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Hernández-Magaña A, Bensussen A, Martínez-García JC, Álvarez-Buylla ER. Engineering principles for rationally design therapeutic strategies against hepatocellular carcinoma. Front Mol Biosci 2024; 11:1404319. [PMID: 38939509 PMCID: PMC11208463 DOI: 10.3389/fmolb.2024.1404319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/23/2024] [Indexed: 06/29/2024] Open
Abstract
The search for new therapeutic strategies against cancer has favored the emergence of rationally designed treatments. These treatments have focused on attacking cell plasticity mechanisms to block the transformation of epithelial cells into cancerous cells. The aim of these approaches was to control particularly lethal cancers such as hepatocellular carcinoma. However, they have not been able to control the progression of cancer for unknown reasons. Facing this scenario, emerging areas such as systems biology propose using engineering principles to design and optimize cancer treatments. Beyond the possibilities that this approach might offer, it is necessary to know whether its implementation at a clinical level is viable or not. Therefore, in this paper, we will review the engineering principles that could be applied to rationally design strategies against hepatocellular carcinoma, and discuss whether the necessary elements exist to implement them. In particular, we will emphasize whether these engineering principles could be applied to fight hepatocellular carcinoma.
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Affiliation(s)
| | - Antonio Bensussen
- Departamento de Control Automático, Cinvestav-IPN, Ciudad de México, Mexico
| | | | - Elena R. Álvarez-Buylla
- Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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Jin C, Bai L, Wang S. Multifunctional nanoparticles for targeting liver cancer stem cells and efficient endocytosis. CHEMICAL PAPERS 2023; 77:1395-1403. [DOI: 10.1007/s11696-022-02566-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/25/2022] [Indexed: 11/03/2022]
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Liu X, Shan W, Li T, Gao X, Kong F, You H, Kong D, Qiao S, Tang R. Cellular retinol binding protein-1 inhibits cancer stemness via upregulating WIF1 to suppress Wnt/β-catenin pathway in hepatocellular carcinoma. BMC Cancer 2021; 21:1224. [PMID: 34775955 PMCID: PMC8590789 DOI: 10.1186/s12885-021-08967-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 10/27/2021] [Indexed: 12/25/2022] Open
Abstract
Background CRBP-1, a cytosolic chaperone of vitamin A, is identified in a serious number of cancers; however, its biological role in hepatocellular carcinoma (HCC) needs to be further explored. The aim of our present study is to explore the roles and mechanisms of CRBP-1 in regulating liver cancer by using in vitro and in vivo biology approaches. Methods The expression level of CRBP-1 was detected using immunohistochemistry in HCC and matching adjacent non-tumorous liver tissues. Following established stable CRBP-1 overexpressed HCC cell lines, the cell growth and tumorigenicity were investigated both in vitro and in vivo. Intracellular retinoic acid was quantified by ELISA. The relationship between CRBP-1 and WIF1 was validated by using dual luciferase and ChIP analyses. Results The low expression of CRBP-1 was observed in HCC tissues compared to the normal liver tissues, while high CRBP-1 expression correlated with clinicopathological characteristics and increased overall survival in HCC patients. Overexpression of CRBP-1 significantly inhibited cell growth and tumorigenicity both in vitro and in vivo. Moreover, overexpression of CRBP-1 suppressed tumorsphere formation and cancer stemness related genes expression in HCC. Mechanically, CRBP-1 inhibited Wnt/β-catenin signaling pathway to suppress cancer cell stemness of HCC. Furthermore, our results revealed that CRBP-1 could increase the intracellular levels of retinoic acid, which induced the activation of RARs/RXRs leading to the transcriptional expression of WIF1, a secreted antagonist of the Wnt/β-catenin signaling pathway, by physically interacting with the region on WIF1 promoter. Conclusion Our findings reveal that CRBP-1 is a crucial player in the initiation and progression of HCC, which provide a novel independent prognostic biomarker and therapeutic target for the diagnosis and treatment of HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08967-2.
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Affiliation(s)
- Xiangye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China.
| | - Wenhua Shan
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Tingting Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Xiaoge Gao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Delong Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Shuxi Qiao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China.
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Carissimi F, Barbaglia MN, Salmi L, Ciulli C, Roccamatisi L, Cordaro G, Mallela VR, Minisini R, Leone BE, Donadon M, Torzilli G, Pirisi M, Romano F, Famularo S. Finding the seed of recurrence: Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment. World J Gastrointest Surg 2021; 13:967-978. [PMID: 34621473 PMCID: PMC8462072 DOI: 10.4240/wjgs.v13.i9.967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/25/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as "seeds" in peripheral blood, then reach the target organ as dormant cells which could be subsequently "awakened" and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.
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Affiliation(s)
- Francesca Carissimi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | | | - Livia Salmi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Cristina Ciulli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Linda Roccamatisi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Giuseppe Cordaro
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Venkata Ramana Mallela
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Biagio Eugenio Leone
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Unit of Pathology, San Gerardo Hospital, Monza 20900, Italy
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Fabrizio Romano
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Medicine and Surgery, University of Milan-Bicocca, Monza 20900, Italy
| | - Simone Famularo
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
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Caetano Oliveira R, Martins R, Abrantes AM, Jesus Â, Teixeira P, Canhoto C, Guerreiro P, Costa B, Silva MR, Tralhão JG, Cipriano MA. Morphophenotypic Classification of Hepatocellular Carcinoma: the Biliary/Stem Cell Subgroup and Worst Outcome-Implications on Patient Selection. J Gastrointest Surg 2021; 25:698-707. [PMID: 32410177 DOI: 10.1007/s11605-020-04611-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 04/11/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the third cause of cancer-related death. Current clinical/pathological criteria contribute to risk stratification, but are far from the desired on individualized medicine. Recently, HCC classifications have been published based on immunohistochemical and morphological features. METHODS A retrospective review of patients submitted to surgical treatment-partial hepatectomy (PH) or liver transplantation (LT), with pathological diagnosis of HCC, in a 9-year period (2007-2015) was performed. RESULTS Applying the classification of Srivastava et al. (#1), based on the expression of CD31, p53, AFP and CD44, tumour size and presence of vascular invasion, HCC were categorized as low- and high-risk HCC. With the classification of Tsujikawa et al. (#2), HCC were classified into biliary/stem cell marker positive, Wnt signalling positive and the "all negative" HCC, according to the expression of CK19, SALL4, β-catenin glutamine synthetase, EpCAM and p53. There were sixty-six patients (53 males; 13 females), with median age of 64.5 ± 9.46 years (range 38-86), with solitary HCC, comprehending 37 PH (56.1%) and 29 LT (43.9%). The mean overall survival (OS) was 75.4 ± 6.9 months. Biliary/stem cell type of HCC was a predictive factor of worse OS on the overall population (24.4 versus 78.3 months, p = 0.032) and in PH cohort (11.5 versus 64.01 months, p = 0.016), on uni- and multivariate analyses. CONCLUSION These results support the relevance of a risk stratification classification of HCC. Classification #2 seems adequate to our reality demonstrating OS impact, allowing its application in future biopsies, prompting individualized medicine.
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Affiliation(s)
- Rui Caetano Oliveira
- Serviço de Anatomia Patológica, Pathology Department, Centro Hospitalar e Universitário de Coimbra, Piso-3, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
- Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
| | - Ricardo Martins
- Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Pediatric and Adult Liver Transplantation Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Ana Margarida Abrantes
- Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Ângela Jesus
- Serviço de Anatomia Patológica, Pathology Department, Centro Hospitalar e Universitário de Coimbra, Piso-3, Praceta Mota Pinto, 3000-075, Coimbra, Portugal
| | - Paulo Teixeira
- Serviço de Anatomia Patológica, Pathology Department, Centro Hospitalar e Universitário de Coimbra, Piso-3, Praceta Mota Pinto, 3000-075, Coimbra, Portugal
| | - Carolina Canhoto
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Pedro Guerreiro
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Beatriz Costa
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Mário Rui Silva
- Serviço de Anatomia Patológica, Pathology Department, Centro Hospitalar e Universitário de Coimbra, Piso-3, Praceta Mota Pinto, 3000-075, Coimbra, Portugal
| | - José Guilherme Tralhão
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Pediatric and Adult Liver Transplantation Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Maria Augusta Cipriano
- Serviço de Anatomia Patológica, Pathology Department, Centro Hospitalar e Universitário de Coimbra, Piso-3, Praceta Mota Pinto, 3000-075, Coimbra, Portugal
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SOX9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma. Biomed Pharmacother 2020; 129:110315. [PMID: 32554246 DOI: 10.1016/j.biopha.2020.110315] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 04/16/2020] [Accepted: 05/21/2020] [Indexed: 12/16/2022] Open
Abstract
Sorafenib is a multi-kinase blocker and one of the few suggested drug treatments for aggressive hepatocellular carcinoma (HCC) patients. However, drug resistance to sorafenib may often occur over time and cause further tumor aggression. Recently, cancer stem cells were found in HCC and were speculated to be involved in tumor progression. SOX9 is highly expressed in HCC cancer stem cells and promotes cell proliferation and self-renewal. Meanwhile, HCC patients with higher SOX9 expression show poorer prognosis. Whether SOX9 is involved in sorafenib resistance in HCC is still unclear. Here, we found that sorafenib treatment increased the proportion of SOX9 positive cells in HCC cell lines. Overexpression of exogenous SOX9 in HCC increased sorafenib resistance both in vitro and in vivo, whereas down-regulation led to inhibition of sorafenib resistance. Knock-down of SOX9 by RNA interference caused down-regulation of downstream genes, including ATP binding cassette subfamily G member 2 (ABCG2). The drug resistance to sorafenib caused by SOX9 overexpression could be ameliorated by ABCG2 inhibition in HCC cell lines. In the cohort of patients taken sorafenib, we found that patients with lower SOX9 expression had more prolonged overall survival (OS) and progression-free survival (PFS). Univariate and multivariate Cox analysis shows that SOX9 expression exerts as an independent risk factor for the OS and PFS of HCC patients with sorafenib treatment. These findings demonstrate that SOX9 enhances sorafenib resistance and may regulate this process by modulating ABCG2 expression.
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Balcik-Ercin P, Cetin M, Yalim-Camci I, Uygur T, Yagci T. Hepatocellular Carcinoma Cells with Downregulated ZEB2 Become Resistant to Resveratrol by Concomitant Induction of ABCG2 Expression. Mol Biol 2020. [DOI: 10.1134/s0026893320010033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Chen A, Xu C, Luo Y, Liu L, Song K, Deng G, Yang M, Cao J, Yuan L, Li X. Disruption of crosstalk between LX-2 and liver cancer stem-like cells from MHCC97H cells by DFOG via inhibiting FOXM1. Acta Biochim Biophys Sin (Shanghai) 2019; 51:1267-1275. [PMID: 31750892 DOI: 10.1093/abbs/gmz129] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic stellate cell (HSC) line LX-2 is activated by liver cancer stem-like cells (LCSLCs) and produces various cytokines that make up most of the hepatocellular carcinoma (HCC) microenvironment. The new genistein derivative, 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), shows anticancer effects in multiple malignancies by controlling forkhead box M1 (FOXM1). In this study, we aimed to assess whether DFOG disrupts the crosstalk between human HSC LX-2 cells and LCSLCs. Distinct generations of MHCC97H-derived spheres were obtained with the second generation considered as LCSLCs which displayed enhanced self-renewal ability and elevated expression levels of CD133, CD44, and EpCAM proteins, as well as tumorigenicity, as revealed by colony formation assay in vitro and tumorigenicity assay in vivo. LX-2 and MHCC97H cells were co-cultured with/without DFOG (1, 5, and 10 μM, respectively) using the transwell system. FOXM1 overexpression and/or knockdown were employed for mechanistic investigations. Our results suggested that Co-CM promoted LX-2 cell transformation into liver cancer-associated HSCs. Meanwhile, FOXM1 was up-regulated and the level of hepatocyte growth factor (HGF) was increased in LX-2 cells and in the supernatant after Co-CM stimulation. Sphere and colony formation abilities in MHCC97H cells, and protein levels of CD133, CD44, and EpCAM, were also markedly elevated. DFOG dose-dependently inhibited the above effects, similar to FOXM1 knockdown in LX-2 cells. FOXM1 overexpression reversed the inhibitory effects of DFOG or FOXM1 knockdown or both on LX-2 cell activation and LCSLC feature induction in MHCC97H cells by LCSLC/LX-2 co-culture. This study demonstrated that DFOG disrupts the crosstalk between HSCs and LCSLCs to suppress LCSLC features via down-regulating FOXM1 expression and reducing HGF secretion in HSCs.
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Affiliation(s)
- A Chen
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Chang Xu
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Yimin Luo
- Pathology department, Medical College, University of South China, Hengyang 421001, China
| | - Lihua Liu
- Department of Pharmacology, Shenzhen People's Hospital 2nd Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Kun Song
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Guangqi Deng
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Mengjie Yang
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Jianguo Cao
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Liming Yuan
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Xiang Li
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
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Farcas M, Gavrea AA, Gulei D, Ionescu C, Irimie A, Catana CS, Berindan-Neagoe I. SIRT1 in the Development and Treatment of Hepatocellular Carcinoma. Front Nutr 2019; 6:148. [PMID: 31608282 PMCID: PMC6773871 DOI: 10.3389/fnut.2019.00148] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 08/27/2019] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Current treatment options for inoperable HCCs have decreased therapeutic efficacy and are associated with systemic toxicity and chemoresistance. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide–dependent enzyme that is frequently overexpressed in HCC, where it promotes tumorigenicity, metastasis, and chemoresistance. SIRT1 also maintains the tumorigenic and self-renewal proprieties of liver cancer stem cells. Multiple tumor-suppressive microRNAs (miRNAs) are downregulated in HCC and, as a consequence, permit SIRT1-induced tumorigenicity. However, either directly targeting SIRT1, combining conventional chemotherapy with SIRT1 inhibitors, or upregulating tumor-suppressive miRNAs may improve therapeutic efficacy and patient outcomes. Here, we present the interaction between SIRT1, miRNAs, and liver cancer stem cells and discuss the consequences of their interplay for the development and treatment of HCC.
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Affiliation(s)
- Marius Farcas
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Andrei-Alexandru Gavrea
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Calin Ionescu
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,5th Surgical Department, Municipal Hospital, Cluj-Napoca, Romania
| | - Alexandru Irimie
- 11th Department of Oncological Surgery and Gynecological Oncology, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania.,Department of Surgery, The Oncology Institute "Prof. Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
| | - Cristina S Catana
- Department of Medical Biochemistry, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
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Abdel-Salam IM, Awadein NES, Ashour M. Cytotoxicity of Luffa cylindrica (L.) M.Roem. extract against circulating cancer stem cells in hepatocellular carcinoma. JOURNAL OF ETHNOPHARMACOLOGY 2019; 229:89-96. [PMID: 30287196 DOI: 10.1016/j.jep.2018.09.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 09/22/2018] [Accepted: 09/26/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Luffa cylindrica (L.) M.Roem. has been recognized as traditional medicine for the treatment of various diseases like inflammatory diseases, diarrhea and viral infections. The usual parts used include fruit, seeds and leaves. AIM OF THE STUDY To evaluate the anticancer activity of the hot water extract of the whole plant of Luffa cylindrica using circulating tumor cells and cancer stem cells isolated from the peripheral blood of hepatocellular carcinoma patients in vitro. MATERIALS AND METHODS Seventy five adult patients who reported as stage II and III Hepatocellular carcinoma were selected. Blood samples were withdrawn and the circulating tumor cells were isolated from the whole blood. Tumor cells and cancer stem cells were detected and isolated by flow cytometric techniques. The isolated cell types were cultured and propagated in the tissue culture facility, the extract was tested on the isolated cells. RESULTS Luffa cylindrica hot water extract has shown cytotoxic activity against circulating tumor cells of hepatocellular carcinoma especially the cells sub-population CD133+/CD44+ with little effect among CD133+/CD44- sub-population. CONCLUSION Hot water extract of Luffa cylindrica whole plant could decrease the ratio of cancer stem cells in blood of HCC patients and may be used to minimize recurrence and metastasis in hepatocellular carcinoma patients.
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Affiliation(s)
| | | | - Mohamed Ashour
- Medical Research Department, National Institute of Occupational Safety and Health, Egypt, 156 - EL Hegas Street, Cairo, Egypt.
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Lin Y, Wen Q, Guo L, Wang H, Sui G, Sun Z. A network meta-analysis on the efficacy and prognosis of different interventional therapies for early-stage hepatocellular carcinoma. Int J Hyperthermia 2018; 35:450-462. [PMID: 30354777 DOI: 10.1080/02656736.2018.1507047] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/29/2018] [Accepted: 07/29/2018] [Indexed: 02/07/2023] Open
Abstract
PURPOSE It is unclear which kind of interventional therapies is the best when treating early-stage hepatocellular carcinoma (HCC). We conducted Bayesian network meta-analyses to compare local tumor progression (LTP), total tumor recurrence and survival rates and to rank the best intervention arm. MATERIALS AND METHODS A literature search of Pubmed, Embase, Cochrane library and Clinicaltrials.gov was conducted and randomized controlled trials (RCTs) comparing the outcomes of interventional therapies on early-stage HCC were enrolled. The quality assessment was conducted using Cochrane Collaboration's tool, while the outcome synthesis of the network meta-analysis was conducted using R-3.3.4 software. RESULTS A total of 35 RCTs were enrolled for further analysis. Using network meta-analysis, it was demonstrated that radiofrequency ablation (RFA) plus adjuvant therapies achieved the best performance in decreasing the LTP rate in early-stage HCC, while hepatic resection ranked as the best arm among all the interventional techniques for LTP at 3 years. Meanwhile, hepatic resection and RFA plus adjuvant therapies were the top two best arms in decreasing total recurrence. Furthermore, RFA plus adjuvant therapeutics ranked the best in achieving overall survival outcome, followed by hepatic resection. For disease-free survival, hepatic resection was the best, while for LTP-free survival, the difference among the included treatments was not significant. CONCLUSIONS Our network meta-analysis showed that RFA-based adjuvant therapies might be the most effective interventions in achieving the best outcomes, while hepatic resection exhibited the best performance in several situations in treating early-stage HCC. More RCTs are needed to draw more solid conclusions.
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Affiliation(s)
- Yuanqiang Lin
- a Department of Ultrasonography , China-Japan Union Hospital of Jilin University , Changchun , Jilin Province , China
| | - Qiang Wen
- b Department of Nuclear Medicine , China-Japan Union Hospital of Jilin University , Changchun , Jilin Province , China
| | - Li Guo
- c Department of Material Supply , China-Japan Union Hospital of Jilin University , Changchun , Jilin Province , China
| | - Hui Wang
- a Department of Ultrasonography , China-Japan Union Hospital of Jilin University , Changchun , Jilin Province , China
| | - Guoqing Sui
- a Department of Ultrasonography , China-Japan Union Hospital of Jilin University , Changchun , Jilin Province , China
| | - Zhixia Sun
- a Department of Ultrasonography , China-Japan Union Hospital of Jilin University , Changchun , Jilin Province , China
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Saluja TS, Ali M, Mishra P, Kumar V, Singh SK. Prognostic Value of Cancer Stem Cell Markers in Potentially Malignant Disorders of Oral Mucosa: A Meta-analysis. Cancer Epidemiol Biomarkers Prev 2018; 28:144-153. [DOI: 10.1158/1055-9965.epi-18-0672] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/15/2018] [Accepted: 10/05/2018] [Indexed: 11/16/2022] Open
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13
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García-Vilas JA, Medina MÁ. Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications. World J Gastroenterol 2018; 24:3695-3708. [PMID: 30197476 PMCID: PMC6127652 DOI: 10.3748/wjg.v24.i33.3695] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/28/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.
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Affiliation(s)
| | - Miguel Ángel Medina
- Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Andalucía Tech, Universidad de Málaga, Málaga 29071, Spain
- Unidad 741 de CIBER “de Enfermedades Raras” (CIBERER), Málaga 29071, Spain
- Institute of Biomedical Research in Málaga, Málaga 29071, Spain
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14
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Hernández-Camarero P, Jiménez G, López-Ruiz E, Barungi S, Marchal JA, Perán M. Revisiting the dynamic cancer stem cell model: Importance of tumour edges. Crit Rev Oncol Hematol 2018; 131:35-45. [PMID: 30293704 DOI: 10.1016/j.critrevonc.2018.08.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/22/2018] [Indexed: 02/07/2023] Open
Abstract
The lack of an effective treatment against cancer is not only due to its huge heterogeneity, but also to the fact that we don't have an answer to the question on how cancer originates. Among the proposed models to explain the development of cancer, the hierarchical model has been widely accepted. Nevertheless, this model fails to explain several experimental observations such as the cancer stem cells (CSCs) location inside a tumour or the differences between primary and metastatic tumours. Moreover, increasing evidence shows that the CSC phenotype is not a rigid state. Here, we present a critical review on the assumed tumour development models emphasizing the relevance of the dynamic and changing nature of cancer and the CSCs population in which the tumour microenvironment plays a crucial role and we propose a new model of tumour origin that could have an impact on new therapeutic strategies.
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Affiliation(s)
| | - Gema Jiménez
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, E- 18016, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, E-18071, Spain
| | - Elena López-Ruiz
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, E- 18016, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, E-18071, Spain
| | - Shivan Barungi
- Department of Health Sciences, University of Jaén, Jaén E-23071, Spain
| | - Juan Antonio Marchal
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, E- 18016, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, E-18071, Spain.
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Jaén E-23071, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain.
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15
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Wu L, Sun B, Lin X, Liu C, Qian H, Chen L, Yang Y, Shen F, Su C. I 131 reinforces antitumor activity of metuximab by reversing epithelial-mesenchymal transition via VEGFR-2 signaling in hepatocellular carcinoma. Genes Cells 2017; 23:35-45. [PMID: 29210217 DOI: 10.1111/gtc.12545] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 10/31/2017] [Indexed: 02/06/2023]
Abstract
CD147 is highly expressed in hepatocellular carcinoma (HCC) and associated with the invasion and metastasis of HCC. The efficacy of I131 -metuximab (I131 -mab), a newly developed agent that targets CD147, as a radio-immunotherapy for local HCC, has been validated in clinical practice. However, the synergistic anticancer activity and molecular mechanism of different conjugated components within I131 -mab remain unclear. In this study, the cytological experiments proved that I131 -mab inhibited the proliferation and invasion of HCC cells. Mechanically, this inhibition effect was mainly mediated by the antibody component part of I131 -mab, which could reverse the epithelial-mesenchymal transition of HCC cells partially by suppressing the phosphorylation of VEGFR-2. The inhibitory effect of I131 on HCC cell proliferation and invasion is limited, whereas, when combined with metuximab, I131 significantly enhanced the sensitivity of HCC cells to CD147-mab and consequently reinforced the anticancer effects of CD147-mab, suggesting that the two components of I131 -mab exerted synergistic anti-HCC capability. Furthermore, the experiments using SMMC-7721 human HCC xenografts in athymic nude mice showed that I131 -mab and CD147-mab significantly inhibited the growth of xenograft tumors and that I131 -mab was more effective than CD147-mab. In conclusion, our results elucidated the mechanism underlying the anti-HCC effects of I131 -mab and provided a theoretical foundation for the clinical application of I131 -mab.
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Affiliation(s)
- Lu Wu
- Department of Hepatic Surgery & Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Bin Sun
- Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China
| | - Xuejing Lin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China
| | - Chunying Liu
- Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China
| | - Haihua Qian
- Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China
| | - Lei Chen
- Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China
| | - Yefa Yang
- Department of Hepatic Surgery & Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery & Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Changqing Su
- Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China
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