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Rahman MA, Rakib-Uz-Zaman SM, Chakraborti S, Bhajan SK, Gupta RD, Jalouli M, Parvez MAK, Shaikh MH, Hoque Apu E, Harrath AH, Moon S, Kim B. Advancements in Utilizing Natural Compounds for Modulating Autophagy in Liver Cancer: Molecular Mechanisms and Therapeutic Targets. Cells 2024; 13:1186. [PMID: 39056768 PMCID: PMC11274515 DOI: 10.3390/cells13141186] [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: 04/16/2024] [Revised: 06/30/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Autophagy, an intrinsic catabolic mechanism that eliminates misfolded proteins, dysfunctional organelles, and lipid droplets, plays a vital function in energy balance and cytoplasmic quality control, in addition to maintaining cellular homeostasis. Liver cancer such as hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths globally and shows resistance to several anticancer drugs. Despite the rising incidence and poor prognosis of malignant HCC, the underlying molecular mechanisms driving this aggressive cancer remain unclear. Several natural compounds, such as phytochemicals of dietary and non-dietary origin, affect hepatocarcinogenesis signaling pathways in vitro and in vivo, which may help prevent and treat HCC cells. Current HCC cells treatments include chemotherapy, radiation, and surgery. However, these standard therapies have substantial side effects, and combination therapy enhances side effects for an acceptable therapeutic benefit. Therefore, there is a need to develop treatment strategies for HCC cells that are more efficacious and have fewer adverse effects. Multiple genetic and epigenetic factors are responsible for the HCC cells to become resistant to standard treatment. Autophagy contributes to maintain cellular homeostasis, which activates autophagy for biosynthesis and mitochondrial regulation and recycling. Therefore, modifying autophagic signaling would present a promising opportunity to identify novel therapies to treat HCC cells resistant to current standard treatments. This comprehensive review illustrates how natural compounds demonstrate their anti-hepatocellular carcinoma function through autophagy.
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Affiliation(s)
- Md Ataur Rahman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA;
| | - S M Rakib-Uz-Zaman
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
- Biotechnology Program, Department of Mathematics and Natural Sciences, School of Data and Sciences, BRAC University, Dhaka 1212, Bangladesh
| | - Somdeepa Chakraborti
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
| | - Sujay Kumar Bhajan
- Department of Biotechnology & Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science & Technology University, Gopalganj 8100, Bangladesh;
| | - Rajat Das Gupta
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA;
| | - Maroua Jalouli
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia;
| | | | - Mushfiq H. Shaikh
- Department of Otolaryngology-Head & Neck Surgery, Western University, London, ON N6A 4V2, Canada;
| | - Ehsanul Hoque Apu
- Department of Biomedical Sciences, College of Dental Medicine, Lincoln Memorial University, Knoxville, TN 37923, USA;
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN 37752, USA
- Division of Hematology and Oncology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Abdel Halim Harrath
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Seungjoon Moon
- Department of Pathology, College of Korean Medicine, Kyung Hee University, 1–5 Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea;
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, 1–5 Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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He T, Zou J, Sun K, Yang J. Global research status and frontiers on autophagy in hepatocellular carcinoma: a comprehensive bibliometric and visualized analysis. Int J Surg 2024; 110:2788-2802. [PMID: 38376850 PMCID: PMC11093451 DOI: 10.1097/js9.0000000000001202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/04/2024] [Indexed: 02/21/2024]
Abstract
BACKGROUND An extensive body of research has explored the role of autophagy in hepatocellular carcinoma (HCC), revealing its critical involvement in the disease's pathogenesis, progression, and therapeutic targeting. However, there is a discernible deficit in quantitative, analytical studies concerning autophagy in the context of HCC. Accordingly, this investigation endeavored to meticulously assess the evolution of autophagy research, employing bibliometric citation analysis to offer a comprehensive evaluation of the findings in this field. METHODS The authors conducted a literature search on 2 August 2023, to extract relevant publications spanning from 2013 to 2022, indexed in the Science Citation Index-Expanded (SCIE) of the Web of Science Core Collection (WOSCC). Subsequently, the authors performed a bibliometric assessment of the compiled documents using visualization tools such as CiteSpace and VOSviewer. RESULTS The search yielded 734 publications penned by 4699 authors, encompassing contributions from 41 countries and 909 institutions, disseminated across 272 journals, and comprising 26 295 co-cited references from 2667 journals. Notably, China led in publication volume with 264 articles (amounting to 35.9%) and exhibited the most robust collaboration with the United States. The mechanisms underlying autophagy's influence on the emergence and advancement of HCC, as well as the implicated proteins and genes, have garnered significant attention. In recent years, investigations of targeting autophagy and the resistance to sorafenib have surfaced as pivotal themes and emerging frontiers in this domain. CONCLUSIONS This study rigorously collated and distilled the prevailing research narratives and novel insights on autophagy in HCC. The resultant synthesis provides a substantive foundation for medical professionals and researchers, as well as pivotal implications for future investigative endeavors in this arena.
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Affiliation(s)
- Tao He
- Department of Hepatobiliary Surgery
| | - Jieyu Zou
- Department of Oncology, Chengdu Second People’s Hospital, Chengdu, Sichuan, People’s Republic of China
| | - Ke Sun
- Department of Hepatobiliary Surgery
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Shafieizadeh Z, Shafieizadeh Z, Davoudi M, Afrisham R, Miao X. Role of Fibrinogen-like Protein 1 in Tumor Recurrence Following Hepatectomy. J Clin Transl Hepatol 2024; 12:406-415. [PMID: 38638375 PMCID: PMC11022061 DOI: 10.14218/jcth.2023.00397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/29/2023] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Partial hepatectomy is a first-line treatment for hepatocellular carcinoma. Within 2 weeks following partial hepatectomy, specific molecular pathways are activated to promote liver regeneration. Nevertheless, residual microtumors may also exploit these pathways to reappear and metastasize. Therapeutically targeting molecules that are differentially regulated between normal cells and malignancies, such as fibrinogen-like protein 1 (FGL1), appears to be an effective approach. The potential functions of FGL1 in both regenerative and malignant cells are discussed within the ambit of this review. While FGL1 is normally elevated in regenerative hepatocytes, it is normally downregulated in malignant cells. Hepatectomy does indeed upregulate FGL1 by increasing the release of transcription factors that promote FGL1, including HNF-1α and STAT3, and inflammatory effectors, such as TGF-β and IL6. This, in turn, stimulates certain proliferative pathways, including EGFR/Src/ERK. Hepatectomy alters the phase transition of highly differentiated hepatocytes from G0 to G1, thereby transforming susceptible cells into cancerous ones. Activation of the PI3K/Akt/mTOR pathway by FGL1 allele loss on chromosome 8, a tumor suppressor area, may also cause hepatocellular carcinoma. Interestingly, FGL1 is specifically expressed in the liver via HNF-1α histone acetylase activity, which triggers lipid metabolic reprogramming in malignancies. FGL1 might also be involved in other carcinogenesis processes such as hypoxia, epithelial-mesenchymal transition, immunosuppression, and sorafenib-mediated drug resistance. This study highlights a research gap in these disciplines and the necessity for additional research on FGL1 function in the described processes.
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Affiliation(s)
- Zahra Shafieizadeh
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Zohreh Shafieizadeh
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Davoudi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Afrisham
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Xiaolei Miao
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
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Kroh A, Walter J, Fragoulis A, Möckel D, Lammers T, Kiessling F, Andruszkow J, Preisinger C, Egbert M, Jiao L, Eickhoff RM, Heise D, Berndt N, Cramer T, Neumann UP, Egners A, Ulmer TF. Hepatocellular loss of mTOR aggravates tumor burden in nonalcoholic steatohepatitis-related HCC. Neoplasia 2023; 46:100945. [PMID: 37976569 PMCID: PMC10685311 DOI: 10.1016/j.neo.2023.100945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 10/13/2023] [Indexed: 11/19/2023]
Abstract
Obesity and associated nonalcoholic steatohepatitis (NASH) are on the rise globally. NASH became an important driver of hepatocellular carcinoma (HCC) in recent years. Activation of the central metabolic regulator mTOR (mechanistic target of rapamycin) is frequently observed in HCCs. However, mTOR inhibition failed to improve the outcome of HCC therapies, demonstrating the need for a better understanding of the molecular and functional consequences of mTOR blockade. We established a murine NASH-driven HCC model based on long-term western diet feeding combined with hepatocellular mTOR-inactivation. We evaluated tumor load and whole-body fat percentage via µCT-scans, analyzed metabolic blood parameters and tissue proteome profiles. Additionally, we used a bioinformatic model to access liver and HCC mitochondrial metabolic functions. The tumor burden was massively increased via mTOR-knockout. Several signs argue for extensive metabolic reprogramming of glucose, fatty acid, bile acid and cholesterol metabolism. Kinetic modeling revealed reduced oxygen consumption in KO-tumors. NASH-derived HCC pathogenesis is driven by metabolic disturbances and should be considered separately from those caused by other etiologies. We conclude that mTOR functions as tumor suppressor in hepatocytes especially under long-term western diet feeding. However, some of the detrimental consequences of this diet are attenuated by mTOR blockade.
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Affiliation(s)
- Andreas Kroh
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.
| | - Jeanette Walter
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany
| | - Athanassios Fragoulis
- Department of Anatomy and Cell Biology, RWTH Aachen University Hospital Aachen, Germany
| | - Diana Möckel
- Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
| | - Twan Lammers
- Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
| | - Fabian Kiessling
- Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
| | - Julia Andruszkow
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany
| | - Christian Preisinger
- Proteomics Facility, Interdisciplinary Center for Clinical Research (IZKF) Aachen, Medical School, RWTH Aachen University Hospital, Aachen, Germany
| | - Maren Egbert
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Long Jiao
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Roman M Eickhoff
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Daniel Heise
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Nikolaus Berndt
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany; Institute of Computer-assisted Cardiovascular Medicine, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Antje Egners
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Tom Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
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Bang J, Jun M, Lee S, Moon H, Ro SW. Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma. Pharmaceutics 2023; 15:2130. [PMID: 37631344 PMCID: PMC10458925 DOI: 10.3390/pharmaceutics15082130] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/AKT/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we explore recent advancements in understanding the role of the EGFR/PI3K/AKT/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies.
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Affiliation(s)
| | | | | | | | - Simon Weonsang Ro
- Department of Genetics and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Republic of Korea; (J.B.); (M.J.); (S.L.); (H.M.)
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Üremiş N, Üremiş MM, Çiğremiş Y, Tosun E, Baysar A, Türköz Y. Cucurbitacin I exhibits anticancer efficacy through induction of apoptosis and modulation of JAK/STAT3, MAPK/ERK, and AKT/mTOR signaling pathways in HepG2 cell line. J Food Biochem 2022; 46:e14333. [PMID: 35866877 DOI: 10.1111/jfbc.14333] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/15/2022] [Accepted: 07/06/2022] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma is a common cancer type, especially among men. Although cucurbitacin I (CuI), widely found in plants belonging to the Ecballium elaterium (E. L) plant family, has been shown to have antitumorigenic properties in many cancer types, its anticancer effect, molecular mechanism, and apoptotic effect mediated by signal pathways on hepatocellular carcinoma have not been fully clarified. In the present study, we investigated the anticancer effect of CuI treated at different doses on the HepG2 cell line and the underlying mechanism in vitro. High-purity CuI was obtained from the E. elaterium plant with the aid of HPLC. The effects of this substance on the viability of cells were studied by the MTT assay. The effects of CuI on cell cycle progression and apoptosis were studied with flow cytometry. DNA breaks were analyzed by the Comet assay method. The proteins and genes involved in the JAK/STAT3, MAPK/ERK, and AKT/mTOR signaling pathways were investigated using Western blot and qRT-PCR, respectively. The results of this study demonstrated that CuI significantly reduced HepG2 cell growth in vitro, induced antiproliferation, and G2/M phase of the cell cycle was interrupted. PRACTICAL APPLICATIONS: CuI administration was shown to downregulate the levels of proteins in the PI3K/AKT/mTOR, MAPK, and JAK2/STAT3 cascades in HepG2 cells. CuI also reduced the expression of MAPK, STAT3, mTOR, JAK2, and Akt genes in different concentrations. DNA breaks are formed as a result of this effect. CuI, by reducing cell proliferation and promoting apoptosis, was found to have potential as a chemotherapeutic agent of hepatocellular carcinoma.
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Affiliation(s)
- Nuray Üremiş
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Muhammed Mehdi Üremiş
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Yılmaz Çiğremiş
- Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Emir Tosun
- Department of Chemical Engineering, Faculty of Engineering, Inonu University, Malatya, Turkey
| | - Ahmet Baysar
- Department of Chemical Engineering, Faculty of Engineering, Inonu University, Malatya, Turkey
| | - Yusuf Türköz
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
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Sun EJ, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9111639. [PMID: 34829868 PMCID: PMC8615614 DOI: 10.3390/biomedicines9111639] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/24/2022] Open
Abstract
Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.
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Affiliation(s)
- Eun Jin Sun
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
- College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia
| | - Miriam Wankell
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
| | - Pranavan Palamuthusingam
- Institute of Surgery, The Townsville University Hospital, Townsville, QLD 4811, Australia;
- Mater Hospital, Townsville, QLD 4811, Australia
| | - Craig McFarlane
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
| | - Lionel Hebbard
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW 2145, Australia
- Correspondence:
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Gallage S, García-Beccaria M, Szydlowska M, Rahbari M, Mohr R, Tacke F, Heikenwalder M. The therapeutic landscape of hepatocellular carcinoma. MED 2021; 2:505-552. [PMID: 35590232 DOI: 10.1016/j.medj.2021.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/23/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
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Deng LJ, Lei YH, Quan JY, Li BJ, Zhang DM, Tian HY, Chen Y, Zhang EX, Chen L, Ye WC, Ning WM, Yu LZ, Liu JS. 1β-OH-arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 266:113443. [PMID: 33022344 DOI: 10.1016/j.jep.2020.113443] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 09/24/2020] [Accepted: 09/30/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chansu, dried secretions from Bufonidae, has long been used for cancer treatment as a traditional Chinese medicine. In searching for effective anti-hepatoma agents from Chansu, our preliminary drug screening found that a bufadienolide, namely 1β-hydroxyl-arenobufagin (1β-OH-ABF), displays anti-hepatoma activities. However, the anti-hepatoma effects and molecular mechanisms of 1β-OH-ABF have not been defined. AIM OF THE STUDY To evaluate the anti-hepatoma activity of 1β-OH-ABF against liver cancer Hep3B and HepG2 cells in vitro and in vivo, as well as explore the underlying mechanisms. MATERIALS AND METHODS The anti-proliferative effects of 1β-OH-ABF on liver cancer Hep3B, HepG2, HuH7, SK-HEP-1 and normal hepatocyte LO2 cells were examined by MTT assay and colony formation assay. Hoechst 33258 staining and Annexin V-FITC/PI staining assay were used to analyze apoptosis induced by 1β-OH-ABF. The collapse of the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining assay. Western blotting was used to examine the expression levels of targeted proteins. The role of mTOR in 1β-OH-ABF-induced apoptosis was investigated using small interfering RNA (siRNA) transfection. Zebrafish xenograft model was established to evaluate the anti-hepatoma effects of 1β-OH-ABF in vivo. RESULTS We found that 1β-OH-ABF inhibits the proliferation of Hep3B, HepG2, HuH7, SK-HEP-1 cells but has little cytotoxicity towards LO2 cells. 1β-OH-ABF induces mitochondria dysfunction and triggers mitochondria apoptotic pathway, which is accompanied by the loss of ΔΨm, upregulation and translocation of Bax, as well as cleavages of caspase-9, caspase-3 and PARP. Mechanistically, 1β-OH-ABF markedly decreases the expression level of p-AKT/AKT and p-mTOR (Ser2248 and Ser2481)/mTOR in a time-dependent manner. Inhibition of mTOR by siRNA strengthens 1β-OH-ABF-mediated apoptosis. Critically, 1β-OH-ABF shows a marked in vivo anti-hepatoma effect on human Hep3B cell xenografts in zebrafish model. CONCLUSION 1β-OH-ABF induces mitochondrial apoptosis through the suppression of mTOR signaling in vitro and in vivo, indicating that 1β-OH-ABF may serve as a potential agent for the treatment of liver cancer.
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Affiliation(s)
- Li-Juan Deng
- Formula Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510630, China.
| | - Yu-He Lei
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, 518000, China.
| | - Jing-Yu Quan
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
| | - Bao-Jing Li
- College of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China.
| | - Dong-Mei Zhang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, 510630, China.
| | - Hai-Yan Tian
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, 510630, China.
| | - Ye Chen
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, 510630, China.
| | - En-Xin Zhang
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, 518000, China.
| | - Lei Chen
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, 518000, China.
| | - Wen-Cai Ye
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, 510630, China.
| | - Wei-Min Ning
- Dongguan Hospital of Traditional Chinese Medicine, Dongguan, 523808, China.
| | - Lin-Zhong Yu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
| | - Jun-Shan Liu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
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Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma. J Hepatol 2020; 73:1446-1459. [PMID: 32610114 DOI: 10.1016/j.jhep.2020.06.027] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 06/10/2020] [Accepted: 06/16/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying causes of this aberrant activation remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor that acts via the mTORC1 axis. METHODS We performed quantitative reverse-transcription PCR (92 pairs), western blot (30 pairs), and immunostaining (225 cases) assays in HCC tissue samples to evaluate VEPH1 expression. We explored the functional effects of VEPH1 on tumor growth and metastasis. Molecular and biochemical strategies were used to gain insight into mechanisms underlying the tumor-suppressive function of VEPH1. RESULTS VEPH1 is frequently silenced in HCC tissues, primarily resulting from let-7d upregulation. Decreased VEPH1 expression is associated with poor prognosis and aggressive tumor phenotypes in patients with HCC. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion in vitro and in vivo. The VEPH1 fragments 580-625aa and 447-579 aa bind directly to TSC1 (719-1,164aa) and TSC2 (1-420 aa), respectively, enhancing TSC1/TCS2 binding and promoting translocation of TSC2 to the membrane, which leads to increased TSC2 Ser1387 phosphorylation. Subsequently, Rheb is inactivated by the GTPase activity of TSC2, inhibiting mTORC1 signaling and contributing to changes in HCC carcinogenesis and metastasis. Rapamycin, the mTOR inhibitor, can inhibit the pro-tumorigenic effect of VEPH1 knockdown. Loss of VEPH1 correlates with decreased TSC2 Ser1387 phosphorylation and increased mTOR activity in HCC specimens. CONCLUSIONS The loss of VEPH1 leads to aberrantly activated mTORC1 signaling in HCC; rapamycin (or rapalogs) may serve as an effective treatment option for patients with HCC and dampened VEPH1 expression. LAY SUMMARY Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression.
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11
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The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2020; 13:ph13120432. [PMID: 33260729 PMCID: PMC7760785 DOI: 10.3390/ph13120432] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
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12
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Expression of MAPK and PI3K/AKT/mTOR Proteins according to the Chronic Liver Disease Etiology in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2020; 2020:4609360. [PMID: 33178273 PMCID: PMC7644337 DOI: 10.1155/2020/4609360] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 10/12/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023]
Abstract
Aims Chronic liver disease (CLD) of different etiologies leads to hepatocellular carcinoma (HCC) by multiple mechanisms that may be translated into clinicopathological differences. We evaluated the tissue expression of the MAPK and PI3K/Akt/mTOR pathway proteins and their association with long-term outcome and other parameters, according to the etiology of the CLD, in HCC patients. Methods Clinicopathological data from 80 patients who underwent orthotopic liver transplantation for HCC treatment in a Brazilian referral center were compared according to CLD etiology. Event (tumor recurrence or death from any cause) occurrence and event-free survival (EFS) were analyzed. Pathway protein expression was assessed by immunohistochemistry (IHQ) in both tumor and underlying cirrhosis and by RT-PCR in tumor tissue. Results Strong expression (SE) of KRAS was more frequent in tumors arising from viral (26.8%) than the nonviral group of liver disease (7.7%, p=0.024) and also than cirrhotic parenchyma (0%, p=0.004). SE of PI3K was more frequent in tumor than in cirrhosis (p=0.048, p < 0.01), without differences in its tumor expression among etiologic groups (p=0.111). mRNA of ERK, PI3K, and BRAF was expressed in the tumor, without differences between CLD etiologies, and there was no association with IHQ findings. Older age and microvascular invasion (MIV) were the only parameters independently associated with the event. MIV was also associated with shorter EFS. Conclusions Hepatitis B and C virus can lead to HCC by different mechanisms compared with nonviral hepatopathy. KRAS and PI3K may have a role in carcinogenesis. The prognostic and therapeutic implications need to be investigated.
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Fan J, Shi Y, Peng Y. Autophagy and Liver Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1207:497-528. [PMID: 32671772 DOI: 10.1007/978-981-15-4272-5_37] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autophagy plays an important role in the physiology and pathology of the liver. It is involved in the development of many liver diseases such as α-1-antitrypsin deficiency, chronic hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, and liver cancer. Autophagy has thus become a new target for the treatment of liver diseases. How to treat liver diseases by regulating autophagy has been a hot topic.
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Affiliation(s)
- Jia Fan
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China.
| | - Yinghong Shi
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China
| | - Yuanfei Peng
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China
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Au KP, Chok KSH. Mammalian target of rapamycin inhibitors after post-transplant hepatocellular carcinoma recurrence: Is it too late? World J Gastrointest Surg 2020; 12:149-158. [PMID: 32426094 PMCID: PMC7215969 DOI: 10.4240/wjgs.v12.i4.149] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/21/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce the risk of tumour recurrence after liver transplantation for hepatocellular carcinoma (HCC). However, their role in established post-transplant HCC recurrence is uncertain.
AIM To investigate whether mTOR inhibitor offers a survival benefit in post-transplant HCC recurrence.
METHODS A retrospective study of 143 patients who developed HCC recurrence after liver transplantation was performed. They were divided into 2 groups based on whether they had received mTOR inhibitor-based immunosuppression. The primary endpoint was post-recurrence survival.
RESULTS Seventy-nine (55%) patients received an mTOR inhibitor-based immunosuppressive regime, while 64 (45%) patients did not. The mTOR inhibitor group had a lower number of recurrent tumours (2 vs 5, P = 0.02) and received more active treatments including radiotherapy (39 vs 22%, P = 0.03) and targeted therapy (59 vs 23%, P < 0.001). The median post-recurrence survival was 21.0 ± 4.1 mo in the mTOR inhibitor group and 11.2 ± 2.5 mo in the control group. Multivariate Cox regression analysis confirmed that mTOR inhibitor therapy was independently associated with improved post-recurrence survival (P = 0.04, OR = 0.482, 95%CI: 0.241-0.966). The number of recurrent tumours and use of other treatment modalities did not affect survival. No survival difference was observed between mTOR inhibitor monotherapy and combination therapy with calcineurin inhibitor.
CONCLUSION mTOR inhibitors prolonged survival after post-transplant HCC recurrence.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, Hong Kong 999077, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong 999077, China
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Pinto AP, Vieira TS, Marafon BB, Batitucci G, Cabrera EMB, da Rocha AL, Kohama EB, Rodrigues KCC, de Moura LP, Pauli JR, Cintra DE, Ropelle ER, de Freitas EC, da Silva ASR. The Combination of Fasting, Acute Resistance Exercise, and Protein Ingestion Led to Different Responses of Autophagy Markers in Gastrocnemius and Liver Samples. Nutrients 2020; 12:nu12030641. [PMID: 32121154 PMCID: PMC7146592 DOI: 10.3390/nu12030641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 12/02/2022] Open
Abstract
The present study verified the responses of proteins related to the autophagy pathway after 10 h of fast with resistance exercise and protein ingestion in skeletal muscle and liver samples. The rats were distributed into five experimental groups: control (CT; sedentary and without gavage after fast), exercise immediately (EXE-imm; after fast, rats were submitted to the resistance protocol and received water by gavage immediately after exercise), exercise after 1 h (EXE-1h; after fast, rats were submitted to the resistance protocol and received water by gavage 1 h after exercise), exercise and supplementation immediately after exercise (EXE/Suppl-imm; after fast, rats were submitted to the resistance protocol and received a mix of casein: whey protein 1:1 (w/w) by gavage immediately after exercise), exercise and supplementation 1 h after exercise (EXE/Suppl-1h; after fast, rats were submitted to the resistance protocol and received a mix of casein: whey protein 1:1 (w/w) by gavage 1 h after exercise). In summary, the current findings show that the combination of fasting, acute resistance exercise, and protein blend ingestion (immediately or 1 h after the exercise stimulus) increased the serum levels of leucine, insulin, and glucose, as well as the autophagy protein contents in skeletal muscle, but decreased other proteins related to the autophagic pathway in the liver. These results deserve further mechanistic investigations since athletes are combining fasting with physical exercise to enhance health and performance outcomes.
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Affiliation(s)
- Ana P. Pinto
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo 14049-900, Brazil; (A.P.P.); (A.L.d.R.); (E.B.K.)
| | - Tales S. Vieira
- Postgraduate Program in Nutritional Science, State University of São Paulo Júlio de Mesquita Filho (Araraquara). Araraquara, São Paulo 14800-903, Brazil; (T.S.V.); (G.B.); (E.C.d.F.)
| | - Bruno B. Marafon
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo 14040-907, Brazil;
| | - Gabriela Batitucci
- Postgraduate Program in Nutritional Science, State University of São Paulo Júlio de Mesquita Filho (Araraquara). Araraquara, São Paulo 14800-903, Brazil; (T.S.V.); (G.B.); (E.C.d.F.)
| | - Elisa M. B. Cabrera
- Institute of Translational Nutrigenetics and Nutrigenomics, Department of Molecular Biology and Genomics, Health Sciences University Center, University of Guadalajara, Guadalajara 44100, Mexico;
| | - Alisson L. da Rocha
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo 14049-900, Brazil; (A.P.P.); (A.L.d.R.); (E.B.K.)
| | - Eike B. Kohama
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo 14049-900, Brazil; (A.P.P.); (A.L.d.R.); (E.B.K.)
| | - Kellen C. C. Rodrigues
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (K.C.C.R.); (L.P.d.M.); (J.R.P.); (D.E.C.); (E.R.R.)
| | - Leandro P. de Moura
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (K.C.C.R.); (L.P.d.M.); (J.R.P.); (D.E.C.); (E.R.R.)
| | - José R. Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (K.C.C.R.); (L.P.d.M.); (J.R.P.); (D.E.C.); (E.R.R.)
| | - Dennys E. Cintra
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (K.C.C.R.); (L.P.d.M.); (J.R.P.); (D.E.C.); (E.R.R.)
| | - Eduardo R. Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (K.C.C.R.); (L.P.d.M.); (J.R.P.); (D.E.C.); (E.R.R.)
| | - Ellen C. de Freitas
- Postgraduate Program in Nutritional Science, State University of São Paulo Júlio de Mesquita Filho (Araraquara). Araraquara, São Paulo 14800-903, Brazil; (T.S.V.); (G.B.); (E.C.d.F.)
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo 14040-907, Brazil;
| | - Adelino S. R. da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo 14049-900, Brazil; (A.P.P.); (A.L.d.R.); (E.B.K.)
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo 14040-907, Brazil;
- Correspondence: ; Tel.: +55-16-33150522; Fax: +55-16-33150551
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Dimri M, Satyanarayana A. Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12020491. [PMID: 32093152 PMCID: PMC7072513 DOI: 10.3390/cancers12020491] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.
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17
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Fang J, Pan L, Gu QX, Juengpanich S, Zheng JH, Tong CH, Wang ZY, Nan JJ, Wang YF. Scientometric analysis of mTOR signaling pathway in liver disease. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:93. [PMID: 32175386 DOI: 10.21037/atm.2019.12.110] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background The mTOR pathway is vital for homeostasis, metabolism, cancer transplantation and regeneration in the liver. The aim of this study is to use a bibliometric method to reveal current research hotspots and promising future trends in mTOR signaling in liver diseases. Methods Publications were searched and downloaded from the Web of Science Core Collection (WOSCC) Database. CiteSpace, Carrot2, and VOSviewer programs were utilized to analyze the contribution of various countries/regions, institutes, and authors; and to reveal research hotspots and promising future trends in this research area. Results Until May 21, 2019, a total of 2,232 papers regarding mTOR signaling pathway in liver disease were included, and each paper was cited 23.21 times on average. The most active country was the USA. 5 landmark articles with centrality and burstiness were determined by co-citation analysis. Research hotspots included "liver transplantation" "hepatic stellate cell proliferation" "NAFLD" "therapy of HCC". Moreover, six key clusters were discovered during the procedure of "clustering", including "liver transplantation" "protein synthesis" "mTOR inhibitor" "following early cyclosporine withdrawal" "srebp-1 activation", and "hepatocellular cancer". Conclusions Various scientific methods were applied to reveal scientific productivity, collaboration, and research hotspots in the mTOR signaling pathway in liver disease. Liver transplantation, hepatic stellate cell proliferation, non-alcoholic fatty liver disease (NAFLD), therapy of hepatocellular carcinoma (HCC), cell growth and autophagy, are research hotspots and are likely to be promising in the next few years. Further studies in this field are needed.
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Affiliation(s)
- Jing Fang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Long Pan
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Qiu-Xia Gu
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Sarun Juengpanich
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Jun-Hao Zheng
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Chen-Hao Tong
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Department of General Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing 312000, China
| | - Zi-Yuan Wang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China
| | - Jun-Jie Nan
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China
| | - Yi-Fan Wang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
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Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma. DRUG REPURPOSING IN CANCER THERAPY 2020. [PMCID: PMC7471801 DOI: 10.1016/b978-0-12-819668-7.00008-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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19
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Fukuhara S, Tahara H, Hirata Y, Ono K, Hamaoka M, Shimizu S, Hashimoto S, Kuroda S, Ohira M, Ide K, Kobayashi T, Ohdan H. Hepatic epithelioid hemangioendothelioma successfully treated with living donor liver transplantation: A case report and literature review. Clin Case Rep 2020; 8:108-115. [PMID: 31998498 PMCID: PMC6982499 DOI: 10.1002/ccr3.2558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/24/2019] [Accepted: 10/20/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatic epithelioid hemangioendothelioma is a rare neoplasm with a variable malignant potential and a high risk of recurrence. No general treatment guidelines have been established. Fortunately, we were able to minimize immunosuppressant after liver transplantation because of a full HLA-matched case. There was no recurrence 1 year after treatment.
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Affiliation(s)
- Sotaro Fukuhara
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Hiroyuki Tahara
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Yoshito Hirata
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kosuke Ono
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Michinori Hamaoka
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Seiichi Shimizu
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Shinji Hashimoto
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kentaro Ide
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
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Dai Q, Zhang C, Yuan Z, Sun Q, Jiang Y. Current discovery strategies for hepatocellular carcinoma therapeutics. Expert Opin Drug Discov 2019; 15:243-258. [PMID: 31809618 DOI: 10.1080/17460441.2020.1696769] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Qiuzi Dai
- Department of Chemistry, Tsinghua University, Beijing, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
| | - Cunlong Zhang
- Shenzhen Bay Laboratory, Shenzhen, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
| | - Zigao Yuan
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
| | - Qinsheng Sun
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
| | - Yuyang Jiang
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
- Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, P. R. China
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Kroh A, Walter J, Schüler H, Nolting J, Eickhoff R, Heise D, Neumann UP, Cramer T, Ulmer TF, Fragoulis A. A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis. Int J Mol Sci 2019; 20:ijms20225658. [PMID: 31726709 PMCID: PMC6888677 DOI: 10.3390/ijms20225658] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/07/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) has become a major risk factor for hepatocellular cancer (HCC) due to the worldwide increasing prevalence of obesity. However, the pathophysiology of NASH and its progression to HCC is incompletely understood. Thus, the aim of this study was to generate a model specific NASH-derived HCC cell line. A murine NASH-HCC model was conducted and the obtained cancer cells (N-HCC25) were investigated towards chromosomal aberrations, the expression of cell type-specific markers, dependency on nutrients, and functional importance of mTOR. N-HCC25 exhibited several chromosomal aberrations as compared to healthy hepatocytes. Hepatocytic (HNF4), EMT (Twist, Snail), and cancer stem cell markers (CD44, EpCAM, CK19, Sox9) were simultaneously expressed in these cells. Proliferation highly depended on the supply of glucose and FBS, but not glutamine. Treatment with a second generation mTOR inhibitor (KU-0063794) resulted in a strong decrease of cell growth in a dose-dependent manner. In contrast, a first generation mTOR inhibitor (Everolimus) only slightly reduced cell proliferation. Cell cycle analyses revealed that the observed growth reduction was most likely due to G1/G0 cell cycle arrest. These results indicate that N-HCC25 is a highly proliferative HCC cell line from a NASH background, which might serve as a suitable in vitro model for future investigations of NASH-derived HCC.
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Affiliation(s)
- Andreas Kroh
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Correspondence: ; Tel.: +49-241-80-89-501
| | - Jeanette Walter
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Herdit Schüler
- Institute of Human Genetics, Uniklinik RWTH Aachen, 52074 Aachen, Germany;
| | - Jochen Nolting
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Roman Eickhoff
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Daniel Heise
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
- ESCAM—European Surgery Center Aachen Maastricht, 52074 Aachen, Germany
- ESCAM—European Surgery Center Aachen Maastricht, 6200 MD Maastricht, The Netherlands
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
- ESCAM—European Surgery Center Aachen Maastricht, 52074 Aachen, Germany
- ESCAM—European Surgery Center Aachen Maastricht, 6200 MD Maastricht, The Netherlands
| | - Tom Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
| | - Athanassios Fragoulis
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen, 52074 Aachen, Germany
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Roy G, Guan S, Liu H, Zhang L. Rotundic Acid Induces DNA Damage and Cell Death in Hepatocellular Carcinoma Through AKT/mTOR and MAPK Pathways. Front Oncol 2019; 9:545. [PMID: 31293977 PMCID: PMC6606729 DOI: 10.3389/fonc.2019.00545] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 06/04/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth largest cause of cancer-related deaths worldwide with limited therapeutic interventions. Renewed interest in natural products as drug leads has resulted in a paradigm shift toward the rapid screening of medicinal plants for the discovery of new chemical entities. Rotundic acid (RA), a plant-derived triterpenoid, has been anecdotally reported to possess anti-inflammatory and cardio-protective abilities. The present study highlights the anti-cancer efficacy of RA on HCC in vitro and in vivo. The inhibitory effects of RA on HCC cell viability was determined by MTT. Soft agar colony formation and clonogenic assays also showed that RA inhibited HCC cell proliferation. Flow cytometry, confocal, and western blot results further indicated that RA induced cell cycle arrest, DNA damage, and apoptosis by modulating the AKT/mTOR and MAPK pathways. Besides the suppression of migration and invasion, tube formation and VEGF-ELISA revealed the anti-angiogenic abilities of RA on HCC. Moreover, RA also inhibited tumor growth in a HepG2 xenograft mouse model. To our best knowledge, this is the first extensive study of the anticancer activity of RA on HCC. The results demonstrate that RA could be a potential drug candidate for HCC treatment.
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Affiliation(s)
- Gaurab Roy
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Su Guan
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Hexiang Liu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Lei Zhang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.,Guangdong Provincial Engineering and Technological Centre for Biopharmaceuticals, South China University of Technology, Guangzhou, China
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23
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Gai X, Tang B, Liu F, Wu Y, Wang F, Jing Y, Huang F, Jin D, Wang L, Zhang H. mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs. J Genet Genomics 2019; 46:235-245. [PMID: 31186161 DOI: 10.1016/j.jgg.2019.03.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 03/06/2019] [Accepted: 03/06/2019] [Indexed: 12/28/2022]
Abstract
Golgi membrane protein 1 (GOLM1/GP73) is a serum marker of hepatocellular carcinoma (HCC). We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression. In this study, we demonstrated that the mammalian target of rapamycin (mTOR) was a negative regulator of microRNA-145 (miR-145) expression. miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1 gene. GOLM1 and miR-145 were inversely correlated in human HCC tissues. GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases (GSK-3β/MMPs) signaling axis of recipient cells and accelerated cell proliferation and migration. In contrast, miR-145 suppressed tumorigenesis and metastasis. We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.
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Affiliation(s)
- Xiaochen Gai
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Bufu Tang
- First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China; Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, 323000, China; Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 323000, China
| | - Fangming Liu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Yuting Wu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Fang Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Yanling Jing
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Fuqiang Huang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Di Jin
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Ling Wang
- First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.
| | - Hongbing Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China; Department of Neurology, Institute of Neural Regeneration and Repair, The First People's Hospital of Yichang, College of Medicine, Three Gorges University, Yichang, 443000, China.
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Yu XN, Chen H, Liu TT, Wu J, Zhu JM, Shen XZ. Targeting the mTOR regulatory network in hepatocellular carcinoma: Are we making headway? Biochim Biophys Acta Rev Cancer 2019; 1871:379-391. [PMID: 30951815 DOI: 10.1016/j.bbcan.2019.03.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 03/20/2019] [Accepted: 03/20/2019] [Indexed: 12/24/2022]
Abstract
The mechanistic target of rapamycin (mTOR) pathway coordinates organismal growth and homeostasis in response to growth factors, nutrients, and cellular energy stage. The pathway regulates several major cellular processes and is implicated in various pathological conditions, including hepatocellular carcinoma (HCC). This review summarizes recent advances of the mTOR pathway, highlights the potential of the mTOR pathway as a therapeutic target, and explores clinical trials targeting the mTOR pathway in HCC. Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.
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Affiliation(s)
- Xiang-Nan Yu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hong Chen
- Department of Endocrinology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Jian Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China; Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ji-Min Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China.
| | - Xi-Zhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China; Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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25
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Dandelion polysaccharides exert anticancer effect on Hepatocellular carcinoma by inhibiting PI3K/AKT/mTOR pathway and enhancing immune response. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.02.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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26
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Chi HC, Tsai CY, Tsai MM, Yeh CT, Lin KH. Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases. J Biomed Sci 2019; 26:24. [PMID: 30849993 PMCID: PMC6407245 DOI: 10.1186/s12929-019-0517-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 02/26/2019] [Indexed: 02/07/2023] Open
Abstract
The liver is controlled by several metabolic hormones, including thyroid hormone, and characteristically displays high lysosomal activity as well as metabolic stress-triggered autophagy, which is stringently regulated by the levels of hormones and metabolites. Hepatic autophagy provides energy through catabolism of glucose, amino acids and free fatty acids for starved cells, facilitating the generation of new macromolecules and maintenance of the quantity and quality of cellular organelles, such as mitochondria. Dysregulation of autophagy and defective mitochondrial homeostasis contribute to hepatocyte injury and liver-related diseases, such as non-alcoholic fatty liver disease (NAFLD) and liver cancer. Thyroid hormones (TH) mediate several critical physiological processes including organ development, cell differentiation, metabolism and cell growth and maintenance. Accumulating evidence has revealed dysregulation of cellular TH activity as the underlying cause of several liver-related diseases, including alcoholic or non-alcoholic fatty liver disease and liver cancer. Data from epidemiologic, animal and clinical studies collectively support preventive functions of THs in liver-related diseases, highlighting the therapeutic potential of TH analogs. Elucidation of the molecular mechanisms and downstream targets of TH should thus facilitate the development of therapeutic strategies for a number of major public health issues. Here, we have reviewed recent studies focusing on the involvement of THs in hepatic homeostasis through induction of autophagy and their implications in liver-related diseases. Additionally, the potential underlying molecular pathways and therapeutic applications of THs in NAFLD and HCC are discussed.
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Affiliation(s)
- Hsiang-Cheng Chi
- Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Chung-Ying Tsai
- Kidney Research Center and Department of Nephrology, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan, Taiwan, 333.,Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan, 613.,Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology , Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, 333
| | - Kwang-Huei Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, 333. .,Department of Biochemistry, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, 333, Taiwan, Republic of China. .,Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology , Taoyuan, Taiwan.
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27
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Phase IB Study of Induction Chemotherapy With XELOX, Followed by Radiation Therapy, Carboplatin, and Everolimus in Patients With Locally Advanced Esophageal Cancer. Am J Clin Oncol 2019; 42:331-336. [PMID: 30789414 DOI: 10.1097/coc.0000000000000524] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation. MATERIALS AND METHODS Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. RESULTS Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively. CONCLUSIONS The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.
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mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non-Alcoholic Steatohepatitis in Both Mouse Models and Humans. Cancers (Basel) 2018; 10:cancers10120465. [PMID: 30469530 PMCID: PMC6315895 DOI: 10.3390/cancers10120465] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 11/12/2018] [Accepted: 11/20/2018] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) can cause liver fibrosis and cirrhosis, with final progression to hepatocellular carcinoma (HCC) in some cases. Various factors have been suggested to be involved in the development of NASH. Considering the many possible contributing factors, we postulated that mechanisms of progression from NASH to HCC could differ depending on the risk factors. In the present study, we applied two mouse models of NASH⁻HCC and performed histopathological and proteome analyses of mouse liver tumors. Furthermore, to compare the mechanisms of NASH⁻HCC progression in mice and humans, we investigated HCCs in humans with a background of metabolic syndrome and NASH, as well as HCCs associated with hepatitis virus infection by immunohistochemistry. It was demonstrated that upstream regulators associated with the mammalian target of rapamycin (mTOR) pathway were altered in liver tumors of mice with metabolic syndrome characteristics (TSOD mice) using proteome analysis. Immunohistochemical analysis showed that mTOR was characteristically phosphorylated in liver tumors of TSOD mice and HCCs from metabolic syndrome cases in humans. These results indicated that the mTOR pathway is characteristically activated in liver tumors with metabolic syndrome and NASH, unlike liver tumors with other etiologies.
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29
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Badawi M, Kim J, Dauki A, Sutaria D, Motiwala T, Reyes R, Wani N, Kolli S, Jiang J, Coss CC, Jacob ST, Phelps MA, Schmittgen TD. CD44 positive and sorafenib insensitive hepatocellular carcinomas respond to the ATP-competitive mTOR inhibitor INK128. Oncotarget 2018; 9:26032-26045. [PMID: 29899840 PMCID: PMC5995255 DOI: 10.18632/oncotarget.25430] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 04/26/2018] [Indexed: 12/18/2022] Open
Abstract
The mTOR pathway is activated in about 50% of patients with hepatocellular carcinoma (HCC). In an effort to identify new pathways and compounds to treat advanced HCC, we considered the ATP-competitive mTOR inhibitor INK128. ATP-competitive mTOR inhibitors attenuate both mTORC1 and mTORC2. INK128 was evaluated in sorafenib sensitive and insensitive HCC cell lines, CD44low and CD44high HCC and those cell lines with acquired sorafenib resistance. CD44 was significantly increased in Huh7 cells made resistant to sorafenib. Forced expression of CD44 enhanced cellular proliferation and migration, and rendered the cells more sensitive to the anti-proliferative effects of INK128. INK128 suppressed CD44 expression in HCC cells while allosteric mTOR inhibitors did not. CD44 inhibition correlated with 4EBP1 phosphorylation status. INK128 showed better anti-proliferative and anti-migration effects on the mesenchymal-like HCC cells, CD44high HCC cells compared to the allosteric mTOR inhibitor everolimus. Moreover, a combination of INK128 and sorafenib showed improved anti-proliferative effects in CD44high HCC cells. INK128 was efficacious at reducing tumor growth in CD44high SK-Hep1 xenografts in mice when given as monotherapy or in combination with sorafenib. Since the clinical response to sorafenib is highly variable, our findings suggest that ATP-competitive mTOR inhibitors may be effective in treating advanced, CD44-expressing HCC patients who are insensitive to sorafenib.
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Affiliation(s)
- Mohamed Badawi
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Jihye Kim
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Anees Dauki
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Dhruvitkumar Sutaria
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
- College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Tasneem Motiwala
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Ryan Reyes
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Nissar Wani
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Shamalatha Kolli
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jinmai Jiang
- College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Christopher C. Coss
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Samson T. Jacob
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mitch A. Phelps
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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Yildiz G. Integrated multi-omics data analysis identifying novel drug sensitivity-associated molecular targets of hepatocellular carcinoma cells. Oncol Lett 2018; 16:113-122. [PMID: 29930714 PMCID: PMC6006500 DOI: 10.3892/ol.2018.8634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 02/01/2018] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third-leading cause of malignancy-associated mortality worldwide. HCC cells are highly resistant to chemotherapeutic agents. Therefore, there are currently only two US Food and Drug Administration-approved drugs available for the treatment of HCC. The objective of the present study was to analyze the results of previously published high-throughput drug screening, and in vitro genomic and transcriptomic data from HCC cell lines, and to integrate the obtained results to define the underlying molecular mechanisms of drug sensitivity and resistance in HCC cells. The results of treatment with 225 different small molecules on 14 different HCC cell lines were retrieved from the Genomics of Drug Sensitivity in Cancer database and analyzed. Cluster analysis using the treatment results determined that HCC cell lines consist of two groups, according to their drug response profiles. Continued analyses of these two groups with Gene Set Enrichment Analysis method revealed 6 treatment-sensitive molecular targets (epidermal growth factor receptor, mechanistic target of rapamycin, deoxyribonucleic acid-dependent protein kinase, the Aurora kinases, Bruton's tyrosine kinase and phosphoinositide 3-kinase; all P<0.05) and partially effective drugs. Genetic and genome-wide gene expression data analyses of the determined targets and their known biological partners revealed 2 somatically mutated and 13 differentially expressed genes, which differed between drug-resistant and drug-sensitive HCC cells. Integration of the obtained data into a short molecular pathway revealed a drug treatment-sensitive signaling axis in HCC cells. In conclusion, the results of the present study provide novel drug sensitivity-associated molecular targets for the development of novel personalized and targeted molecular therapies against HCC.
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Affiliation(s)
- Gokhan Yildiz
- Department of Medical Biology, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey
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31
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Sirolimus and metformin synergistically inhibit hepatocellular carcinoma cell proliferation and improve long-term survival in patients with HCC related to hepatitis B virus induced cirrhosis after liver transplantation. Oncotarget 2018; 7:62647-62656. [PMID: 27577068 PMCID: PMC5308754 DOI: 10.18632/oncotarget.11591] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 08/11/2016] [Indexed: 02/06/2023] Open
Abstract
Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM). Kaplan-Meier and Log-rank tests were used to assess survival. Cell proliferation and tumor xenograft assays were performed to disclose the mechanisms underlying the sirolimus and metformin effects. The Sir+Met group showed significantly prolonged survival compared to the other groups. The most significant cytotoxicity was seen in the Sir+Met group, with significantly decreased levels of phosphorylated PI3K, AKT, AMPK, mTOR, 4EBP1 and S6K, compared with the other groups. In agreement, Sir+Met had the highest suppressive effect on tumor growth among all groups (P<0.01). In summary, Sir+Met treatment significantly prolonged survival, likely by suppressing cell proliferation. Therefore, this combination could represent a potential routine-regimen for patients post LT.
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Watari K, Nishitani A, Shibata T, Noda M, Kawahara A, Akiba J, Murakami Y, Yano H, Kuwano M, Ono M. Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma. Oncotarget 2018; 7:47403-47417. [PMID: 27329724 PMCID: PMC5216950 DOI: 10.18632/oncotarget.10161] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 06/07/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although recent studies facilitate the identification of crucial genes and relevant regulatory pathways, therapeutic approaches against advanced HCC are insufficiently effective. Therefore, we aimed here to develop potent therapeutics to provide a reliable biomarker for the therapeutic efficacy in patients with HCC. To this end, we first compared the cytotoxic effects of various anti-cancer drugs between well differentiated (HAK-1A) and poorly differentiated (HAK-1B) cell lines established from a single HCC tumor. Of various drug screened, HAK-1B cells were more sensitive by a factor of 2,000 to the mTORC1 inhibitors (rapalogs), rapamycin and everolimus, than HAK-1A cells. Although rapalogs inhibited phosphorylation of mTOR Ser2448 in HAK-1A and HAK-1B cells, phosphorylation of mTOR Ser2481 was specifically inhibited only in HAK-1B cells. Silencing of Raptor induced apoptosis and inhibited the growth of only HAK-1B cells. Further, three other cell lines established independently from the tumors of three patients with HCC were also approximately 2,000-fold times more sensitive to rapamycin, which correlated closely with the inhibition of mTOR Ser2481 phosphorylation by rapamycin. Treatment with everolimus markedly inhibited the growth of tumors induced by poorly differentiated HAK-1B and KYN-2 cells and phosphorylation of mTOR Ser2481 in vivo. To our knowledge, this is the first study showing that the phosphorylation of mTOR Ser2481 is selectively inhibited by rapalogs in mTORC1-addicted HCC cells and may be a potential reliable biomarker for the therapeutic efficacy of rapalogs for treating HCC patients.
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Affiliation(s)
- Kosuke Watari
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ayumi Nishitani
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomohiro Shibata
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Noda
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akihiko Kawahara
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan
| | - Jun Akiba
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Yuichi Murakami
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.,Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Michihiko Kuwano
- Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan
| | - Mayumi Ono
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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33
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Targeting AMPK, mTOR and β-Catenin by Combined Metformin and Aspirin Therapy in HCC: An Appraisal in Egyptian HCC Patients. Mol Diagn Ther 2017; 22:115-127. [PMID: 29094287 DOI: 10.1007/s40291-017-0307-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Giakoustidis AE, Giakoustidis DE. Immunosuppression strategies in liver transplantation patient; patients with hepatocellular carcinoma. Immunotherapy 2017; 9:197-206. [PMID: 28128716 DOI: 10.2217/imt-2016-0110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) consists the main primary malignant tumor of the liver. There is an underlining liver cirrhosis mainly attributed to chronic hepatitis B virus or hepatitis C virus, alcoholic liver disease, nonalcoholic steatohepatitis and other pathologic conditions. Liver transplantation consists a radical management, treating both cancer and cirrhosis. By introducing the Milan Criteria for liver transplantation in HCC patients there was a 5-year survival escalation. Even though there is a careful selection of patients with HCC for transplantation, recurrent disease is still high. The role of immusuppression therapy is of paramount importance, in order to avoid acute and chronic graft rejection while protecting the patient from tumor recurrence. In recent years newer immunosuppressive agents such as the mTOR inhibitors are proposed, having dual properties, as both immunosuppressive and antitumors agents.
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Affiliation(s)
- Alexander E Giakoustidis
- Hepato-Pancreato-Biliary Surgery Department, The Royal London Hospital, Barts Health, Whitechapel Road, London E1 1BB, UK
| | - Dimitrios E Giakoustidis
- Division of Transplant Surgery, Department of Surgery, School of Health Sciences, Aristotle University of Thessaloniki & Hippokration General Hospital, Thessaloniki, Greece
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Wang M, Huang C, Su Y, Yang C, Xia Q, Xu DJ. Astragaloside II sensitizes human hepatocellular carcinoma cells to 5-fluorouracil via suppression of autophagy. ACTA ACUST UNITED AC 2017; 69:743-752. [PMID: 28266023 DOI: 10.1111/jphp.12706] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 01/12/2017] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Inhibition of autophagy has been increasingly recognized as a potential therapeutic approach against cancer. Our previous reports showed that Astragaloside II improves hepatic cancer cells resistance by downregulating MDR1 and P-gp .The purpose of this study was to further investigated the effect of autophagy on AS-II reversing multidrug resistance and its molecular mechanism in hepatocellular carcinoma cells in vitro. METHODS Bel-7402 and Bel-7402/FU cell lines were used in this study. Western blot was used to detect the expression of autophagy-related protein, p-mTOR and p-p79s6k, MTT was used to analyse cell viability, GFP-LC3 punctate dots distribution was observed by GFP-LC3 transient transfection under fluorescence microscopy and silencing of autophagy-related genes was detected by small interfering RNA transfection. KEY FINDINGS Astragaloside II was able to significantly decrease the expression of LC3-II and Beclin-1 in a dose-dependent manner, Astragaloside II (80 μm) further decreased LC3-II formation, Beclin-1 and GFP-LC3 puncta dots stimulated with 5-fluorouracil (0.2 mm) in Bel-7402/FU cells (P < 0.05). In addition, Astragaloside II is capable of sensitizing cells to 5-fluorouracil-induced cell death via inhibition of pro-survival autophagy involvement of MAPK-mTOR pathway. CONCLUSIONS These findings suggested that Astragaloside II could suppress autophagy by interfering with Beclin-1 and LC3 via MAPK-mTOR pathway, through which sensitized human cancer resistant cells to 5-FU-induced cell death.
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Affiliation(s)
- Meng Wang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Can Huang
- Department of Pharmacy, Affiliated Anqing Hospital of Anhui Medical University, Anqing, Anhui, China
| | - Yong Su
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Cui Yang
- Department of Pharmacy, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Du-Juan Xu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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36
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Montella L, Palmieri G, Addeo R, Del Prete S. Hepatocellular carcinoma: Will novel targeted drugs really impact the next future? World J Gastroenterol 2016; 22:6114-6126. [PMID: 27468204 PMCID: PMC4945973 DOI: 10.3748/wjg.v22.i27.6114] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 05/09/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Cancer treatment has been revolutionized by the advent of new molecular targeted and immunotherapeutic agents. Identification of the role of tumor angiogenesis changed the understanding of many tumors. After the unsuccessful results with chemotherapy, sorafenib, by interfering with angiogenic pathways, has become pivotal in the treatment of hepatocellular carcinoma. Sorafenib is the only systemic treatment to show a modest but statistically significant survival benefit. All novel drugs and strategies for treatment of advanced hepatocellular carcinoma must be compared with the results obtained with sorafenib, but no new drug or drug combination has yet achieved better results. In our opinion, the efforts to impact the natural history of the disease will be directed not only to drug development but also to understanding the underlying liver disease (usually hepatitis B virus- or hepatitis C virus-related) and to interrupting the progression of cirrhosis. It will be important to define the role and amount of mutations in the complex pathogenesis of hepatocellular carcinoma and to better integrate locoregional and systemic therapies. It will be important also to optimize the therapeutic strategies with existing chemotherapeutic drugs and new targeted agents.
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37
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Lamarca A, Mendiola M, Barriuso J. Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology. Crit Rev Oncol Hematol 2016; 105:65-72. [PMID: 27372199 DOI: 10.1016/j.critrevonc.2016.06.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 03/15/2016] [Accepted: 06/14/2016] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. The high rate of diagnosis in non-curable stages and the lack of novel active treatments make it necessary to review all the possible sources of misleading results in this scenario. The incidence of HCC shows clear geographical variation with higher annual incidence in Asia and Africa than in Western countries; we aimed to review the literature to find if there are different trends in the main activated molecular pathways. Hyperactivation of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signalling and epithelial to mesenchymal transition (EMT) process are more prevalent in the Western population; however, fibroblast growth factor (FGF), transforming growth factor β (TGFβ) and Notch pathways seems to be more relevant in Asian population. Whether these variations just reflect the distinct distribution of known causes of HCC or proper ethnical differences remain to be elucidated. Nevertheless, these clearly different patterns are relevant to regional or worldwide clinical trial design. If this information is neglected by sponsors and researchers the rate of failure in HCC trials will not improve.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Marta Mendiola
- Cancer Molecular Pathology and Therapeutic Targets Research Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Jorge Barriuso
- Faculty of Life Sciences, University of Manchester, Manchester, UK.
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Yanik EL, Chinnakotla S, Gustafson SK, Snyder JJ, Israni AK, Segev DL, Engels EA. Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma. Liver Transpl 2016; 22:627-34. [PMID: 26784951 PMCID: PMC4846564 DOI: 10.1002/lt.24395] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 12/11/2015] [Accepted: 01/07/2016] [Indexed: 12/16/2022]
Abstract
For recipients of liver transplantations (LTs) for hepatocellular carcinoma (HCC), HCC recurrence after transplantation remains a major concern. Sirolimus (SRL), an immunosuppressant with anticarcinogenic properties, may reduce HCC recurrence and improve survival. In our study, the US Scientific Registry of Transplant Recipients was linked to pharmacy claims. For liver recipients transplanted for HCC, Cox regression was used to estimate associations of early SRL use with recurrence, cancer-specific mortality, and all-cause mortality, adjusting for recipient ethnicity, calendar year of transplant, total tumor volume, alpha-fetoprotein, transplant center size, use of interleukin 2 induction therapy, and allocated and calculated Model for End-Stage Liver Disease score. We performed stratified analyses among recipients who met Milan criteria, among those without renal failure, among those with deceased liver donors, by age at transplantation, and by tumor size. Among the 3936 included HCC LTs, 234 (6%) were SRL users. In total, there were 242 recurrences and 879 deaths, including 261 cancer-related deaths. All-cause mortality was similar in SRL users and nonusers (adjusted hazard ratio [aHR], 1.01; 95% CI, 0.73-1.39). HCC recurrence and cancer-specific mortality rates appeared lower in SRL users, but associations were not statistically significant (recurrence aHR, 0.86; 95% CI, 0.45-1.65; cancer-specific mortality aHR, 0.80; 95% CI, 0.43-1.50). Among recipients >55 years old, associations were suggestive of better outcomes for SRL users (all-cause mortality aHR, 0.62; 95% CI, 0.38-1.01; recurrence aHR, 0.52; 95% CI, 0.19-1.44; cancer-specific mortality aHR, 0.34; 95% CI, 0.11-1.09), whereas among recipients ≤55 years old, SRL users had worse outcomes (all-cause mortality aHR, 1.76; 95% CI, 1.12-2.75; recurrence aHR, 1.49; 95% CI, 0.62-3.61; cancer-specific mortality aHR, 1.54; 95% CI, 0.71-3.32). In conclusion, among HCC liver recipients overall, SRL did not appear beneficial in reducing all-cause mortality. However, there were suggestions of reductions in recurrence and cancer-specific mortality, and effects appeared to be modified by age at transplantation. Liver Transplantation 22 627-634 2016 AASLD.
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Affiliation(s)
- Elizabeth L. Yanik
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | | | - Sally K. Gustafson
- Scientific Registry of Transplant Recipients, Minneapolis Medical Research Foundation, Minneapolis, MN
| | - Jon J. Snyder
- Scientific Registry of Transplant Recipients, Minneapolis Medical Research Foundation, Minneapolis, MN,Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Ajay K. Israni
- Scientific Registry of Transplant Recipients, Minneapolis Medical Research Foundation, Minneapolis, MN,Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN,Hennepin County Medical Center, School of Medicine, University of Minnesota, Minneapolis, MN
| | - Dorry L. Segev
- Scientific Registry of Transplant Recipients, Minneapolis Medical Research Foundation, Minneapolis, MN,School of Medicine, Johns Hopkins University, Baltimore, MD
| | - Eric A. Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
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Khorsandi SE, Heaton N. Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence. Transl Gastroenterol Hepatol 2016; 1:25. [PMID: 28138592 DOI: 10.21037/tgh.2016.03.18] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/01/2016] [Indexed: 12/12/2022] Open
Abstract
The introduction of liver transplant listing criteria for hepatocellular cancer (HCC) has significantly improved oncological outcomes and survival. But despite this HCC recurrence is still problematic. There is emerging evidence that the choice of immunosuppression (IS) after transplant for HCC can influence oncological survival and HCC recurrence. The following is a short summary of what has been published on HCC recurrence with the different classes of immunosuppressive agents in present use, concluding with the possible rationalization of the use of these immunosuppressive agents in the post-transplant patient at high risk of recurrence.
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Affiliation(s)
- Shirin Elizabeth Khorsandi
- Institute of Liver Studies, King's Healthcare Partners at Denmark Hill, King's College Hospital NHSFT, London, SE5 9RS, UK
| | - Nigel Heaton
- Institute of Liver Studies, King's Healthcare Partners at Denmark Hill, King's College Hospital NHSFT, London, SE5 9RS, UK
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40
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Chen Y, Zhang L, Yang C, Han J, Wang C, Zheng C, Zhou Y, Lv J, Song Y, Zhu J. Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma. Bioorg Med Chem 2016; 24:957-66. [PMID: 26819001 DOI: 10.1016/j.bmc.2016.01.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 01/06/2016] [Accepted: 01/06/2016] [Indexed: 01/04/2023]
Abstract
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is related to cellular activities. Abnormalities of this signaling pathway were discovered in various cancers, including hepatocellular carcinoma (HCC). The PI3K/mTOR dual inhibitors were proposed to have enhanced antitumor efficacies by targeting multiple points of the signaling pathway. We synthesized a series of propynyl-substituted benzenesulfonamide derivatives as PI3K/mTOR dual inhibitors. Compound 7k (NSC781406) was identified as a highly potent dual inhibitor, which exhibited potent tumor growth inhibition in the hepatocellular carcinoma BEL-7404 xenograft model. Compound 7k may be a potential therapeutic drug candidate for HCC.
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Affiliation(s)
- Ying Chen
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Ling Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Chao Yang
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Jinsong Han
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Chongqing Wang
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Canhui Zheng
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Youjun Zhou
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Jiaguo Lv
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Yunlong Song
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
| | - Ju Zhu
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
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Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling. Sci Rep 2016; 6:21260. [PMID: 26879559 PMCID: PMC4754634 DOI: 10.1038/srep21260] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 01/20/2016] [Indexed: 12/22/2022] Open
Abstract
This study aimed to determine the expression of progranulin (PGRN) in hepatocellular carcinoma (HCC) cells in response to interleukin 6 (IL-6), a non-cellular component of the tumor microenvironment, and the molecular mechanism of PGRN oncogenic activity in hepatocarcinogenesis. Levels of IL-6 and PGRN were increased and positively correlated in HCC tissues. IL-6 dose- and time-dependently increased PGRN level in HCC cells. IL-6-driven PGRN expression was at least in part mediated by Erk/C/EBPβ signaling, and reduced expression of PGRN impaired IL-6-stimulated proliferation, migration and invasion of HepG2 cells. PGRN activated mammalian target of rapamycin (mTOR) signaling, as evidenced by increased phosphorylation of p70S6K, 4E-BP1, and Akt-Ser473/FoxO1. Inhibition of mTOR signaling with rapamycin, an mTOR signaling inhibitor, disturbed PGRN- or IL-6-mediated proliferation, migration and invasion of HCC cells in vitro. Persistent activation of mTOR signaling by knockdown of TSC2 restored PGRN-knockdown-attenuated pro-proliferation effects of IL-6 in HepG2 cells. In addition, rapamycin treatment in vivo in mice slowed tumor growth stimulated by recombinant human PGRN. Our findings provide a better understanding of the biological activities of the IL-6/PGRN/mTOR cascade in the carcinogenesis of HCC, which may suggest a novel target in the treatment of HCC.
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42
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Lee YJ, Jang BK. The Role of Autophagy in Hepatocellular Carcinoma. Int J Mol Sci 2015; 16:26629-43. [PMID: 26561802 PMCID: PMC4661843 DOI: 10.3390/ijms161125984] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 10/26/2015] [Accepted: 10/30/2015] [Indexed: 12/23/2022] Open
Abstract
Autophagy is a catabolic process involved in cellular homeostasis under basal and stressed conditions. Autophagy is crucial for normal liver physiology and the pathogenesis of liver diseases. During the last decade, the function of autophagy in hepatocellular carcinoma (HCC) has been evaluated extensively. Currently, autophagy is thought to play a dual role in HCC, i.e., autophagy is involved in tumorigenesis and tumor suppression. Recent investigations of autophagy have suggested that autophagy biomarkers can facilitate HCC prognosis and the establishment of therapeutic approaches. In this review, we briefly summarize the current understanding of autophagy and discuss recent evidence for its role in HCC.
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MESH Headings
- AMP-Activated Protein Kinases/genetics
- AMP-Activated Protein Kinases/metabolism
- Animals
- Apoptosis Regulatory Proteins/genetics
- Apoptosis Regulatory Proteins/metabolism
- Autophagy/genetics
- Autophagy-Related Protein-1 Homolog
- Beclin-1
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Liver Neoplasms/diagnosis
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Mechanistic Target of Rapamycin Complex 1
- Mice
- Multiprotein Complexes/genetics
- Multiprotein Complexes/metabolism
- Prognosis
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Signal Transduction
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
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Affiliation(s)
- Yoo Jin Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu 700-712, Korea.
| | - Byoung Kuk Jang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu 700-712, Korea.
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43
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Chen X, Wang Y, Tao J, Shi Y, Gai X, Huang F, Ma Q, Zhou Z, Chen H, Zhang H, Liu Z, Sun Q, Peng H, Chen R, Jing Y, Yang H, Mao Y, Zhang H. mTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice. Gastroenterology 2015; 149:741-52.e14. [PMID: 25980751 DOI: 10.1053/j.gastro.2015.05.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 04/10/2015] [Accepted: 05/06/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Levels of the Golgi protein 73 (GP73) increase during development of hepatocellular carcinoma (HCC); GP73 is a serum marker for HCC. However, little is known about the mechanisms or effects of GP73 during hepatic carcinogenesis. METHODS GP73 was overexpressed from a retroviral vector in HepG2 cells, which were analyzed in proliferation and migration assays. Xenograft tumors were grown from these cells in nude mice. The effects of monoclonal antibodies against GP73 were studied in mice and cell lines. GP73(-/-), GP73(+/-), and GP73(+/+) mice were given injections of diethylnitrosamine to induce liver injury. Levels of GP73 were reduced in MHCC97H, HCCLM3, and HepG2.215 cell lines using small hairpin RNAs; xenograft tumors were grown in mice from MHCC97H-small hairpin GP73 or MHCC97H-vector cells. We used microarray analysis to compare expression patterns between GP73-knockdown and control MHCC97H cells. We studied the effects of the mechanistic target of rapamycin (mTOR) inhibitor rapamycin on GP73 expression in different cancer cell lines and on growth of tumors in mice. Levels of GP73 and activated mTOR were quantified in human HCC tissues. RESULTS Xenograft tumors grown from HepG2 cells that expressed GP73 formed more rapidly and more metastases than control HepG2 cells in mice. A monoclonal antibody against GP73 reduced proliferation of HepG2 cells and growth of xenograft tumors in mice. GP73(-/-) mice had less liver damage after administration of diethylnitrosamine than GP73(+/-) or GP73(+/+) mice. In phosphatase and tensin homolog-null mouse embryonic fibroblasts with constitutively activated mTOR, GP73 was up-regulated compared with control mouse embryonic fibroblasts; this increase was reversed after incubation with rapamycin. Expression of GP73 also was reduced in HCC and other cancer cell lines incubated with rapamycin. mTORC1 appeared to regulate expression of GP73 in cell lines. Activated mTOR correlated with the level of GP73 in human HCC tissues. Injection of rapamycin slowed the growth of xenograft tumors from MHCC97H-vector cells, compared with MHCC97H-short hairpin GP73 cells. CONCLUSIONS Increased expression of GP73 promotes proliferation and migration of HCC cell lines and growth of xenograft tumors in mice. mTORC1 regulates the expression of GP73, so GP73 up-regulation can be blocked with rapamycin. mTOR inhibitors or other reagents that reduce the level or activity of GP73 might be developed for the treatment of HCC.
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Affiliation(s)
- Xinxin Chen
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yanan Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jun Tao
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuzhuo Shi
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaochen Gai
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Fuqiang Huang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Ma
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhenzhen Zhou
- Department of Physiology, Dalian Medical University, Dalian, China
| | - Hongyu Chen
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Haihong Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhibo Liu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Sun
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Haiyong Peng
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Rongrong Chen
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yanling Jing
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Hongbing Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
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Nayeb-Hashemi H, Desai A, Demchev V, Bronson RT, Hornick JL, Cohen DE, Ukomadu C. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development. Biochem Biophys Res Commun 2015. [PMID: 26225745 DOI: 10.1016/j.bbrc.2015.07.078] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC.
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Affiliation(s)
- Hamed Nayeb-Hashemi
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Anal Desai
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Valeriy Demchev
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Roderick T Bronson
- Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Jason L Hornick
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - David E Cohen
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Chinweike Ukomadu
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Yeo W, Chan SL, Mo FKF, Chu CM, Hui JWY, Tong JHM, Chan AWH, Koh J, Hui EP, Loong H, Lee K, Li L, Ma B, To KF, Yu SCH. Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response. BMC Cancer 2015; 15:395. [PMID: 25962426 PMCID: PMC4434865 DOI: 10.1186/s12885-015-1334-6] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 04/22/2015] [Indexed: 02/06/2023] Open
Abstract
Background The oncogenic PI3K/Akt/mTOR pathway is frequently activated in HCC. Data on the mTOR inhibitor, temsirolimus, is limited in HCC patients with concomitant chronic liver disease. The objectives of this study were: (1) In phase I, to determine DLTs and MTD of temsirolimus in HCC patients with chronic liver disease; (2) In phase II, to assess activity of temsirolimus in HCC, and (3) to explore potential biomarkers for response. Methods Major eligibility criteria included histologically confirmed advanced HCC and adequate organ function. In Phase I part of the study, temsirolimus was given weekly in 3-weekly cycle; dose levels were 20 mg (level 1), 25 mg (level 2) and 30 mg (level 3). The MTD was used in the subsequent phase II part; the primary endpoint was PFS and secondary endpoints were response and OS. In addition, exploratory analysis was conducted on pre-treatment tumour tissues to determine stathmin, pS6, pMTOR or p-AKT expressions as potential biomarkers for response. Overall survival and PFS were calculated using the Kaplan-Meier method. Reassessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3. Results The Phase I part consisted of 19 patients, 2 of 6 patients at level 3 experienced DLT; dose level 2 was determined to be the MTD. The phase II part consisted of 36 patients. Amongst 35 assessable patients, there were 1 PR, 20 SD and 14 PD. Overall, the median PFS was 2.83 months (95% C.I. 1.63-5.24). The median OS was 8.89 months (95% C.I. 5.89-13.30). Grade ≥ 3 that occurred in > 10% of patients included thrombocytopenia (4) and hyponatraemia (4). Exploratory analysis revealed that disease stabilization (defined as CR + PR + SD > 12 weeks) in tumours having high and low pMTOR H-scores to be 70% and 29% respectively (OR 5.667, 95% CI 1.129-28.454, p = 0.035). Conclusions In HCC patients with chronic liver disease, the MTD of temsirolimus was 25 mg weekly in a 3-week cycle. The targeted PFS endpoint was not reached. However, further studies to identify appropriate patient subgroup are warranted. Trial registration This study has been registered in ClinicalTrials.gov (Id: NCT00321594) on 1 December 2010.
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Affiliation(s)
- Winnie Yeo
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Stephen L Chan
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Frankie K F Mo
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Cheuk M Chu
- Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Joyce W Y Hui
- Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Joanne H M Tong
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Anthony W H Chan
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Jane Koh
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Edwin P Hui
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Herbert Loong
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Kirsty Lee
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Leung Li
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Brigette Ma
- Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Ka F To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Simon C H Yu
- Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
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Influence of Rictor and Raptor Expression of mTOR Signaling on Long-Term Outcomes of Patients with Hepatocellular Carcinoma. Dig Dis Sci 2015; 60:919-28. [PMID: 25371154 DOI: 10.1007/s10620-014-3417-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 10/27/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Aberrant signaling mediated by the mammalian target of rapamycin (mTOR) occurs at high frequency in hepatocellular carcinoma (HCC), indicating that mTOR is a candidate for targeted therapy. mTOR forms two complexes called mTORC1 (mTOR complexed with raptor) and mTORC2 (mTOR complexed with rictor). There are minor studies of the expression kinetics of mTORC1 and mTORC2 in HCC. METHODS We studied 62 patients with HCC who underwent curative resection. We used univariate and multivariate analyses to identify factors that potentially influence disease and overall survival after hepatectomy. The mRNA and protein levels of mTOR, rictor and raptor in cancer and non-cancer tissues were analyzed using quantitative RT-PCR, immunohistochemistry and Western blotting. RESULTS/CONCLUSION High ratio of the levels of rictor and raptor mRNAs in tumors was identified as independent prognostic indicators for disease-free survival. Low and high levels of preoperative serum albumin and mTOR mRNA in the tumor, respectively, were identified as independent indicators of overall survival. HCC is likely to recur early after hepatic resection in patients with high levels of mTOR and rictor mRNAs and high rictor/raptor ratios in cancer tissues. We conclude that analysis of mTOR expression in cancer tissues represents an essential strategy to predict HCC recurrence after curative treatment.
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Dramatic improvement of proteomic analysis of zebrafish liver tumor by effective protein extraction with sodium deoxycholate and heat denaturation. Int J Anal Chem 2015; 2015:763969. [PMID: 25873971 PMCID: PMC4383156 DOI: 10.1155/2015/763969] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 12/17/2014] [Accepted: 12/17/2014] [Indexed: 12/18/2022] Open
Abstract
Majority of the proteomic studies on tissue samples involve the use of gel-based approach for profiling and digestion. The laborious gel-based approach is slowly being replaced by the advancing in-solution digestion approach. However, there are still several difficulties such as difficult-to-solubilize proteins, poor proteomic analysis in complex tissue samples, and the presence of sample impurities. Henceforth, there is a great demand to formulate a highly efficient protein extraction buffer with high protein extraction efficiency from tissue samples, high compatibility with in-solution digestion, reduced number of sample handling steps to reduce sample loss, low time consumption, low cost, and ease of usage. Here, we evaluated various existing protein extraction buffers with zebrafish liver tumor samples and found that sodium deoxycholate- (DOC-) based extraction buffer with heat denaturation was the most effective approach for highly efficient extraction of proteins from complex tissues such as the zebrafish liver tumor. A total of 4,790 proteins have been identified using shotgun proteomics approach with 2D LC, which to our knowledge is the most comprehensive study for zebrafish liver tumor proteome.
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Duvoux C, Toso C. mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation? Transplant Rev (Orlando) 2015; 29:168-74. [PMID: 26071984 DOI: 10.1016/j.trre.2015.02.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 02/12/2015] [Accepted: 02/17/2015] [Indexed: 02/07/2023]
Abstract
Prevention of hepatocellular carcinoma (HCC) recurrence after liver transplantation is a clinical priority. The importance of the mammalian target of rapamycin (mTOR) pathway in cell growth and survival makes it a logical target for antitumor strategies, as borne out by clinical data in various types of malignancy. A number of studies have indicated that the mTOR inhibitors everolimus and sirolimus suppress cell proliferation and tumor growth in animal models of HCC. Coadministration of an mTOR inhibitor could permit lower dosing of chemotherapeutic agents in HCC management, and trials in non-transplant HCC population are exploring combined used with various agents including sorafenib, the vascular endothelial growth factor inhibitor bevacizumab and conventional agents. In terms of a preventive effect after liver transplantation for HCC, data from retrospective studies and non-randomized prospective analyses in which patients received an mTOR inhibitor with concomitant calcineurin inhibitor therapy have indicated that HCC recurrence rates and overall survival may be improved compared to a standard calcineurin inhibitor regimen. Meta-analyses have supported these findings, but controlled trials are required before any firm conclusions can be drawn. In two of the three randomized trials which have assessed de novo mTOR inhibitor therapy after liver transplantation, there was a numerically lower rate of HCC recurrence by one year post-transplant in patients given an mTOR inhibitor versus the control arm, but absolute numbers were low. Overall, based on the available data from retrospective studies, meta-analyses, and post-hoc assessments of randomized trials, it appears advisable to consider mTOR inhibition-based immunosuppression after transplantation for HCC, particularly in patients who exceed the Milan criteria. Prospective data are awaited.
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Affiliation(s)
- Christophe Duvoux
- Department of Hepatology and Liver Transplant Unit Henri Mondor Hospital, Paris Est University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland.
| | - Christian Toso
- Department of Hepatology and Liver Transplant Unit Henri Mondor Hospital, Paris Est University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland
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Cusimano A, Puleio R, D'Alessandro N, Loria GR, McCubrey JA, Montalto G, Cervello M. Cytotoxic activity of the novel small molecule AKT inhibitor SC66 in hepatocellular carcinoma cells. Oncotarget 2015; 6:1707-22. [PMID: 25596737 PMCID: PMC4359326 DOI: 10.18632/oncotarget.2738] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 11/11/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by limited response to current drug therapies. Here, we report that SC66, a novel AKT inhibitor, reduced cell viability in a dose- and time-dependent manner, inhibited colony formation and induced apoptosis in HCC cells. SC66 treatment led to a reduction in total and phospho-AKT levels. This was associated with alterations in cytoskeleton organization, a reduction in expression levels of E-cadherin, β-catenin and phospho-FAK, together with up-regulation of Snail protein levels. All these alterations were coupled with anoikis cell death induction. In addition, SC66 induced the production of reactive oxygen species (ROS) and DNA damage. Pre-treatment with the ROS scavenger N-Acetyl-cysteine (NAC) prevented SC66-induced cell growth inhibition and anoikis. SC66 significantly potentiated the effects of both conventional chemotherapeutic and targeted agents, doxorubicin and everolimus, respectively. In vivo, SC66 inhibited tumor growth of Hep3B cells in xenograft models, with a similar mechanism observed in the in vitro model. Taken together, these data indicate that the AKT inhibitor SC66 had antitumor effects on HCC cells. This was mediated by ROS production, induction of anoikis-mediated cell death and inhibition of the AKT cell survival pathway. Our results provide a rational basis for the use of SC66 in HCC treatment.
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Affiliation(s)
- Antonella Cusimano
- Institute of Biomedicine and Molecular Immunology “Alberto Monroy”, National Research Council, Palermo, Italy
| | - Roberto Puleio
- Istituto Zooprofilattico Sperimentale della Sicilia “A. Mirri”, Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica, Palermo, Italy
| | - Natale D'Alessandro
- Dipartimento di Scienze per la Promozione della Salute e Materno Infantile “G. D'Alessandro”, Università di Palermo, Palermo, Italy
| | - Guido R. Loria
- Istituto Zooprofilattico Sperimentale della Sicilia “A. Mirri”, Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica, Palermo, Italy
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Giuseppe Montalto
- Institute of Biomedicine and Molecular Immunology “Alberto Monroy”, National Research Council, Palermo, Italy
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy
| | - Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology “Alberto Monroy”, National Research Council, Palermo, Italy
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50
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Castelli G, Burra P, Giacomin A, Vitale A, Senzolo M, Cillo U, Farinati F. Sorafenib use in the transplant setting. Liver Transpl 2014; 20:1021-8. [PMID: 24809799 DOI: 10.1002/lt.23911] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 05/06/2014] [Indexed: 12/14/2022]
Abstract
Liver transplantation (LT) is an established treatment for hepatocellular carcinoma (HCC), and sorafenib (SFN) is a validated treatment for patients harboring advanced tumors. It is still not clear whether the combination of the 2 treatments, with SFN used in the neoadjuvant, adjuvant, or recurrence setting, is useful and cost-effective. This article summarizes the present evidence in favor of and against the use of SFN in the setting of LT for HCC, and it also includes the problem of toxicity, particularly when mammalian target of rapamycin inhibitors, which play a central role in regulating cellular growth and proliferation, are used as immunosuppressants. Overall, the data do not support the use of SFN in the pre- or post-LT setting as adjuvant therapy, and additional studies are needed to reach sound conclusions on the topic.
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Affiliation(s)
- Giulia Castelli
- Department of Surgery, Oncology, and Gastroenterology, Padua University School of Medicine, Padua, Italy
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