. Abdel-Mageed
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;
| | - Maha M. AlRasheed
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;
| | - Gamal A. Shazly
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;
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29
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Pennisi G, Celsa C, Giammanco A, Spatola F, Petta S. The Burden of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: Screening Issue and Future Perspectives. Int J Mol Sci 2019; 20:ijms20225613. [PMID: 31717576 PMCID: PMC6887792 DOI: 10.3390/ijms20225613] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 02/07/2023] Open
Abstract
In recent decades, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the Western world, and the occurrence of its complications, such as hepatocellular carcinoma (HCC), has rapidly increased. Obesity and diabetes are considered not only the main triggers for the development of the disease, but also two independent risk factors for HCC. Single nucleotide polymorphisms (such as PNPLA3, TM6SF2 and MBOAT7) are related to the susceptibility to the development of HCC and its progression. Therefore, an appropriate follow-up of these patients is needed for the early diagnosis and treatment of HCC. To date, international guidelines recommend the use of ultrasonography with or without alpha-fetoprotein (AFP) in patients with advanced fibrosis. Furthermore, the use of non-invasive tools could represent a strategy to implement surveillance performance. In this review, we analyzed the main risk factors of NAFLD-related HCC, the validated screening methods and the future perspectives.
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Affiliation(s)
- Grazia Pennisi
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
- Correspondence: (G.P.); (S.P.); Tel.: +39-0916552170 (G.P.); +39-0916552170 (S.P.)
| | - Ciro Celsa
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
| | - Antonina Giammanco
- Sezione di Astanteria e MCAU, PROMISE, University of Palermo, 90127 Palermo, Italy;
| | - Federica Spatola
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
| | - Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
- Correspondence: (G.P.); (S.P.); Tel.: +39-0916552170 (G.P.); +39-0916552170 (S.P.)
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30
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Zhou W, Weng J, Wu K, Xu X, Wang H, Zhang J, Zhao C, Yang J, Zhang Y, Shen W. Silencing of TAZ inhibits the motility of hepatocellular carcinoma cells through autophagy induction. Cancer Manag Res 2019; 11:8743-8753. [PMID: 31576176 PMCID: PMC6769033 DOI: 10.2147/cmar.s215466] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 08/22/2019] [Indexed: 12/12/2022] Open
Abstract
Purpose The aim of the present study was to investigate the effect of knockdown and knockout of the transcriptional co-activator with PDZ-binding motif (TAZ) on the migration, invasion and autophagy of the hepatocellular carcinoma (HCC) cell lines, as well as the functional connection between the autophagy and cell migratory processes induced by loss of TAZ in HCC cell lines. Methods HCC cell lines SMMC-7721 and SK-HEP1 stably knockdown and knockout of TAZ were established by the lentiviral-mediated TAZ knockdown and knockout approaches. Reverse transcription-quantitative real-time polymerase chain reaction and Western blotting were performed to examine the expression of TAZ and indicated genes in downstream pathways in HCC cell lines. Transwell assay and autophagic flux assay were used to evaluate the effect of TAZ knockdown and knockout on the motility and the autophagy of HCC cell lines. Results We initially found that TAZ exhibited highly abundant and was expressed predominantly in HCC cell lines with different spontaneous metastatic potential. Through performing loss-of-function assays, we demonstrated that both TAZ knockdown and knockout promoted HCC cell autophagy and reduced HCC cell migration, invasion and epithelial-to-mesenchymal transition. In addition, autophagy inhibition in TAZ knockdown and knockout SMMC-7721 and SK-HEP1 cells in the presence of 3-methyladenine or chloroquine partially abrogated the migratory and invasive ability induced by TAZ knockdown and knockout. Conclusion Our findings indicated that loss of TAZ in HCC cells suppressed cell motility probably via altering the autophagy, suggesting that TAZ emerges as an important target in regulating cell motility and autophagy in HCC cells, and blocking TAZ may be a novel therapeutic strategy against HCC.
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Affiliation(s)
- Wei Zhou
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China.,Department of Internal Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, People's Republic of China
| | - Jiachun Weng
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China
| | - Keyan Wu
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China.,Department of Internal Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, People's Republic of China
| | - Xiao Xu
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China
| | - Hui Wang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China
| | - Jing Zhang
- Department of Internal Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, People's Republic of China
| | - Chengxue Zhao
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China
| | - Jie Yang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China
| | - Yu Zhang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's Republic of China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, People's Republic of China
| | - Weigan Shen
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, People's Republic of China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's Republic of China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, People's Republic of China
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31
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Pope ED, Kimbrough EO, Vemireddy LP, Surapaneni PK, Copland JA, Mody K. Aberrant lipid metabolism as a therapeutic target in liver cancer. Expert Opin Ther Targets 2019; 23:473-483. [PMID: 31076001 DOI: 10.1080/14728222.2019.1615883] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers. Progress has been made in treatment of HCC; however, improved outcomes are much needed. The increased metabolic needs of cancer cells underscore the importance of metabolic pathways in cancer cell survival. Lipid metabolism has a role in HCC development; aberrant overexpression of several key enzymes is seen in many solid human tumors. Areas covered: We discuss aberrant lipid metabolism and the promise of multiple targets, in particular related to HCC treatment. We searched PubMed and clinicaltrials.gov for published and unpublished studies from 2000 to 2019. These terms were used: lipids, fatty acid metabolism, lipid metabolism, liver cancer, HCC, de novo fatty acid synthesis, ATP citrate lyase, stearoyl CoA denaturase, fatty acid synthase, acetyl coenzyme A carboxylase, CD147, KLF4, monoglyceride lipase, AMP activated protein kinase. Expert opinion: The importance of dysregulation of fatty acid synthesis in cancer is a growing area of research. HCC demonstrates significant alteration in lipid metabolism, representing great potential as a target for novel therapeutics. Various agents have demonstrated promising anti-neoplastic activity. This strategy deserves further development for improved outcomes.
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Affiliation(s)
- Evans D Pope
- a Cancer Clinical Studies Unit , Mayo Clinic , Jacksonville , FL , USA
| | | | | | | | - John A Copland
- d Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA
| | - Kabir Mody
- c Division of Hematology and Medical Oncology , Mayo Clinic , Jacksonville , FL , USA
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32
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Vahdat S, Bakhshandeh B. Prediction of putative small molecules for manipulation of enriched signalling pathways in hESC-derived early cardiovascular progenitors by bioinformatics analysis. IET Syst Biol 2019; 13:77-83. [PMID: 33444476 DOI: 10.1049/iet-syb.2018.5037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 08/25/2018] [Accepted: 09/21/2018] [Indexed: 11/20/2022] Open
Abstract
Human pluripotent stem cell-derived cardiovascular progenitor cells (CPCs) are considered as powerful tools for cardiac regenerative medicine and developmental study. Mesoderm posterior1+ (MESP1+ ) cells are identified as the earliest CPCs from which almost all cardiac cell types are generated. Molecular insights to the transcriptional regulatory factors of early CPCs are required to control cell fate decisions. Herein, the microarray data set of human embryonic stem cells (hESCs)-derived MESP1+ cells was analysed and differentially expressed genes (DEGs) were identified in comparison to undifferentiated hESCs and MESP1-negative cells. Then, gene ontology and pathway enrichment analysis of DEGs were carried out with the subsequent prediction of putative regulatory small molecules for modulation of CPC fate. Some key signalling cascades of cardiogenesis including Hippo, Wnt, transforming growth factor-β, and PI3K/Akt were highlighted in MESP1+ cells. The transcriptional regulatory network of MESP1+ cells were visualised through interaction networks of DEGs. Additionally, 35 promising chemicals were predicted based on correlations with gene expression signature of MESP1+ cells for effective in vitro CPC manipulation. Studying the transcriptional profile of MESP1+ cells resulted into the identification of important signalling pathways and chemicals which could be introduced as powerful tools to manage proliferation and differentiation of hESC-derived CPCs more efficiently.
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Affiliation(s)
- Sadaf Vahdat
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Behnaz Bakhshandeh
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
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Di Carlo C, Brandi J, Cecconi D. Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma. World J Stem Cells 2018; 10:172-182. [PMID: 30631392 PMCID: PMC6325076 DOI: 10.4252/wjsc.v10.i11.172] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/10/2018] [Accepted: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.
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Affiliation(s)
- Claudia Di Carlo
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
| | - Jessica Brandi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy.
| | - Daniela Cecconi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
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Li J, Liu R, Sun Z, Tang S, Wang L, Liu C, Zhao W, Yao Y, Sun C. The association between statin use and endometrial cancer survival outcome: A meta-analysis. Medicine (Baltimore) 2018; 97:e13264. [PMID: 30461633 PMCID: PMC6393075 DOI: 10.1097/md.0000000000013264] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Previous studies on the association between statin use and survival outcomes in gynecologic cancers have presented conflicting results. No independent studies to elucidate the association between statin use and survival outcomes of endometrial cancer (EC) have been conducted. METHODS To gather updated evidence, we carried out an extensive literature search on Medline (PubMed and OvidSP), Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), wanfang data, and Vip network to identify all potential studies on the effect of statins on the prognosis of endometrial carcinoma. The design and quality of all studies were evaluated, and a fixed-effects model was used to calculate pooled hazard ratios (HRs) for overall survival (OS) and disease-specific survival (DSS). RESULTS Of the 219 articles screened, 9 articles were eligible, including 8 articles and 1 abstract. A total of 5923 patients with endometrial cancer who used statins were identified. Statin use was related to increased overall survival (HR, 0.80; 95% confidence interval [CI], 0.66-0.95, without significant heterogeneity, I = 52%, P = .080). Statin users also had increased disease-specific survival (HR, 0.69; 95% CI, 0.61-0.79, I = 0.0%). CONCLUSION Statins are beneficial to the survival outcome of patients with endometrial cancer. The selection of statins as a 1st-line agent seems justified for endometrial carcinoma.
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Affiliation(s)
- Jia Li
- Weifang Medical University
| | - Ruijuan Liu
- Weifang Traditional Chinese Hospital, Weifang City
| | - Zhengdi Sun
- Weifang Traditional Chinese Hospital, Weifang City
| | - Shifeng Tang
- Weifang Traditional Chinese Hospital, Weifang City
| | - Lu Wang
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Cun Liu
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | | | | | - Changgang Sun
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
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Athuluri-Divakar SK, Hoshida Y. Generic chemoprevention of hepatocellular carcinoma. Ann N Y Acad Sci 2018; 1440:23-35. [PMID: 30221358 DOI: 10.1111/nyas.13971] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 08/21/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023]
Abstract
Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after curative treatment of early-stage HCC tumor, the carcinogenic microenvironment persists in the remnant diseased liver and supports the development of de novo HCC tumors (de novo HCC recurrence). Therefore, prevention of HCC development in patients at risk of not only first-primary but also second-primary HCC tumors is theoretically the most impactful strategy to improve patient prognosis. However, no such therapy has been established to date. One major challenge is the identification of clinically relevant targets that can be achieved by utilizing the reverse-engineering strategy of chemoprevention discovery, which integrates omics information from clinical cohorts with completed follow-up for cancer development. Clinical and experimental studies have suggested etiology-specific and generic candidate HCC chemoprevention strategies, including statins, antidiabetic drugs, selective molecular targeted agents, and dietary and nutritional substances. Clinical testing of the candidate compounds can be cost-effectively performed by combining it with HCC risk biomarker evaluation to specify the target patient population most likely to benefit from the therapy. Nontoxic, generic agents will have broad clinical applicability across the diverse HCC etiologies and clinical contexts and are expected to substantially improve the still dismal prognosis of HCC.
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Affiliation(s)
- Sai Krishna Athuluri-Divakar
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Yao C, Liu BB, Qian XD, Li LQ, Cao HB, Guo QS, Zhou GF. Crocin induces autophagic apoptosis in hepatocellular carcinoma by inhibiting Akt/mTOR activity. Onco Targets Ther 2018; 11:2017-2028. [PMID: 29670377 PMCID: PMC5898595 DOI: 10.2147/ott.s154586] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background Autophagy induction is a common mechanism for antitumor chemicals in induction of cancer cell death. However, the role of autophagy in crocin-induced apoptosis is barely studied in hepatocellular carcinoma (HCC). Materials and methods The influence of crocin on growth, apoptosis, and autophagy and its mutual relations were analyzed by Cell Counting Kit-8 assay, flow cytometer, EGFP-LC3 puncta analysis, and Western blot in HCC cells. The activities of Akt/mTOR axis and its roles in autophagy regulation were also detected by Western blot in HCC cells treated with crocin. Finally, the roles of Akt/mTOR axis in crocin-induced autophagic apoptosis were analyzed by Western blot and flow cytometer in HCC cells. Results The results showed that crocin can induce growth inhibition in a does- and time-dependent pattern by apoptosis. Increased LC3 puncta and upregulated LC3-II accumulation was observed as early as at 6 hours in HepG2 and HCCLM3 cells treated with 3 mg/mL crocin. Moreover, apoptosis analysis using flow cytometer and cleaved poly (ADP-ribose) polymerase detection revealed that autophagy initiation was prior to apoptosis activation in HCC cells treated with crocin. When autophagy was blocked with 3-methyladenine, crocin-induced apoptosis was inhibited in HCC cells. Furthermore, crocin treatment constrained the activities of key proteins in Akt/mTOR signaling, such as p-Akt (S473), p-mTOR (S2448), and p-p70S6K (T389), suggesting that crocin could induce autophagic apoptosis in HCC cells in an Akt/mTOR-dependent mechanism. Indeed, when autophagy was suppressed by forced expression of Akt, the crocin-induced apoptosis was also impaired in HCC cells. Conclusion The results suggested that crocin could induce autophagic apoptosis in HCC cells by inhibiting Akt/mTOR activity. This study originally revealed that autophagic apoptosis is a novel cytotoxic function of crocin, which lays the theoretical foundation for clinical application of crocin in HCC.
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Affiliation(s)
- Chong Yao
- Institute of Chinese Medicinal Materials, Nanjing Agricultural University, Nanjing 210095, China.,Pharmaceutical Department, Huzhou Central Hospital, Huzhou 313003, China
| | - Bing-Bing Liu
- Pharmaceutical Department, TCM Hospital of Changxin, Huzhou 313100, China
| | - Xiao-Dong Qian
- Pharmaceutical Department, Huzhou Central Hospital, Huzhou 313003, China
| | - Li-Qin Li
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou 313000, China
| | - Heng-Bin Cao
- Pharmaceutical Department, Huzhou Central Hospital, Huzhou 313003, China
| | - Qiao-Sheng Guo
- Institute of Chinese Medicinal Materials, Nanjing Agricultural University, Nanjing 210095, China
| | - Gui-Fen Zhou
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
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Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018; 68:526-549. [PMID: 28989095 PMCID: PMC5818315 DOI: 10.1016/j.jhep.2017.09.016] [Citation(s) in RCA: 514] [Impact Index Per Article: 73.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/24/2017] [Accepted: 09/25/2017] [Indexed: 01/27/2023]
Abstract
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a "one-size-fits-all" approach to HCC screening for early tumour detection, as recommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations, such as those with chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC prevention and substantially improving the dismal prognosis of HCC.
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Affiliation(s)
- Naoto Fujiwara
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Japan
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA.
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Xia K, Zhang P, Hu J, Hou H, Xiong M, Xiong J, Yan N. Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells. Oncol Lett 2018. [PMID: 29541202 PMCID: PMC5835881 DOI: 10.3892/ol.2018.7831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma is the sixth most prevalent malignant tumor and the third most common cause of cancer-associated mortality. Statins have been investigated for carcinoma prevention and treatment. In addition, receptor-interacting protein 140 (RIP140) has been observed to inhibit the Wnt/β-catenin signaling pathway and cell growth. The present study aimed to investigate whether simvastatin (SV) is able to induce SMCC-7721 cell apoptosis through the Wnt/β-catenin signaling pathway. Initially, a cell model of RIP140 overexpression was established, and then cells were treated with SV. The cell growth, viability and apoptosis were measured by cell counting kit-8 and flow cytometry. Furthermore, the expression levels of RIP140, β-catenin, c-myc and cyclin D1 were detected by reverse transcription-quantitative polymerase chain, western blot analysis and immunofluorescence. The results demonstrated that SV significantly increased the expression of RIP140 in SMCC-7721 cells; however, β-catenin, c-myc and cyclin D1 levels were significantly decreased. Furthermore, the immunofluorescence assay of β-catenin confirmed that SV decreased the content of this protein in SMCC-7721 cells. Notably, RIP140 exerted a synergistic effect on the apoptosis rate induced by SV (RIP140 + SV group), while the alteration in RIP140, β-catenin, c-myc and cyclin D1 levels was more evident in the combination group as compared with the RIP140 or SV alone groups. In conclusion, these results suggested that SV is able to induce the apoptosis of SMCC-7721 cells through the Wnt/β-catenin signaling pathway, as well as that RIP140 and SV exert a synergistic effect on the inhibition of cell proliferation and survival.
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Affiliation(s)
- Kun Xia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Panpan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jian Hu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Huan Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Mingdi Xiong
- Basic Medical Experiments Center, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Junping Xiong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Nianlong Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Shi J, Ning H, He G, Huang Y, Wu Z, Jin L, Jiang X. Rottlerin inhibits cell growth, induces apoptosis and cell cycle arrest, and inhibits cell invasion in human hepatocellular carcinoma. Mol Med Rep 2017; 17:459-464. [PMID: 29115596 DOI: 10.3892/mmr.2017.7924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 08/01/2017] [Indexed: 11/06/2022] Open
Abstract
Rottlerin, a polyphenolic compound, has been demonstrated to exhibit antitumor activity in various types of human cancer. Several studies have revealed that rottlerin exerts its anticancer function through PKC‑dependent and independent pathways. The transcriptional co‑activator with PDZ‑binding motif (TAZ) oncopreotein is an important molecule in regulation of the Hippo pathway in human cancer. The present study investigated whether rottlerin has a tumor suppressive role via inhibiting the expression of TAZ, using cell viability assay, apoptosis and cell cycle analyses, western blot analysis and Tanswell invasion assay. The results demonstrated that rottlerin suppressed cell growth, triggered cell apoptosis and induced cell cycle arrest. In addition, rottlerin inhibited cell migration and invasion in hepatocellular carcinoma (HCC) cells. Mechanistically, the results demonstrated that rottlerin exerted its antitumor activity partly through the inhibition of TAZ. In addition, the depletion of TAZ led to inhibited cell growth and invasion, whereas the overexpression of TAZ enhanced cell growth and invasion in the HCC cells. Taken together, these findings indicated that the inhibition of TAZ by rottlerin may be a novel strategy for treating HCC.
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Affiliation(s)
- Jichan Shi
- Department of Infectious Disease, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
| | - Hongye Ning
- Department of Infectious Disease, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
| | - Guiqing He
- Department of Infectious Disease, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
| | - Yitong Huang
- Department of Gynecologic Oncology, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhengxing Wu
- Department of Infectious Disease, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
| | - Lingling Jin
- Department of Infectious Disease, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiangao Jiang
- Department of Infectious Disease, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
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Xie W, Ning L, Huang Y, Liu Y, Zhang W, Hu Y, Lang J, Yang J. Statin use and survival outcomes in endocrine-related gynecologic cancers: A systematic review and meta-analysis. Oncotarget 2017; 8:41508-41517. [PMID: 28489569 PMCID: PMC5522329 DOI: 10.18632/oncotarget.17242] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 04/11/2017] [Indexed: 01/02/2023] Open
Abstract
Previous studies investigating the association between statin use and survival outcomes in gynecologic cancers have yielded controversial results. We conducted a systematic review and meta-analysis to evaluate the association based on available evidence. We searched the databases of the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from inception to January 2017. Studies that evaluated the association between statin use and survival outcomes in gynecologic cancers were included. Pooled hazard ratios (HRs) for overall survival, disease-specific survival and progression-free survival were calculated using a fixed-effects model. A total of 11 studies involving more than 6,920 patients with endocrine-related gynecologic cancers were identified. In a meta-analysis of 7 studies involving 5,449 patients with endocrine-related gynecologic cancers, statin use was linked to improved overall survival (HR, 0.71; 95% confidence interval [CI], 0.63 to 0.80) without significant heterogeneity (I2 = 33.3%). Statin users also had improved disease-specific survival (3 studies, HR, 0.72; 95% CI, 0.58 to 0.90, I2 = 35.1%) and progression-free survival (3 studies, HR, 0.68; 95% CI, 0.49 to 0.93, I2 = 33.6%) in endocrine-related gynecologic cancers. Our findings support that statin use has potential survival benefits for patients with endocrine-related gynecologic cancers. Further large-scale prospective studies are required to validate our findings.
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Affiliation(s)
- Weimin Xie
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Ning
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuenan Huang
- Department of General Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yan Liu
- Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Wen Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingchao Hu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinghe Lang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaxin Yang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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