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Wan LH, Mao BJ, Wang B. Relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy: A meta-analysis. World J Clin Oncol 2025; 16:102611. [DOI: 10.5306/wjco.v16.i5.102611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/01/2025] [Accepted: 04/01/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Many studies have found that sarcopenia is related to the survival of patients with liver cancer, which may lead to worse prognosis.
AIM To investigate the relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy by meta-analysis.
METHODS PubMed, Embase, Cochrane Library, and Web of Science were searched for clinical studies on the relationship between skeletal muscle index (SMI) and the prognosis of patients with liver cancer receiving targeted therapy from inception to March 1, 2022. Meta-analysis and sensitivity analysis of the data were performed using Stata 16.0 software.
RESULTS A total of 6877 studies were searched, and finally 12 articles with 1715 cases were included. Meta-analysis result of 8 articles showed that compared with non-low SMI group, the overall survival (OS) of patients with liver cancer in the low SMI group was significantly shorter (hazard ratio = 1.60, 95% confidence interval: 1.44-1.77, P = 0.000). Meta-analysis result of 4 articles showed that, compared with low SMI group, patients in the non-low SMI group had longer OS (hazard ratio = 0.59, 95% confidence interval: 0.38-0.91, P = 0.018).
CONCLUSION Skeletal muscle mass is positively correlated with OS in patients with liver cancer receiving targeted therapy.
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Affiliation(s)
- Ling-Hong Wan
- Department of Gastroenterology, Daping Hospital, Army Medical University, Third Military Medical University, Chongqing 400042, China
| | - Bi-Jing Mao
- Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Bin Wang
- Department of Oncology, The Seventh People’s Hospital of Chongqing, Affiliated Central Hospital of Chongqing University of Technology, Chongqing 400054, China
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Tang L, Yang X, He L, Zhu C, Chen Q. Preclinical advance in nanoliposome-mediated photothermal therapy in liver cancer. Lipids Health Dis 2025; 24:31. [PMID: 39891269 PMCID: PMC11783920 DOI: 10.1186/s12944-024-02429-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 12/31/2024] [Indexed: 02/03/2025] Open
Abstract
Liver cancer is a highly lethal malignant tumor with a high incidence worldwide. Therefore, its treatment has long been a focus of medical research. Although traditional treatment methods such as surgery, radiotherapy, and chemotherapy have increased the survival rate of patients, their efficacy remains unsatisfactory owing to the nonspecific distribution of drugs, high toxicity, and drug resistance of tumor tissues. In recent years, the application of nanotechnology in the medical field has opened a new avenue for the treatment of liver cancer. Among these treatment methods, photothermal therapy (PTT) based on nanoliposomes has attracted wide attention owing to its unique targeting and high efficiency. This article reviews the latest preclinical research progress of nanoliposome-based PTT for liver cancer and its metastasis, discusses the preclinical challenges in this field, and proposes directions for improvement, with the aim of improving the effectiveness of liver cancer treatment.
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Affiliation(s)
- Lixuan Tang
- School of Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Xiao Yang
- The department of oncology, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Liwen He
- School of Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Chaogeng Zhu
- The department of hepatobiliary pancreatic hernia surgery, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410208, China.
| | - Qingshan Chen
- The department of hepatobiliary pancreatic hernia surgery, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410208, China.
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3
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Patresan J, Patel H, Chandrasekaran K, Reynolds G. Current Treatment Paradigm and Approach to Advanced Hepatocellular Carcinoma. Cureus 2024; 16:e75471. [PMID: 39791050 PMCID: PMC11717138 DOI: 10.7759/cureus.75471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2024] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common forms of primary liver cancer worldwide. Herein, we present a review article that provides a broad overview of the current landscape of HCC, including the etiology, potential risk factors, and molecular pathways that can serve as potential therapeutic targets. The risk factors tend to vary depending on the geographic distribution; hepatitis B-induced cirrhosis and HCC occur more frequently in Asia and Sub-Saharan Africa, whereas metabolic disorders are the culprits in Western Europe and the Americas. The exact molecular alterations that drive hepatocarcinogenesis have yet to be elucidated; however, a complex interplay exists between oxidative stress and chronic inflammation. Diagnostic modalities such as tri-phasic MRI or CT also have distinct patterns for HCC, which aid significantly in diagnosis. Furthermore, the review aims to highlight treatment strategies, including transplantation, locoregional radiation therapies, and interventional radiological techniques such as chemotherapy or radioembolization. Finally, systemic therapies will be discussed, taking advantage of molecular pathways that influence cellular proliferation and survival as well as immunotherapy.
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Affiliation(s)
- John Patresan
- Hematology and Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, USA
| | - Harsh Patel
- Gastroenterology and Hepatology, New York-Presbyterian Brooklyn Methodist Hospital, Weill Cornell Medicine, Brooklyn, USA
| | - Karthik Chandrasekaran
- Internal Medicine and Gastroenterology, New York-Presbyterian Brooklyn Methodist Hospital, Weill Cornell Medicine, Brooklyn, USA
| | - Griffin Reynolds
- Hematology and Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, USA
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Xu K, Xiang C, Yu Z, Li J, Liu C. Survival Benefit of Synchronous Lenvatinib Combined PD-1 Inhibitors for Advanced Hepatocellular Carcinoma Beyond Oligometastasis. Immunotargets Ther 2024; 13:305-317. [PMID: 38910584 PMCID: PMC11192195 DOI: 10.2147/itt.s458700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 06/05/2024] [Indexed: 06/25/2024] Open
Abstract
Purpose Strategies therapy for hepatocellular carcinoma (HCC) beyond oligometastasis are limited. The optimal sequence of systemic treatment for advanced HCC is not yet clear. Our study aims to evaluate the effectiveness of simultaneous lenvatinib combined PD-1 inhibitor on advanced HCC beyond oligometastasis. Patients and Methods A total of 232 patients were enrolled in our retrospective study. Patients divided into three groups. (a) Lenvatinib plus simultaneous PD-1 inhibitor (Simultaneous group, n=58); (b) patients received PD-1 inhibitor before the tumor progression with continued lenvatinib administration (Before PD group, n=77); (c) patients received PD-1 inhibitor after the tumor progression (After PD group, n=97). To analyze overall survival (OS) and progression-free survival (PFS) among the three groups. Results The estimated 6-, 12-, 18- and 24-mon OS for Simultaneous group patients were 100%, 93.1%, 63.4%, 48.3%, whereas the OS rates were 100%, 78%, 36.3%, 23.6% in Before PD group, and 99%, 61.2%, 22.1%, 7.5% in After PD group. The OS rates were obviously improved with the use of simultaneous PD-1 inhibitor among the three groups (P <0.001). The estimated 3-, 6-, 9- and 12-month PFS rates for patients were 89.6%, 44.8%, 24.6%, 6% in After PD group, 90.9%, 59.7%, 27.3%, 12.4% in Before PD group and 98.3%, 81%, 51.7%, 39.7% in Simultaneous group, respectively. PFS rate was significantly different among the three groups (P <0.001). Conclusion Synchronous administration of lenvatinib and PD-1 inhibitors improved survival rate significantly. The synchronous combination could represent a promising strategy in HCC beyond oligometastasis.
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Affiliation(s)
- Kaiwu Xu
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, 410005, People’s Republic of China
| | - Cailing Xiang
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, 410005, People’s Republic of China
| | - Zhige Yu
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, 410005, People’s Republic of China
| | - Jia Li
- Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, 410005, People’s Republic of China
| | - Changjun Liu
- Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, 410005, People’s Republic of China
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5
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Cai Q, Wu D, Shen Y, Li S, Liu L, Liu D, Li Y, Chen X, Wang L, Zheng J. Exploring the mechanism of LncRNA CASC15 affecting hepatocellular carcinoma through miRNA. Medicine (Baltimore) 2024; 103:e35859. [PMID: 38306545 PMCID: PMC10843454 DOI: 10.1097/md.0000000000035859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 10/09/2023] [Indexed: 02/04/2024] Open
Abstract
This study aimed to determine the potential mechanisms through which long noncoding (Lnc) RNA cancer susceptibility candidate 15 (CASC15) affects hepatocellular carcinoma (HCC). We retrieved HCC RNA-seq and clinical information from the UCSC Xena database. The differential expression (DE) of CASC15 was detected. Overall survival was analyzed using Kaplan-Meier (K-M) curves. Molecular function and signaling pathways affected by CASC15 were determined using Gene Set Enrichment Analysis. Associations between CASC15 and the HCC microenvironment were investigated using immuno-infiltration assays. A differential CASC15-miRNA-mRNA network and HCC-specific CASC15-miRNA-mRNA ceRNA network were constructed. The overexpression of CASC15 in HCC tissues was associated with histological grade, clinical stage, pathological T stage, poor survival, more complex immune cell components, and 12 immune checkpoints. We identified 27 DE miRNAs and 270 DE mRNAs in the differential CASC15-miRNA-mRNA network, and 10 key genes that were enriched in 12 cancer-related signaling pathways. Extraction of the HCC-specific CASC15-miRNA-mRNA network revealed that IGF1R, MET, and KRAS were associated with HCC progression and occurrence. Our bioinformatic findings confirmed that CASC15 is a promising prognostic biomarker for HCC, and elevated levels in HCC are associated with the tumor microenvironment. We also constructed a disease-specific CASC15-miRNA-mRNA regulatory ceRNA network that provides a new perspective for the precise indexing of patients with elevated levels of CASC15.
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Affiliation(s)
- Qingshan Cai
- Department of Hepatobiliary Surgery, Tangshan Central Hospital, Hebei Province, China
| | - Dongyang Wu
- Department of Hepatobiliary Surgery, Tangshan Central Hospital, Hebei Province, China
| | - Yueling Shen
- Department of Otolaryngology, Qian ‘an People’s Hospital, Hebei Province, China
| | - Shudong Li
- Department of Hepatobiliary Surgery, Tangshan Central Hospital, Hebei Province, China
| | - Liyou Liu
- Department of Hepatobiliary Surgery, Tangshan Central Hospital, Hebei Province, China
| | - Dong Liu
- Department of Hepatobiliary Surgery, Tangshan Central Hospital, Hebei Province, China
| | - Yong Li
- Department of General Surgery, Tangshan Eighth Hospital, Hebei Province, China
| | - Xiaonan Chen
- Hepatobiliary Surgery Department, Tangshan Gongren Hospital, Hebei Province, China
| | - Limin Wang
- Department of Hepatobiliary Surgery, Tangshan Central Hospital, Hebei Province, China
| | - Jianxing Zheng
- Department of Hepatobiliary Surgery, Tangshan Central Hospital, Hebei Province, China
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Gajbhiye KR, Salve R, Narwade M, Sheikh A, Kesharwani P, Gajbhiye V. Lipid polymer hybrid nanoparticles: a custom-tailored next-generation approach for cancer therapeutics. Mol Cancer 2023; 22:160. [PMID: 37784179 PMCID: PMC10546754 DOI: 10.1186/s12943-023-01849-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/23/2023] [Indexed: 10/04/2023] Open
Abstract
Lipid-based polymeric nanoparticles are the highly popular carrier systems for cancer drug therapy. But presently, detailed investigations have revealed their flaws as drug delivery carriers. Lipid polymer hybrid nanoparticles (LPHNPs) are advanced core-shell nanoconstructs with a polymeric core region enclosed by a lipidic layer, presumed to be derived from both liposomes and polymeric nanounits. This unique concept is of utmost importance as a combinable drug delivery platform in oncology due to its dual structured character. To add advantage and restrict one's limitation by other, LPHNPs have been designed so to gain number of advantages such as stability, high loading of cargo, increased biocompatibility, rate-limiting controlled release, and elevated drug half-lives as well as therapeutic effectiveness while minimizing their drawbacks. The outer shell, in particular, can be functionalized in a variety of ways with stimuli-responsive moieties and ligands to provide intelligent holding and for active targeting of antineoplastic medicines, transport of genes, and theragnostic. This review comprehensively provides insight into recent substantial advancements in developing strategies for treating various cancer using LPHNPs. The bioactivity assessment factors have also been highlighted with a discussion of LPHNPs future clinical prospects.
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Affiliation(s)
- Kavita R Gajbhiye
- Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth, Erandwane, Pune, 411038, India
| | - Rajesh Salve
- Nanobioscience, Agharkar Research Institute, Pune, 411038, India
- Savitribai Phule Pune University, Pune, 411007, India
| | - Mahavir Narwade
- Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth, Erandwane, Pune, 411038, India
| | - Afsana Sheikh
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
- Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
| | - Virendra Gajbhiye
- Nanobioscience, Agharkar Research Institute, Pune, 411038, India.
- Savitribai Phule Pune University, Pune, 411007, India.
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7
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Manzi J, Hoff CO, Ferreira R, Glehn-Ponsirenas R, Selvaggi G, Tekin A, O'Brien CB, Feun L, Vianna R, Abreu P. Cell-Free DNA as a Surveillance Tool for Hepatocellular Carcinoma Patients after Liver Transplant. Cancers (Basel) 2023; 15:3165. [PMID: 37370775 PMCID: PMC10296050 DOI: 10.3390/cancers15123165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/30/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
The liver is the world's sixth most common primary tumor site, responsible for approximately 5% of all cancers and over 8% of cancer-related deaths. Hepatocellular carcinoma (HCC) is the predominant type of liver cancer, accounting for approximately 75% of all primary liver tumors. A major therapeutic tool for this disease is liver transplantation. Two of the most significant issues in treating HCC are tumor recurrence and graft rejection. Currently, the detection and monitoring of HCC recurrence and graft rejection mainly consist of imaging methods, tissue biopsies, and alpha-fetoprotein (AFP) follow-up. However, they have limited accuracy and precision. One of the many possible components of cfDNA is circulating tumor DNA (ctDNA), which is cfDNA derived from tumor cells. Another important component in transplantation is donor-derived cfDNA (dd-cfDNA), derived from donor tissue. All the components of cfDNA can be analyzed in blood samples as liquid biopsies. These can play a role in determining prognosis, tumor recurrence, and graft rejection, assisting in an overall manner in clinical decision-making in the treatment of HCC.
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Affiliation(s)
- Joao Manzi
- School of Medicine, University of Sao Paulo, Sao Paulo 05508-900, Brazil
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Camilla O Hoff
- School of Medicine, University of Sao Paulo, Sao Paulo 05508-900, Brazil
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Raphaella Ferreira
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | | | - Gennaro Selvaggi
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Akin Tekin
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Christopher B O'Brien
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Lynn Feun
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Rodrigo Vianna
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Phillipe Abreu
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
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Qu L, Liu Y, Deng J, Ma X, Fan D. Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma. J Pharm Anal 2023; 13:463-482. [PMID: 37305788 PMCID: PMC10257150 DOI: 10.1016/j.jpha.2023.03.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/17/2023] [Accepted: 03/21/2023] [Indexed: 06/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Ginsenoside Rk3, an important and rare saponin in heat-treated ginseng, is generated from Rg1 and has a smaller molecular weight. However, the anti-HCC efficacy and mechanisms of ginsenoside Rk3 have not yet been characterized. Here, we investigated the mechanism by which ginsenoside Rk3, a tetracyclic triterpenoid rare ginsenoside, inhibits the growth of HCC. We first explored the possible potential targets of Rk3 through network pharmacology. Both in vitro (HepG2 and HCC-LM3 cells) and in vivo (primary liver cancer mice and HCC-LM3 subcutaneous tumor-bearing mice) studies revealed that Rk3 significantly inhibits the proliferation of HCC. Meanwhile, Rk3 blocked the cell cycle in HCC at the G1 phase and induced autophagy and apoptosis in HCC. Further proteomics and siRNA experiments showed that Rk3 regulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit HCC growth, which was validated by molecular docking and surface plasmon resonance. In conclusion, we report the discovery that ginsenoside Rk3 binds to PI3K/AKT and promotes autophagy and apoptosis in HCC. Our data strongly support the translation of ginsenoside Rk3 into novel PI3K/AKT-targeting therapeutics for HCC treatment with low toxic side effects.
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Affiliation(s)
- Linlin Qu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China
- Xi'an Giant Biotechnology Co., Ltd., Xi'an, 710076, China
| | - Yannan Liu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China
| | - Jianjun Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China
| | - Xiaoxuan Ma
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, China
- Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China
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Madani SP, Mirza-Aghazadeh-Attari M, Mohseni A, Pawlik T, Kamel IR. Diffuse infiltrative hepatocellular carcinoma: Multimodality imaging manifestations. J Surg Oncol 2023; 127:385-393. [PMID: 36374195 DOI: 10.1002/jso.27138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, being the third most common cause of cancer-related death globally. HCC most frequently develops in the context of hepatic cirrhosis. HCC can manifest as various morphologic subtypes. Each pattern exhibits distinct behaviors in terms of imaging features, disease progression, response to therapy, and prognosis. While the nodular pattern is the most frequent subtype, infiltrative HCC is the least prevalent and makes up about 8%-20% of all HCC cases. Infiltrative HCC manifests as small tumor nodules that often spread across the entire liver or across a hepatic segment/lobe and is not identified as a focal tumor. On ultrasonography, infiltrative HCC presents as a markedly heterogeneous area with ill-defined echotexture, making it difficult to distinguish from background hepatic cirrhosis. On magnetic resonance imaging (MRI), infiltrating HCC typically manifests as a mild, poorly defined hepatic region with heterogeneous or homogenous aberrant signal intensity. Specifically, on T1-weighted MRI scans, infiltrating HCC frequently appears as largely hypointense and typically homogenous and mildly to moderately hyperintense on T2-weighted imaging. Infiltrative HCC frequently lacks a clearly defined boundary on cross-sectional imaging and can consequently fade into the background of the cirrhotic liver. As a result, infiltrating HCC is frequently not discovered until an advanced stage and has an associated poor prognosis. Thus, understanding imaging features associated with infiltrative HCC diagnosis is crucial for abdominal radiologists to ensure effective and timely care. We herein review imaging characteristics of infiltrative HCC.
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Affiliation(s)
- Seyedeh Panid Madani
- Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins Hospital, Johns Hopkins University, Baltimore, Maryland, USA
| | - Mohammad Mirza-Aghazadeh-Attari
- Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins Hospital, Johns Hopkins University, Baltimore, Maryland, USA
| | - Alireza Mohseni
- Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins Hospital, Johns Hopkins University, Baltimore, Maryland, USA
| | - Timothy Pawlik
- Department of Surgery, Wexner Medical Center, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Ihab R Kamel
- Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins Hospital, Johns Hopkins University, Baltimore, Maryland, USA
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10
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Wang X, Liu C, Wen H, Duan X, Jiao Y, Liu Y, Chen M, Zhu K, Mao X, Zhou Q. Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis. Clin Transl Med 2023; 13:e1214. [PMID: 36855781 PMCID: PMC9975463 DOI: 10.1002/ctm2.1214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor-1 (PD-1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD-1 inhibitor on the advanced HCC beyond oligometastasis. METHODS In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD-1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD-1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression-free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). RESULTS The 6-, 12- and 24-month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30-0.66; p < .001). The 6-, 12- and 18-month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33-0.63; p < .001) between the two collections. CONCLUSIONS Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD-1 inhibitor led to significant improvements in survival.
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Affiliation(s)
- Xiao‐Hui Wang
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, ChangshaHunan ProvinceChina
| | - Chang‐Jun Liu
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, ChangshaHunan ProvinceChina
| | - Hao‐Quan Wen
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, ChangshaHunan ProvinceChina
| | - Xiao‐Hui Duan
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, ChangshaHunan ProvinceChina
| | - Yu‐Qing Jiao
- Department of Minimally Invasive Interventional RadiologyThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of RadiologyThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Yu‐Jiang Liu
- Department of Interventional UltrasoundChinese PLA General HospitalBeijingChina
| | - Min‐Shan Chen
- Department of Liver SurgerySun Yat‐Sen University Cancer CenterGuangzhouGuangdongChina
| | - Kang‐Shun Zhu
- Department of Minimally Invasive Interventional RadiologyThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of RadiologyThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Xian‐Hai Mao
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, ChangshaHunan ProvinceChina
| | - Qun‐Fang Zhou
- Department of Interventional UltrasoundChinese PLA General HospitalBeijingChina
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Chen JJ, Yan QL, Bai M, Liu Q, Song SJ, Yao GD. Deoxyelephantopin, a germacrane-type sesquiterpene lactone from Elephantopus scaber, induces mitochondrial apoptosis of hepatocarcinoma cells by targeting Hsp90α in vitro and in vivo. Phytother Res 2023; 37:702-716. [PMID: 36420857 DOI: 10.1002/ptr.7654] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 09/06/2022] [Accepted: 09/10/2022] [Indexed: 11/25/2022]
Abstract
Hepatocellular carcinoma has been known as the most frequent subtype of liver cancer with a high rate of spread, metastases, and recurrence, also dismal treatment effects. However, effective therapies for HCC are still required. Nowadays, natural products have been known as a valuable source for drug discovery. In this research, 44 sesquiterpene lactones isolated from the Elephantopus scaber Linn. (Asteraceae) were tested by MTT assay for the antitumor activities. Deoxyelephantopin (DET) was found to exert significant cytotoxicity on HepG2 and Hep3B cells. Moreover, we found that DET treatment markedly reduced the growth of HCC cells in a concentration-dependent manner, which was better than sorafenib. Furthermore, DET induced mitochondrial dysfunction, oxidative stress, and cellular apoptosis. Additionally, we found that DET and sorafenib synergistically induced apoptosis and mitochondrial dysfunction in HCC cells. DET combined with sorafenib was also efficacious in tumor xenograft model. Molecular docking experiments revealed that DET had a potentially high binding affinity with Hsp90α. Moreover, Drug Affinity Responsive Target Stability assay suggested that DET could directly target Hsp90α. Additionally, the expression of Hsp90α was both decreased in vitro and in vivo. Altogether, this study revealed that DET might be a promising agent for HCC therapy by targeting Hsp90α.
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Affiliation(s)
- Jing-Jie Chen
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Qiu-Lin Yan
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Ming Bai
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Qingbo Liu
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Shao-Jiang Song
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Guo-Dong Yao
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
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12
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Ye Y, Liu M, Wu F, Ou S, Wang W, Fei J, Xie F, Bai L. TRMT6 promotes hepatocellular carcinoma progression through the PI3K/AKT signaling pathway. Eur J Med Res 2023; 28:48. [PMID: 36707905 PMCID: PMC9881333 DOI: 10.1186/s40001-022-00951-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 12/14/2022] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma is one of the most common and deadly cancers. The aim of this study was to elucidate the role of tRNA methyltransferase 6 (TRMT6) during HCC progression. METHODS The role of TRMT6 in the progression and prognosis of HCC was confirmed by analysis of online databases and clinical human samples. The effects of up-regulation or down-regulation of TRMT6 on HCC cell proliferation and PI3K/AKT pathway-related protein expressions were verified. The molecular mechanism was investigated in vivo by constructing subcutaneous xenograft tumor model. RESULTS TRMT6 was overexpressed in HCC tissues and associated with Tumour-Node-Metastasis (TNM) stage, primary tumor (T) and regional lymph node (N) classification. TRMT6 expressions in HCC cell lines were higher than that in normal liver cell. TRMT6 overexpression can promote HCC cell proliferation, increase the number of S phase cells. Interference with TRMT6 reduced the PI3K/AKT pathway-related protein expressions, and was reversed by the addition of IGF1. Interference with TRMT6 inhibited tumor growth in vivo and was related to PI3K/AKT pathway. CONCLUSIONS Overexpression of TRMT6 promote HCC cell proliferation in vivo and in vitro through PI3K/AKT/mTOR axis, which provides a potential choice for the treatment of HCC in clinical practice.
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Affiliation(s)
- Yanqing Ye
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China
- Department of Gastroenterology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Maosheng Liu
- Department of Gastroenterology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Fengfei Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Shiyu Ou
- Department of Gastroenterology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, 545005, Guangxi, People's Republic of China
| | - Weidong Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Jieying Fei
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Fang Xie
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Lan Bai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China.
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13
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Yi Y, Sun BY, Weng JL, Zhou C, Zhou CH, Cai MH, Zhang JY, Gao H, Sun J, Zhou J, Fan J, Ren N, Qiu SJ. Lenvatinib plus anti-PD-1 therapy represents a feasible conversion resection strategy for patients with initially unresectable hepatocellular carcinoma: A retrospective study. Front Oncol 2022; 12:1046584. [PMID: 36505772 PMCID: PMC9731103 DOI: 10.3389/fonc.2022.1046584] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Purpose We aimed to investigate the feasibility of lenvatinib plus anti-PD-1 therapy as a conversion therapy for initially unresectable hepatocellular carcinoma (HCC). Methods Patients with initially unresectable HCC who received combined lenvatinib and anti-PD-1 antibody between May 2020 and Jan 2022 in Zhongshan Hospital were retrospectively analyzed. Tumor response and resectability were assessed by imaging every two months according to RECIST version 1.1 and modified RECIST (mRECIST) criteria. Results A total of 107 patients were enrolled. 30 (28%) of them received conversion surgery within 90.5 (range: 53-456) days after the initiation of lenvatinib plus anti-PD-1 therapy. At baseline, the median largest tumor diameter of these 30 patients was 9.2 cm (range: 3.5-15.0 cm), 26 patients had Barcelona Clinic Liver Cancer stage B-C, and 4 had stage A. Prior to surgery, all cases displayed tumor regression and 15 patients achieved objective response. Pathological complete response (pCR) was observed in 10 patients. No severe drug-related adverse events or surgical complications were observed. After a median follow-up of 16.5 months, 28 patients survived and 11 developed tumor recurrence. Survival analysis showed patients achieving tumor response before surgery or pCR had a longer tumor-free survival. Notably, patients with microvascular invasion (MVI) had significantly higher recurrence rate and poorer overall survival than patients without. Conclusions Lenvatinib combined with anti-PD-1 therapy represents a feasible conversion strategy for patients with initially unresectable HCC. Patients achieving tumor responses are more likely to benefit from conversion resection to access a longer term of tumor-free survival.
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Affiliation(s)
- Yong Yi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Bao-Ye Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jia-Lei Weng
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Cheng Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Chen-Hao Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ming-Hao Cai
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jing-Yun Zhang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Hong Gao
- Department of Hepatobiliary Surgery, Chongqing Emergency Medical Center, The Fourth People’s Hospital of Chongqing, Chongqing University, Chongqing, China
| | - Jian Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ning Ren
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China,Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, and Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China,*Correspondence: Shuang-Jian Qiu, ; Ning Ren,
| | - Shuang-Jian Qiu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China,*Correspondence: Shuang-Jian Qiu, ; Ning Ren,
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14
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Zhang L, Chen C, Chai D, Li C, Guan Y, Liu L, Kuang T, Deng W, Wang W. The association between antibiotic use and outcomes of HCC patients treated with immune checkpoint inhibitors. Front Immunol 2022; 13:956533. [PMID: 36059512 PMCID: PMC9429218 DOI: 10.3389/fimmu.2022.956533] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
Objective Recently, immune checkpoint inhibitor (ICI) treatment has shown encouraging performance in improving the prognosis of hepatocellular carcinoma (HCC) patients. The gut microbiome plays a vital role in altering the efficacy of ICIs, which may be impacted by antibiotics. The aim of the meta-analysis is to estimate the influence of antibiotic use on the survival of HCC patients treated with ICIs. Methods The literature review was conducted using databases like PubMed, EMBASE, Cochrane Library, CNKI, WANFANG DATA, VIP, Google Scholar, and ClinicalTrials.gov before May 15, 2022. The primary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results A total of six retrospective studies met the inclusion criteria. 1056 patients were included in the study, of which 352 (33.33%) received antibiotic treatment. The meta-analysis results revealed antibiotic use did not affect the OS (HR: 1.41, 95% CI: 0.96-2.08, P = 0.088) and PFS (HR: 1.21, 95% CI: 0.73-2.00, P = 0.459) in HCC patients treated with ICIs. Besides, the use of antibiotics did not reduce the ORR (OR: 1.06, 95% CI: 0.69-1.64, P = 0.784) and DCR (OR: 0.42, 95% CI: 0.09-2.06, P = 0.286) in HCC patients treated with ICIs. Conclusion Current evidence reveals that antibiotic use does alter the therapeutic efficacy of ICIs in HCC patients. Systematic Review Registration https://www.crd.york.ac.uk/, identifier CRD42022311948.
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Affiliation(s)
- Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Chen Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dongqi Chai
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Chunlei Li
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Yongjun Guan
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Li Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Tianrui Kuang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Wenhong Deng, ; Weixing Wang,
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Wenhong Deng, ; Weixing Wang,
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15
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Missiaen R, Anderson NM, Kim LC, Nance B, Burrows M, Skuli N, Carens M, Riscal R, Steensels A, Li F, Simon MC. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment. Cell Metab 2022; 34:1151-1167.e7. [PMID: 35839757 PMCID: PMC9357184 DOI: 10.1016/j.cmet.2022.06.010] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 04/01/2022] [Accepted: 06/20/2022] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor regression. These data suggest novel strategies to treat human liver cancers through targeting SLC7A1 and/or a combination of arginine restriction, inhibition of GCN2, and senolytic agents.
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Affiliation(s)
- Rindert Missiaen
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicole M Anderson
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Laura C Kim
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Bailey Nance
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Michelle Burrows
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicolas Skuli
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Madeleine Carens
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Romain Riscal
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - An Steensels
- Department of Medicine, Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Department of Pediatrics, Comprehensive Bone Marrow Failure Center, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Fuming Li
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
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16
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Du F, Sun H, Sun F, Yang S, Tan H, Li X, Chai Y, Jiang Q, Han D. Knockdown of TANK-Binding Kinase 1 Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular-Targeted Drugs. Front Pharmacol 2022; 13:924523. [PMID: 35747750 PMCID: PMC9209752 DOI: 10.3389/fphar.2022.924523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 04/25/2022] [Indexed: 12/25/2022] Open
Abstract
The protein kinase, TANK-binding kinase 1 (TBK1), not only regulates various biological processes but also functions as an important regulator of human oncogenesis. However, the detailed function and molecular mechanisms of TBK1 in hepatocellular carcinoma (HCC), especially the resistance of HCC cells to molecular-targeted drugs, are almost unknown. In the present work, the role of TBK1 in regulating the sensitivity of HCC cells to molecular-targeted drugs was measured by multiple assays. The high expression of TBK1 was identified in HCC clinical specimens compared with paired non-tumor tissues. The high level of TBK1 in advanced HCC was associated with a poor prognosis in patients with advanced HCC who received the molecular-targeted drug, sorafenib, compared to patients with advanced HCC patients and a low level of TBK1. Overexpression of TBK1 in HCC cells induced their resistance to molecular-targeted drugs, whereas knockdown of TBK1 enhanced the cells’ sensitivity to molecular-targeted dugs. Regarding the mechanism, although overexpression of TBK1 enhanced expression levels of drug-resistance and pro-survival-/anti-apoptosis-related factors, knockdown of TBK1 repressed the expression of these factors in HCC cells. Therefore, TBK1 is a promising therapeutic target for HCC treatment and knockdown of TBK1 enhanced sensitivity of HCC cells to molecular-targeted drugs.
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Affiliation(s)
- Fengxia Du
- Department of Pharmacy, Medical Support Center of PLA General Hospital, Beijing, China
| | - Huiwei Sun
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Institute of Infectious Diseases, Beijing, China
| | - Fang Sun
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Institute of Infectious Diseases, Beijing, China
| | - Shiwei Yang
- Organ Transplant Center and Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Haidong Tan
- Organ Transplant Center and Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Xiaojuan Li
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Institute of Infectious Diseases, Beijing, China
| | - Yantao Chai
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Institute of Infectious Diseases, Beijing, China
| | - Qiyu Jiang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Institute of Infectious Diseases, Beijing, China
- *Correspondence: Dongdong Han, ; Qiyu Jiang,
| | - Dongdong Han
- Organ Transplant Center and Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, China
- *Correspondence: Dongdong Han, ; Qiyu Jiang,
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Wen M, Xu H, Peng H, Sheng Y, Yang W, Yan J. MiR-27a-3p targets USP46 to inhibit the cell proliferation of hepatocellular carcinoma. Chem Biol Drug Des 2022; 100:280-289. [PMID: 35637630 DOI: 10.1111/cbdd.14063] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/05/2022] [Accepted: 05/08/2022] [Indexed: 12/24/2022]
Abstract
Micro-RNAs are involved in the occurrence and development of hepatocellular carcinoma (HCC) as potential therapeutic targets for HCC. In this study, we found that miR-27a-3p was highly expressed in HCC, which was associated with lower survival rates of HCC patients. In vivo and in vitro functional experiments confirmed that over-expression or knock-down miR-27a-3p could significantly affect the proliferation ability of HCCLM3 and Huh-7, two HCC cell lines. Ubiquitin-specific protease 46 (USP46) was confirmed as the key target gene of miR-27a-3p in HCC via RNA-seq, quantitative polymerase chain reaction, Western blotting, and luciferase report. When knocking down USP46, the proliferation activity of HCC cells was significantly enhanced, while it was significantly inhibited after over-expressing USP4. Above results suggest that the abnormally over-expressed miR-27a-3p in liver promotes the proliferation of cancer cells and accelerates the development of HCC by targeting inhibition the expression of USP46. Targeting miR-27a-3p may be an effective strategy for prevention and treatment of HCC.
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Affiliation(s)
- Minghua Wen
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongyan Xu
- Department of Pathology, The Affiliated Children's Hospital of Nanchang University, Nanchang, China
| | - Hong Peng
- Department of Colorectal Surgery, The 908th Hospital of Chinese People's Liberation Army Joint, Nanchang, China
| | - Yanling Sheng
- Department of Ultrasound, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Wenlong Yang
- Department of Infectious Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinlong Yan
- Department of general surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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18
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Raissa R, Riawan W, Safitri A, Masruri M, Beltran MAG, Aulanniam A. In vitro and in vivo study: Ethanolic extract leaves of Azadirachta indica Juss. variant of Indonesia and Philippines suppresses tumor growth of hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling. F1000Res 2022; 11:477. [PMID: 37829248 PMCID: PMC10565427 DOI: 10.12688/f1000research.109557.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2022] [Indexed: 10/14/2023] Open
Abstract
Background: Azadirachta indica Juss. has been shown to suppress cancer progression through a variety of mechanisms. In order to treat cancer progression, cancer immunotherapy is used to stimulate the immune system where immunosuppression is present in tumor microenvironments. Many cancer cells produce a lot of interleukin-6 (IL-6) and signal transducer activator of transcription 3 (STAT3). STAT3 plays a key role in suppressing the expression of critical immune activation regulators. IL-6-mediated STAT3 activation is common in the tumor microenvironment. Inhibiting the IL-6/STAT3 signaling pathway has become a therapeutic option for cancer progression. As vimentin is also expressed in hepatic stellate cells boosting cancer survival. We focused on the precise effect of extract from leaves of Azadirachta indica Juss, on inhibiting the IL-6/STAT3 signaling cascade on hepatocellular carcinoma by in vitro and in vivo study. Methods: In the in vitro study, the effect of Azadirachta indica Juss. variant Indonesia and Philippines against the expression of IL-6 and STAT3 was examined in liver cancer cell line. In the in vivo study, 24 male rats ( Rattus norvegicus) strain Wistar were induced by diethylnitrosamine and carbon tetrachloride (CCl 4). Based on the therapy given, the groups were divided into negative control, positive control, Indonesia extract, and Philippine extract. Expression of IL-6, STAT3, and vimentin were tested using immunohistochemistry staining. The data were analyzed using analysis of variance, which was then followed by the Tukey test. Results: Statistically significant difference in IL-6 and STAT3 was observed between the treatment groups and positive control group by in vitro study and in vivo study. Generally, there is no significant difference between treatment using Indonesian and Philippine leaves. Conclusion: Both therapy doses of Azadirachta indica variant in Indonesia and Philippines were able to reduce IL-6, STAT3 and vimentin expression of hepatocellular carcinoma cell by in vitro and in vivo experiment.
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Affiliation(s)
- Ricadonna Raissa
- Doctoral Program of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
| | - Wibi Riawan
- Department of Biochemistry, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
| | - Anna Safitri
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
- Research Center for Smart Molecules of Natural Genetic Resources (SMONAGENES), Universitas Brawijaya, Malang, East Java, Indonesia
| | - Masruri Masruri
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
| | | | - Aulanniam Aulanniam
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
- Department of Biochemistry, Faculty of Veterinary Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
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19
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Teng YJ, Deng Z, Ouyang ZG, Zhou Q, Mei S, Fan XX, Wu YR, Long HP, Fang LY, Yin DL, Zhang BY, Guo YM, Zhu WH, Huang Z, Zheng P, Ning DM, Tian XF. Xihuang pills induce apoptosis in hepatocellular carcinoma by suppressing phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin pathway. World J Gastrointest Oncol 2022; 14:872-886. [PMID: 35582102 PMCID: PMC9048534 DOI: 10.4251/wjgo.v14.i4.872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/30/2021] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin (PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills (XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma (HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHP-associated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.
AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.
METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Cell-based experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP (0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay. Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction (RT-qPCR), respectively. Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway. Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.
RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry: Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625 mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose- and time-dependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract (0.625 mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins (e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.
CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3. Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.
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Affiliation(s)
- Yong-Jie Teng
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhe Deng
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhao-Guang Ouyang
- Department of Preventive Dentistry, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510132, Guangdong Province, China
| | - Qing Zhou
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Si Mei
- Department of Physiology, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xing-Xing Fan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China
| | - Yong-Rong Wu
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Hong-Ping Long
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Le-Yao Fang
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Dong-Liang Yin
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Bo-Yu Zhang
- College of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yin-Mei Guo
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Wen-Hao Zhu
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhen Huang
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Piao Zheng
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Di-Min Ning
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xue-Fei Tian
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
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Elms D, Badami A, Dhanarajan A. Systemic Therapy in Metastatic Hepatocellular Carcinoma. Curr Gastroenterol Rep 2022; 24:65-71. [PMID: 35416635 DOI: 10.1007/s11894-022-00842-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE OF REVIEW Multiple new tyrosine kinase inhibitors, immunotherapies and anti-angiogenic therapies are now available for the treatment of advanced hepatocellular carcinoma (HCC). In this article, we reviewed the evidence supporting these new therapies. RECENT FINDINGS The combination of atezolizumab and bevacizumab has become a new standard of care for initial systemic therapy in eligible patients, replacing sorafenib in the first line for many patients. Lenvatinib, a multikinase inhibitor, is also a new first line treatment option for patients who are not eligible for immunotherapy. Several additional options for second line treatment were also reviewed in detail in this paper. New systemic therapies for advanced HCC have prolonged overall survival. However, these new therapies are primarily approved for patients with Child-Pugh A classification with few options for patients with Child-Pugh B disease. Further work is needed to expand options for patients with more advanced liver disease and to optimize the sequencing of these new therapies.
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Affiliation(s)
- Destry Elms
- Division of Hematology and Oncology, Loyola University Medical Center, Maywood, IL, USA
| | - Ami Badami
- Division of Hematology and Oncology, Loyola University Medical Center, Maywood, IL, USA
| | - Asha Dhanarajan
- Division of Hematology and Oncology, Loyola University Medical Center, Maywood, IL, USA.
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21
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Donyavi MH, Salehi-Mazandarani S, Nikpour P. Comprehensive competitive endogenous RNA network analysis reveals EZH2-related axes and prognostic biomarkers in hepatocellular carcinoma. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:286-294. [PMID: 35656182 PMCID: PMC9148400 DOI: 10.22038/ijbms.2022.61570.13623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/28/2022] [Indexed: 11/15/2022]
Abstract
Objectives Hepatocellular carcinoma (HCC) is a common and lethal type of cancer worldwide. The importance of non-coding RNAs such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) have been recognized in the development of HCC. In this study, we constructed a four-component competing endogenous RNA (ceRNA) network in HCC and evaluated prognostic values of the ceRNAs. Materials and Methods The expression profiles of lncRNAs, miRNAs, and mRNAs were retrieved from The Cancer Genome Atlas database. GSE94508 and GSE97332 studies from the Gene Expression Omnibus database were used to identify circRNAs expression profiles. A four-component ceRNA network was constructed based on differentially-expressed RNAs. Survival R package was utilized to identify potential prognostic biomarkers. Results A four-component ceRNA network including 295 edges and 239 nodes was constructed and enrichment analysis revealed important Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. A Protein-Protein Interaction network with 118 nodes and 301 edges was also established. The enhancer of zeste homolog 2 (EZH2) was the highest degree hub gene in the PPI network. Because of the significance of EZH2 in HCC, we presented its axes in the ceRNA network, which play important roles in HCC progression. Furthermore, ceRNAs were identified as potential prognostic biomarkers utilizing survival analysis. Conclusion Our study elucidates the role of ceRNAs and their regulatory interactions in the pathogenesis of HCC and identifies EZH2-related RNAs which may be utilized as novel therapeutic targets and prognostic biomarkers in the future.
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Affiliation(s)
- Mohammad Hossein Donyavi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Sadra Salehi-Mazandarani
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvaneh Nikpour
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan, Iran
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22
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Abd El-Fattah EE, Saber S, Youssef ME, Eissa H, El-Ahwany E, Amin NA, Alqarni M, Batiha GES, Obaidullah AJ, Kaddah MMY, Ahmed Gaafar AG, Mourad AAE, Mostafa-Hedeab G, Abdelhamid AM. AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma. Front Pharmacol 2022; 12:720173. [PMID: 35095479 PMCID: PMC8790251 DOI: 10.3389/fphar.2021.720173] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022] Open
Abstract
HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.
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Affiliation(s)
- Eslam E Abd El-Fattah
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Hanan Eissa
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman El-Ahwany
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Noha A Amin
- Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mohammed Alqarni
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Ahmad J Obaidullah
- Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.,Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohamed M Y Kaddah
- Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, Egypt
| | - Ahmed Gaafar Ahmed Gaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt
| | - Ahmed A E Mourad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt
| | - Gomaa Mostafa-Hedeab
- Pharmacology Department and Health Research Unit, Medical College, Jouf University, Jouf, Saudi Arabia.,Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt
| | - Amir Mohamed Abdelhamid
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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23
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Li Y, Zhang R, Xu Z, Wang Z. Advances in Nanoliposomes for the Diagnosis and Treatment of Liver Cancer. Int J Nanomedicine 2022; 17:909-925. [PMID: 35250267 PMCID: PMC8893038 DOI: 10.2147/ijn.s349426] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
The mortality rate of liver cancer is gradually increasing worldwide due to the increasing risk factors such as fatty liver, diabetes, and alcoholic cirrhosis. The diagnostic methods of liver cancer include ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), among others. The treatment of liver cancer includes surgical resection, transplantation, ablation, and chemoembolization; however, treatment still faces multiple challenges due to its insidious development, high rate of recurrence after surgical resection, and high failure rate of transplantation. The emergence of liposomes has provided new insights into the treatment of liver cancer. Due to their excellent carrier properties and maneuverability, liposomes can be used to perform a variety of functions such as aiding in imaging diagnoses, combinatorial therapies, and integrating disease diagnosis and treatment. In this paper, we further discuss such advantages.
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Affiliation(s)
- Yitong Li
- NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, Changchun, 130021, Jilin, People’s Republic of China
| | - Ruihang Zhang
- Second Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, 450052, Henan, People’s Republic of China
| | - Zhen Xu
- NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, Changchun, 130021, Jilin, People’s Republic of China
| | - Zhicheng Wang
- NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, Changchun, 130021, Jilin, People’s Republic of China
- Correspondence: Zhicheng Wang, NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin, People’s Republic of China, Tel +86 13843131059, Fax +86 431185619443, Email
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24
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Zhou Y, Mao X, Peng R, Bai D. CircRNAs in hepatocellular carcinoma: characteristic, functions and clinical significance. Int J Med Sci 2022; 19:2033-2043. [PMID: 36483595 PMCID: PMC9724243 DOI: 10.7150/ijms.74713] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 09/07/2022] [Indexed: 11/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and serious types of cancer worldwide, with high incidence and mortality rates. Circular RNAs (circRNAs) are a novel class of non-coding RNA with important biological functions. In recent years, multiple circRNAs have been found to be involved in the biological processes of tumorigenesis and tumor development. Increasing evidence has shown that circRNAs also play a crucial role in the occurrence and development of HCC. However, the specific molecular mechanism of circRNAs in HCC has not been fully elucidated. The present review systematically summarized the classification and basic characteristics of circRNAs, their biological functions and their role in the occurrence and development of HCC. By summarizing the previous studies on circRNAs in HCC, this study aimed to indicate potential approaches to improving the early diagnosis and treatment of HCC.
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Affiliation(s)
- Yujun Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Huaihua First People's Hospital, Huaihua, Hunan, P. R. China
| | - Xingkang Mao
- Cardiovascular Center, Huizhou First Municipal People's Hospital, Huizhou, Guangdong, P. R. China
| | - Rui Peng
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, P. R. China
| | - Dousheng Bai
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, P. R. China
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25
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Osman MF, Shawali IH, Metwally LIA, Kamel AH, Ibrahim MES. CT perfusion for response evaluation after interventional ablation of hepatocellular carcinoma: a prospective study. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-021-00660-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Computed tomography (CT) perfusion was found to be useful in assessing treatment response in a variety of cancers through the evaluation in the arterial perfusion changes. We investigated the performance of CT perfusion parameters for assessment of hepatocellular carcinoma (HCC) response to radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE). We conducted a prospective diagnostic test accuracy study that recruited 70 HCC patients who were scheduled to undergo TACE or RFA. For each dynamic CT scan acquisition, four single perfusion CT image maps were generated, including functional maps of blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface (PS).
Results
In TACE-treated lesions, the BV achieved a sensitivity and specific of 100% and 83.3%, at a cutoff level of ≤ 122 ml/min/100 gm, for responders. Likewise, at a cutoff level of > 10 s, transit time had a sensitivity of 90.5% and specificity of 100%. At a cutoff level of ≤ 14 ml/min/100 gm, the PS had a sensitivity of 100% and specificity of 83.33% for responders. In RFA-treated lesions, at a cutoff level of ≤ 170 ml/min/100 gm and ≤ 11 ml/100 gm, the BF and BV had a sensitivity of 100% and specificity 100%, respectively, for responders. At a cutoff level of ≤ 11 ml/min/100 gm, PS had a sensitivity 77.27% and specificity 80%.
Conclusions
The present study confirms the feasibility of CT perfusion for assessment of response to TACE and RFA among patients with HCC.
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26
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Apoptosis of hepatocellular carcinoma HepG2 cells induced by seleno-ovalbumin (Se-OVA) via mitochondrial pathway. Int J Biol Macromol 2021; 192:82-89. [PMID: 34619275 DOI: 10.1016/j.ijbiomac.2021.09.178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 09/21/2021] [Accepted: 09/25/2021] [Indexed: 02/07/2023]
Abstract
Seleno-ovalbumin (Se-OVA) was a selenium conjugating protein synthesized by the combination of ovalbumin (OVA) and inorganic selenium. In this paper, the structure of Se-OVA was characterized, and the anticancer effect of Se-OVA on hepatocellular carcinoma HepG2 cells was investigated. Through FT-IR, UV, endogenous fluorescence and XRD assays, it was found that the structural characterization of Se-OVA changed after seleno-modification. In addition, the cell assays showed that Se-OVA could induce apoptosis of HepG2 cells by arresting cell cycle in S phase, generating intracellular reactive oxygen species, reducing the mitochondrial transmembrane potential, and triggering the Bax- and Bcl-2-mediated mitochondria apoptosis pathway. These findings revealed that Se-OVA might serve as a novel anticancer drug for cancer adjuvant therapy.
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27
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Abdelhamid AM, Saber S, Youssef ME, Gaafar AGA, Eissa H, Abd-Eldayem MA, Alqarni M, Batiha GES, Obaidullah AJ, Shahien MA, El-Ahwany E, Amin NA, Etman MA, Kaddah MMY, Abd El-Fattah EE. Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application. Biomed Pharmacother 2021; 145:112455. [PMID: 34844106 DOI: 10.1016/j.biopha.2021.112455] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/05/2021] [Accepted: 11/16/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is on the rise worldwide, and its incidence in diabetic patients is two to three times that of non-diabetics. Current therapeutic options fail to provide considerable survival benefits to patients with HCC. There is a strong possibility that the FDA-approved antidiabetic combination of empagliflozin and metformin could show complementary effects to control HCC progression. However, their multitarget effects have not yet been studied on HCC development. Therefore, the present study aims to evaluate the antitumorigenic activity of this combination in non-diabetic mice with diethylnitrosamine-induced HCC. Empagliflozin/metformin combination prolonged survival and improved histological features of mice livers. Additionally, Empagliflozin/metformin showed anti-inflammatory potential and relieved oxidative stress. On the one hand these effects are likely attributed to the ability of metformin to inactivate NF-κB in an AMPK-dependent mechanism and on the other hand to the ability of the empagliflozin to inhibit the MAPKs, p38 and ERK1/2. Empagliflozin also showed a less robust effect on AMPK than that of metformin. Moreover, empagliflozin enhanced the autophagy inducing activity of metformin. Furthermore, empagliflozin/metformin exhibited increased apoptotic potential. Consequently, empagliflozin augmented the antitumorigenic function of metformin by exerting better control of angiogenesis, and metastasis. To conclude, our findings suggest empagliflozin as an ideal adjunct to metformin for the inhibition of HCC progression. In addition, since the incidence of hypoglycemia is minimal due to insulin-independent mechanism of action of both treatments, empagliflozin/metformin could be a promising therapeutic modality for the management of diabetic patients with HCC; and even non diabetic ones.
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Affiliation(s)
- Amir Mohamed Abdelhamid
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
| | - Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Ahmed Gaafar Ahmed Gaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt
| | - Hanan Eissa
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Marwa A Abd-Eldayem
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt
| | - Mohammed Alqarni
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
| | - Ahmad J Obaidullah
- Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohamed Awad Shahien
- Department of Clinical Pharmacology, Faculty of Medicine, Damietta University, Damietta, Egypt
| | - Eman El-Ahwany
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Noha A Amin
- Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mohamed Ali Etman
- Research and Development, Department of Drug Stability, Safe Pharma, Pharco Pharmaceuticals, Alexandria, Egypt
| | - Mohamed M Y Kaddah
- Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab 21934, Alexandria, Egypt
| | - Eslam E Abd El-Fattah
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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28
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Lee AQ, Li Y, Gong Z. Inducible Liver Cancer Models in Transgenic Zebrafish to Investigate Cancer Biology. Cancers (Basel) 2021; 13:5148. [PMID: 34680297 PMCID: PMC8533791 DOI: 10.3390/cancers13205148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/20/2022] Open
Abstract
Primary liver cancer is one of the most prevalent and deadly cancers, which incidence continues to increase while treatment response remains poor; thus, in-depth understanding of tumour events is necessary to develop more effective therapies. Animal models for liver cancer are powerful tools to reach this goal. Over the past decade, our laboratory has established multiple oncogene transgenic zebrafish lines that can be robustly induced to develop liver cancer. Histological, transcriptomic and molecular analyses validate the use of these transgenic zebrafish as experimental models for liver cancer. In this review, we provide a comprehensive summary of our findings with these inducible zebrafish liver cancer models in tumour initiation, oncogene addiction, tumour microenvironment, gender disparity, cancer cachexia, drug screening and others. Induced oncogene expression causes a rapid change of the tumour microenvironment such as inflammatory responses, increased vascularisation and rapid hepatic growth. In several models, histologically-proven carcinoma can be induced within one week of chemical inducer administration. Interestingly, the induced liver tumours show the ability to regress when the transgenic oncogene is suppressed by the withdrawal of the chemical inducer. Like human liver cancer, there is a strong bias of liver cancer severity in male zebrafish. After long-term tumour progression, liver cancer-bearing zebrafish also show symptoms of cancer cachexia such as muscle-wasting. In addition, the zebrafish models have been used to screen for anti-metastasis drugs as well as to evaluate environmental toxicants in carcinogenesis. These findings demonstrated that these inducible zebrafish liver cancer models provide rapid and convenient experimental tools for further investigation of fundamental cancer biology, with the potential for the discovery of new therapeutic approaches.
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Affiliation(s)
| | | | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore 119077, Singapore; (A.Q.L.); (Y.L.)
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Kumar A, Sharma A, Handu S, Singh J, Naithani M. Molecular docking analysis of piperlongumine with different apoptotic proteins involved in Hepatocellular Carcinoma. Bioinformation 2021; 17:829-833. [PMID: 35539886 PMCID: PMC9049083 DOI: 10.6026/97320630017829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/21/2021] [Accepted: 09/21/2021] [Indexed: 01/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Numerous signalling pathways are involved in hepatocellular carcinoma. Piperlongumine is a potential candidate for the treatment of hepatocellular carcinoma. Therefore, it is of interest to document the molecular docking analysis of piperlongumine with different apoptotic proteins involved in Hepatocellular Carcinoma. Piperlongumine was docked with the HCC targets such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor, Aurora-2, Nuclear factor Kappa-B (NF-KB), Jak2 Kinase, Fibroblast growth factor receptor 4, Bcl-2-like protein 1,Apopain, and Apoptosis regulator Bcl-2 using in-silico technique with the software grid-based ligand docking with energies. Piperlongumine exhibited the highest negative energy value (E-value) of -6.58 kcal/mol with vascular endothelial growth factor receptor 2, followed by -5.46, -5.34, -5.31, and -5.29 kcal/mol with 1M17, 2BMC, 1SVC, 4C61, 4XCU with epidermal growth factor receptor, aurora-2, nuclear factor Kappa-B (NF-KB), Jak2 kinase, and fibroblast growth factor receptor 4 (FGFR4), respectively for further consideration.
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Affiliation(s)
- Ashish Kumar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rishikesh-249203, Uttarakhand, India
| | - Ambika Sharma
- Department of Biochemistry, College of Veterinary Science, DUVASU, Mathura-281001, Uttar Pradesh, India
| | - Shailendra Handu
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Rishikesh-249203, Uttarakhand, India
| | - Jagjit Singh
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Rishikesh-249203, Uttarakhand, India
| | - Manisha Naithani
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rishikesh-249203, Uttarakhand, India
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Cheung KS, Lam LK, Seto WK, Leung WK. Use of Antibiotics during Immune Checkpoint Inhibitor Treatment Is Associated with Lower Survival in Hepatocellular Carcinoma. Liver Cancer 2021; 10:606-614. [PMID: 34950183 PMCID: PMC8647068 DOI: 10.1159/000518090] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/27/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Recent studies suggested that use of antibiotics may interfere with treatment responses to immune checkpoint inhibitors (ICIs). We determined whether concurrent use of antibiotics during ICI therapy was associated with adverse outcomes in patients with advanced hepatocellular carcinoma (HCC). METHODS This is a territory-wide retrospective cohort study including all advanced HCC patients who received ICIs (nivolumab, pembrolizumab, or ipilimumab) between January 2014 and December 2019. Exclusion criteria included prior liver transplantation and use of cabozantinib, regorafenib, or ramucirumab. The exposure of interest was concurrent antibiotic use within 30 days before or after the commencement of ICI. The adjusted hazard ratio (aHR) of cancer-related mortality and all-cause mortality with antibiotic use was derived by propensity score (PS) matching in 1:2 ratio of covariates including baseline characteristics, causes of cirrhosis, Child-Pugh status, prior HCC treatment, comorbidities, concurrent medications, and laboratory results including alpha fetoprotein. RESULTS A total of 395 HCC patients who had received ICIs were included. During a median follow-up of 16.5 months (interquartile range [IQR]: 5.6-44.3), there were 286 (72.4%) deaths including 231 cancer-related deaths. The median time from the first ICI to event was 7.7 months (IQR: 4.0-16.8). PS matching of 56 antibiotic users with 99 nonusers showed that concurrent antibiotic use with ICI was associated with higher cancer-related (aHR: 1.66; 95% CI: 1.08-2.54) and all-cause mortality (aHR: 1.63; 95% CI: 1.17-2.28). CONCLUSIONS Concurrent antibiotic use during immunotherapy was associated with higher mortality in patients with advanced HCC. Further studies should examine the role of gut dysbiosis on responses to ICI.
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Lok Ka Lam
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Wai Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Wai K. Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China,*Wai K. Leung,
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31
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Ma Z, Li Z, Wang S, Zhou Q, Ma Z, Liu C, Huang B, Zheng Z, Yang L, Zou Y, Zhang C, Huang S, Hou B. SLC39A10 Upregulation Predicts Poor Prognosis, Promotes Proliferation and Migration, and Correlates with Immune Infiltration in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:899-912. [PMID: 34395329 PMCID: PMC8357404 DOI: 10.2147/jhc.s320326] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 07/20/2021] [Indexed: 12/31/2022] Open
Abstract
Background Recent evidence has shown that Solute Carrier Family 39 Member 10 (SLC39A10) promoted tumor progression in several cancer types. The study intended to explore the expression and function of SLC39A10 in hepatocellular carcinoma (HCC). Methods Multiple bioinformatics analyses were used to evaluate SLC39A10 expression and potential role in HCC. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to confirm SLC39A10 expression. Intro studies were performed to assess the effects of SLC39A10 on HCC cells proliferation and migration. Furthermore, flow cytometry was conducted to identify its specific function in apoptosis of HCC. Results SLC39A10 was significantly over-expressed in HCC samples from both bioinformatic databases and our cohort. Survival analyses suggested patients with high expression of SLC39A10 had poor overall survival and disease-free survival (P-value <0.01). Further, the expression of SLC39A10 was positively correlated with tumor-infiltrating lymphocytes and some immune checkpoints like CTLA4, TIM3 and TGFB1. In HCC cell lines, SLC39A10 knockdown inhibited cells proliferation and migration, but promoted apoptosis. Conclusion An increased SLC39A10 expression was found and served as an unfavorable indicator of survival in HCC. Further studies suggested SLC39A10 promotes tumor aggressiveness and may provide a novel target for HCC therapy.
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Affiliation(s)
- Zuyi Ma
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,Shantou University of Medical College, Shantou, 515000, People's Republic of China
| | - Zhenchong Li
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,South China University of Technology School of Medicine, Guangzhou, 51000, People's Republic of China
| | - Shujie Wang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Qi Zhou
- Department of General Surgery, Hui Ya Hospital of the First Affiliated Hospital, Sun Yat-Sen University, Huizhou, 516081, People's Republic of China.,Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, People's Republic of China
| | - Zuguang Ma
- Sanshui Disease Prevention Cure Station, Foshan, 528100, People's Republic of China
| | - Chunsheng Liu
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,Shantou University of Medical College, Shantou, 515000, People's Republic of China
| | - Bowen Huang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Zehao Zheng
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,Shantou University of Medical College, Shantou, 515000, People's Republic of China
| | - LinLing Yang
- Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Yiping Zou
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,Shantou University of Medical College, Shantou, 515000, People's Republic of China
| | - Chuanzhao Zhang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,South China University of Technology School of Medicine, Guangzhou, 51000, People's Republic of China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Shanzhou Huang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,South China University of Technology School of Medicine, Guangzhou, 51000, People's Republic of China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Baohua Hou
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.,South China University of Technology School of Medicine, Guangzhou, 51000, People's Republic of China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China
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Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int J Mol Sci 2021; 22:ijms22158298. [PMID: 34361064 PMCID: PMC8347792 DOI: 10.3390/ijms22158298] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Affiliation(s)
- Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Ana Sandoval-Rodriguez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
- Correspondence:
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Ju X, Tang Y, Qu R, Hao S. The Emerging Role of Circ-SHPRH in Cancer. Onco Targets Ther 2021; 14:4177-4188. [PMID: 34285509 PMCID: PMC8286153 DOI: 10.2147/ott.s317403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Circ-SHPRH is a circular RNA that can regulate the expression of target genes by sponging microRNAs (miRNAs) or translating tumor suppressor proteins. Recent studies have suggested that circ-SHPRH may play a role in the development of tumors and cancers. Hence, this paper aimed to review the biological characteristics, molecular mechanisms, and potential clinical significance of circ-SHPRH in a variety of tumors and to evaluate its potential as a new diagnostic and prognostic biomarker. METHODS Numerous experiments were performed regarding the abnormal expression of circ-SHPRH in a variety of tumors, including hepatocellular carcinoma, gastric carcinoma, non-small cell lung cancer, osteosarcoma, colorectal cancer, cholangiocarcinoma, pancreatic ductal adenocarcinoma, retinoblastoma, and glioblastoma. RESULTS Upregulation of circ-SHPRH reportedly inhibits tumor cell proliferation, migration, and invasion, leading to the inhibition of tumor development. The clinicopathological parameters and the functional characteristics of circ-SHPRH in multiple human tumors and cancers were summarized. Circ-SHPRH functions as a tumor suppressor gene and has great potential as a diagnostic and prognostic biomarker for different types of cancer.
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Affiliation(s)
- Xinyue Ju
- Department of Hematology and Oncology, The Second Bethune Clinical Medical College of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Yan Tang
- Department of Hematology and Oncology, The Second Bethune Clinical Medical College of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Rongfeng Qu
- Department of Hematology and Oncology, The Second Bethune Clinical Medical College of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Shuhong Hao
- Department of Hematology and Oncology, The Second Bethune Clinical Medical College of Jilin University, Changchun, Jilin, People’s Republic of China
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34
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Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22052606. [PMID: 33807605 PMCID: PMC7961993 DOI: 10.3390/ijms22052606] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are the major extrinsic risk factors of HCC development. Genetic background is pivotal in HCC pathogenesis, and both germline mutations and single nucleotide polymorphism (SNP) are intrinsic risk factors of HCC. These HCC risk factors predispose to hepatic injury and subsequent activation of fibrogenesis that progresses into cirrhosis and HCC. Probiotic bacteria can mitigate HCC risk by modulating host gut microbiota (GM) to promote growth of beneficial microbes and inhibit HCC-associated dysbiosis, thus preventing pathogen-associated molecular patterns (PAMPs)-mediated hepatic inflammation. Probiotics have antiviral activities against HBV and HCV infections, ameliorate obesity and risk of NAFLD/NASH, and their antioxidant, anti-proliferative, anti-angiogenic, and anti-metastatic effects can prevent the HCC pathogenesis. Probiotics also upregulate the expression of tumor suppressor genes and downregulate oncogene expression. Moreover, metabolites generated by probiotics through degradation of dietary phytochemicals may mitigate the risk of HCC development. These multiple anticancer mechanisms illustrate the potential of probiotics as an adjuvant strategy for HCC risk management and treatment.
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Schipilliti FM, Garajová I, Rovesti G, Balsano R, Piacentini F, Dominici M, Gelsomino F. The Growing Skyline of Advanced Hepatocellular Carcinoma Treatment: A Review. Pharmaceuticals (Basel) 2021; 14:43. [PMID: 33429973 PMCID: PMC7827379 DOI: 10.3390/ph14010043] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/13/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.
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Affiliation(s)
- Francesca Matilde Schipilliti
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy;
| | - Giulia Rovesti
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy;
| | - Federico Piacentini
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Massimo Dominici
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Fabio Gelsomino
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
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Yang C, Chen J, Li Y, Huang X, Liu Z, Wang J, Jiang H, Qin W, Lv Y, Wang H, Wang C. Exploring subclass-specific therapeutic agents for hepatocellular carcinoma by informatics-guided drug screen. Brief Bioinform 2020; 22:5960426. [PMID: 33167027 DOI: 10.1093/bib/bbaa295] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/06/2020] [Accepted: 10/06/2020] [Indexed: 01/02/2023] Open
Abstract
Almost all currently approved systemic therapies for hepatocellular carcinoma (HCC) failed to achieve satisfactory therapeutic effect. Exploring tailored treatment strategies for different individuals provides an approach with the potential to maximize clinical benefit. Previously, multiple studies have reported that hepatoma cell lines belonging to different molecular subtypes respond differently to the same treatment. However, these studies only focused on a small number of typical chemotherapy or targeted drugs across limited cell lines due to time and cost constraints. To compensate for the deficiency of previous experimental researches as well as link molecular classification with therapeutic response, we conducted a comprehensive in silico screening, comprising nearly 2000 compounds, to identify compounds with subclass-specific efficacy. Here, we first identified two transcriptome-based HCC subclasses (AS1 and AS2) and then made comparison of drug response between two subclasses. As a result, we not only found that some agents previously considered to have low efficacy in HCC treatment might have promising therapeutic effects for certain subclass, but also identified novel therapeutic compounds that were not routinely used as anti-tumor drugs in clinic. Discovery of agents with subclass-specific efficacy has potential in changing the status quo of population-based therapies in HCC and providing new insights into precision oncology.
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Affiliation(s)
- Chen Yang
- Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Junfei Chen
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, China. She is focusing on multi-omics analysis of hepatocellular carcinoma.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Yan Li
- Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Xiaowen Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhicheng Liu
- student at Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Hua Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanyuan Lv
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Hui Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Cun Wang
- Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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