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Rahdan F, Abedi F, Dianat-Moghadam H, Sani MZ, Taghizadeh M, Alizadeh E. Autophagy-based therapy for hepatocellular carcinoma: from standard treatments to combination therapy, oncolytic virotherapy, and targeted nanomedicines. Clin Exp Med 2024; 25:13. [PMID: 39621122 PMCID: PMC11611955 DOI: 10.1007/s10238-024-01527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024]
Abstract
Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abedi
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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2
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Xiang Y, Wu J, Qin H. Advances in hepatocellular carcinoma drug resistance models. Front Med (Lausanne) 2024; 11:1437226. [PMID: 39144662 PMCID: PMC11322137 DOI: 10.3389/fmed.2024.1437226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/09/2024] [Indexed: 08/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Surgery has been the major treatment method for HCC owing to HCC's poor sensitivity to radiotherapy and chemotherapy. However, its effectiveness is limited by postoperative tumour recurrence and metastasis. Systemic therapy is applied to eliminate postoperative residual tumour cells and improve the survival of patients with advanced HCC. Recently, the emergence of various novel targeted and immunotherapeutic drugs has significantly improved the prognosis of advanced HCC. However, targeted and immunological therapies may not always produce complete and long-lasting anti-tumour responses because of tumour heterogeneity and drug resistance. Traditional and patient-derived cell lines or animal models are used to investigate the drug resistance mechanisms of HCC and identify drugs that could reverse the resistance. This study comprehensively reviewed the established methods and applications of in-vivo and in-vitro HCC drug resistance models to further understand the resistance mechanisms in HCC treatment and provide a model basis for possible individualised therapy.
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Affiliation(s)
- Yien Xiang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun, China
| | - Jun Wu
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun, China
| | - Hanjiao Qin
- Department of Radiotherapy, the Second Hospital of Jilin University, Changchun, China
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3
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Liu ZY, Tang JM, Yang MQ, Yang ZH, Xia JZ. The role of LncRNA-mediated autophagy in cancer progression. Front Cell Dev Biol 2024; 12:1348894. [PMID: 38933333 PMCID: PMC11199412 DOI: 10.3389/fcell.2024.1348894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) are a sort of transcripts that are more than 200 nucleotides in length. In recent years, many studies have revealed the modulatory role of lncRNAs in cancer. Typically, lncRNAs are linked to a variety of essential events, such as apoptosis, cellular proliferation, and the invasion of malignant cells. Simultaneously, autophagy, an essential intracellular degradation mechanism in eukaryotic cells, is activated to respond to multiple stressful circumstances, for example, nutrient scarcity, accumulation of abnormal proteins, and organelle damage. Autophagy plays both suppressive and promoting roles in cancer. Increasingly, studies have unveiled how dysregulated lncRNAs expression can disrupt autophagic balance, thereby contributing to cancer progression. Consequently, exploring the interplay between lncRNAs and autophagy holds promising implications for clinical research. In this manuscript, we methodically compiled the advances in the molecular mechanisms of lncRNAs and autophagy and briefly summarized the implications of the lncRNA-mediated autophagy axis.
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Affiliation(s)
- Zi-yuan Liu
- Gastroenterological Surgery, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, China
- Department of General Surgery, Jiangnan University Medical Center, Wuxi, China
| | - Jia-ming Tang
- Department of Neurology, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Meng-qi Yang
- Gastroenterological Surgery, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, China
- Department of General Surgery, Jiangnan University Medical Center, Wuxi, China
| | - Zhi-hui Yang
- Department of General Surgery, Jiangnan University Medical Center, Wuxi, China
| | - Jia-zeng Xia
- Gastroenterological Surgery, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, China
- Department of General Surgery, Jiangnan University Medical Center, Wuxi, China
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4
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Hashemi M, Daneii P, Asadalizadeh M, Tabari K, Matinahmadi A, Bidoki SS, Motlagh YSM, Jafari AM, Ghorbani A, Dehghanpour A, Nabavi N, Tan SC, Rashidi M, Taheriazam A, Entezari M, Goharrizi MASB. Epigenetic regulation of hepatocellular carcinoma progression: MicroRNAs as therapeutic, diagnostic and prognostic factors. Int J Biochem Cell Biol 2024; 170:106566. [PMID: 38513802 DOI: 10.1016/j.biocel.2024.106566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 01/28/2024] [Accepted: 03/19/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), a significant challenge for public healthcare systems in developed Western countries including the USA, Canada, and the UK, is influenced by different risk factors including hepatitis virus infections, alcoholism, and smoking. The disruption in the balance of microRNAs (miRNAs) plays a vital function in tumorigenesis, given their function as regulators in numerous signaling networks. These miRNAs, which are mature and active in the cytoplasm, work by reducing the expression of target genes through their impact on mRNAs. MiRNAs are particularly significant in HCC as they regulate key aspects of the tumor, like proliferation and invasion. Additionally, during treatment phases such as chemotherapy and radiotherapy, the levels of miRNAs are key determinants. Pre-clinical experiments have demonstrated that altered miRNA expression contributes to HCC development, metastasis, drug resistance, and radio-resistance, highlighting related molecular pathways and processes like MMPs, EMT, apoptosis, and autophagy. Furthermore, the regulatory role of miRNAs in HCC extends beyond their immediate function, as they are also influenced by other epigenetic factors like lncRNAs and circular RNAs (circRNAs), as discussed in recent reviews. Applying these discoveries in predicting the prognosis of HCC could mark a significant advancement in the therapy of this disease.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Pouria Daneii
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahya Asadalizadeh
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiana Tabari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus University, Torun, Poland
| | - Seyed Shahabadin Bidoki
- Faculty of medicine, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Ali Moghadas Jafari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amin Ghorbani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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5
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Wang G, Jiang X, Torabian P, Yang Z. Investigating autophagy and intricate cellular mechanisms in hepatocellular carcinoma: Emphasis on cell death mechanism crosstalk. Cancer Lett 2024; 588:216744. [PMID: 38431037 DOI: 10.1016/j.canlet.2024.216744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/05/2024] [Accepted: 02/18/2024] [Indexed: 03/05/2024]
Abstract
Hepatocellular carcinoma (HCC) stands as a formidable global health challenge due to its prevalence, marked by high mortality and morbidity rates. This cancer type exhibits a multifaceted etiology, prominently linked to viral infections, non-alcoholic fatty liver disease, and genomic mutations. The inherent heterogeneity of HCC, coupled with its proclivity for developing drug resistance, presents formidable obstacles to effective therapeutic interventions. Autophagy, a fundamental catabolic process, plays a pivotal role in maintaining cellular homeostasis, responding to stressors such as nutrient deprivation. In the context of HCC, tumor cells exploit autophagy, either augmenting or impeding its activity, thereby influencing tumorigenesis. This comprehensive review underscores the dualistic role of autophagy in HCC, acting as both a pro-survival and pro-death mechanism, impacting the trajectory of tumorigenesis. The anti-carcinogenic potential of autophagy is evident in its ability to enhance apoptosis and ferroptosis in HCC cells. Pertinently, dysregulated autophagy fosters drug resistance in the carcinogenic context. Both genomic and epigenetic factors can regulate autophagy in HCC progression. Recognizing the paramount importance of autophagy in HCC progression, this review introduces pharmacological compounds capable of modulating autophagy-either inducing or inhibiting it, as promising avenues in HCC therapy.
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Affiliation(s)
- Gang Wang
- Department of Interventional, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Xiaodi Jiang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, 110020, PR China
| | - Pedram Torabian
- Arnie Charbonneau Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada; Department of Medical Sciences, University of Calgary, Calgary, AB, T2N 4Z6, Canada.
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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6
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Zhang J, Wu L, Wang C, Xie X, Han Y. Research Progress of Long Non-Coding RNA in Tumor Drug Resistance: A New Paradigm. Drug Des Devel Ther 2024; 18:1385-1398. [PMID: 38689609 PMCID: PMC11060174 DOI: 10.2147/dddt.s448707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 03/25/2024] [Indexed: 05/02/2024] Open
Abstract
In the past few decades, chemotherapy has been one of the most effective cancer treatment options. Drug resistance is currently one of the greatest obstacles to effective cancer treatment. Even though drug resistance mechanisms have been extensively investigated, they have not been fully elucidated. Recent genome-wide investigations have revealed the existence of a substantial quantity of long non-coding RNAs (lncRNAs) transcribed from the human genome, which actively participate in numerous biological processes, such as transcription, splicing, epigenetics, the cell cycle, cell differentiation, development, pluripotency, immune microenvironment. The abnormal expression of lncRNA is considered a contributing factor to the drug resistance. Furthermore, drug resistance may be influenced by genetic and epigenetic variations, as well as individual differences in patient treatment response, attributable to polymorphisms in metabolic enzyme genes. This review focuses on the mechanism of lncRNAs resistance to target drugs in the study of tumors with high mortality, aiming to establish a theoretical foundation for targeted therapy.
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Affiliation(s)
- Jing Zhang
- Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi’an, Shaanxi, People’s Republic of China
| | - Le Wu
- Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi’an, Shaanxi, People’s Republic of China
| | - Chenchen Wang
- Department of Critical Care Medicine, the 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, Gansu, People’s Republic of China
| | - Xin Xie
- Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi’an, Shaanxi, People’s Republic of China
| | - Yuying Han
- Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi’an, Shaanxi, People’s Republic of China
- Department of Critical Care Medicine, the 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, Gansu, People’s Republic of China
- Science and Education Department, Xi’an No. 5 Hospital, Xi’an, Shaanxi, People’s Republic of China
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7
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Tang Z, Li X, Zheng Y, Liu J, Liu C, Li X. The role of competing endogenous RNA network in the development of hepatocellular carcinoma: potential therapeutic targets. Front Cell Dev Biol 2024; 12:1341999. [PMID: 38357004 PMCID: PMC10864455 DOI: 10.3389/fcell.2024.1341999] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/16/2024] [Indexed: 02/16/2024] Open
Abstract
The current situation of hepatocellular carcinoma (HCC) management is challenging due to its high incidence, mortality, recurrence and metastasis. Recent advances in gene genetic and expression regulation have unveiled the significant role of non-coding RNA (ncRNA) in various cancers. This led to the formulation of the competing endogenous RNA (ceRNA) hypothesis, which posits that both coding RNA and ncRNA, containing miRNA response elements (MRE), can share the same miRNA sequence. This results in a competitive network between ncRNAs, such as lncRNA and mRNA, allowing them to regulate each other. Extensive research has highlighted the crucial role of the ceRNA network in HCC development, impacting various cellular processes including proliferation, metastasis, cell death, angiogenesis, tumor microenvironment, organismal immunity, and chemotherapy resistance. Additionally, the ceRNA network, mediated by lncRNA or circRNA, offers potential in early diagnosis and prevention of HCC. Consequently, ceRNAs are emerging as therapeutic targets for HCC. The complexity of these gene networks aligns with the multi-target approach of traditional Chinese medicine (TCM), presenting a novel perspective for TCM in combating HCC. Research is beginning to show that TCM compounds and prescriptions can affect HCC progression through the ceRNA network, inhibiting proliferation and metastasis, and inducing apoptosis. Currently, the lncRNAs TUG1, NEAT1, and CCAT1, along with their associated ceRNA networks, are among the most promising ncRNAs for HCC research. However, this field is still in its infancy, necessitating advanced technology and extensive basic research to fully understand the ceRNA network mechanisms of TCM in HCC treatment.
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Affiliation(s)
- Ziwei Tang
- The Ninth People’s Hospital of Chongqing, Chongqing, China
| | - Xue Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanfeng Zheng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Jin Liu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chao Liu
- Chongqing Chemical Industry Vocational College, Chongqing, China
| | - Xia Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Jing F, Li X, Jiang H, Sun J, Guo Q. Combating drug resistance in hepatocellular carcinoma: No awareness today, no action tomorrow. Biomed Pharmacother 2023; 167:115561. [PMID: 37757493 DOI: 10.1016/j.biopha.2023.115561] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the sixth most common cancer worldwide, is associated with a high degree of malignancy and poor prognosis. Patients with early HCC may benefit from surgical resection to remove tumor tissue and a margin of healthy tissue surrounding it. Unfortunately, most patients with HCC are diagnosed at an advanced or distant stage, at which point resection is not feasible. Systemic therapy is now routinely prescribed to patients with advanced HCC; however, drug resistance has become a major obstacle to the treatment of HCC and exploring purported mechanisms promoting drug resistance remains a challenge. Here, we focus on the determinants of drug resistance from the perspective of non-coding RNAs (ncRNAs), liver cancer stem cells (LCSCs), autophagy, epithelial-mesenchymal transition (EMT), exosomes, ferroptosis, and the tumor microenvironment (TME), with the aim to provide new insights into HCC treatment.
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Affiliation(s)
- Fanbo Jing
- The department of clinical pharmacy. The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao Li
- The department of clinical pharmacy. The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hui Jiang
- Qingdao Haici Hospital, Qingdao 266000, China
| | - Jialin Sun
- The department of clinical pharmacy. The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qie Guo
- The department of clinical pharmacy. The Affiliated Hospital of Qingdao University, Qingdao, China.
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9
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Chen W, Ruan M, Zou M, Liu F, Liu H. Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4187. [PMID: 37627215 PMCID: PMC10452865 DOI: 10.3390/cancers15164187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/02/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a widely prevalent and malignantly progressive tumor. Most patients are typically diagnosed with HCC at an advanced stage, posing significant challenges in the execution of curative surgical interventions. Non-coding RNAs (ncRNAs) represent a distinct category of RNA molecules not directly involved in protein synthesis. However, they possess the remarkable ability to regulate gene expression, thereby exerting significant regulatory control over cellular processes. Notably, ncRNAs have been implicated in the modulation of programmed cell death (PCD), a crucial mechanism that various therapeutic agents target in the fight against HCC. This review summarizes the clinical significance of ncRNA regulation of PCD in HCC, including patient diagnosis, prognosis, drug resistance, and side effects. The aim of this study is to provide new insights and directions for the diagnosis and drug treatment strategies of HCC.
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Affiliation(s)
| | | | | | - Fuchen Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; (W.C.); (M.R.)
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; (W.C.); (M.R.)
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Fang Y, Zhang X, Huang H, Zeng Z. The interplay between noncoding RNAs and drug resistance in hepatocellular carcinoma: the big impact of little things. J Transl Med 2023; 21:369. [PMID: 37286982 DOI: 10.1186/s12967-023-04238-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 05/30/2023] [Indexed: 06/09/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in people, and a common primary liver cancer. Lacking early diagnosis and a high recurrence rate after surgical resection, systemic treatment is still an important treatment method for advanced HCC. Different drugs have distinct curative effects, side effects and drug resistance due to different properties. At present, conventional molecular drugs for HCC have displayed some limitations, such as adverse drug reactions, insensitivity to some medicines, and drug resistance. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), have been well documented to be involved in the occurrence and progression of cancer. Novel biomarkers and therapeutic targets, as well as research into the molecular basis of drug resistance, are urgently needed for the management of HCC. We review current research on ncRNAs and consolidate the known roles regulating drug resistance in HCC and examine the potential clinical applications of ncRNAs in overcoming drug resistance barriers in HCC based on targeted therapy, cell cycle non-specific chemotherapy and cell cycle specific chemotherapy.
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Affiliation(s)
- Yuan Fang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan, People's Republic of China
| | - XiaoLi Zhang
- Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - HanFei Huang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan, People's Republic of China.
| | - Zhong Zeng
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan, People's Republic of China.
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11
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Nandi S, Mondal A, Ghosh A, Mukherjee S, Das C. Lnc-ing epigenetic mechanisms with autophagy and cancer drug resistance. Adv Cancer Res 2023; 160:133-203. [PMID: 37704287 DOI: 10.1016/bs.acr.2023.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Long noncoding RNAs (lncRNAs) comprise a diverse class of RNA molecules that regulate various physiological processes and have been reported to be involved in several human pathologies ranging from neurodegenerative disease to cancer. Therapeutic resistance is a major hurdle for cancer treatment. Over the past decade, several studies has emerged on the role of lncRNAs in cancer drug resistance and many trials have been conducted employing them. LncRNAs also regulate different cell death pathways thereby maintaining a fine balance of cell survival and death. Autophagy is a complex cell-killing mechanism that has both cytoprotective and cytotoxic roles. Similarly, autophagy can lead to the induction of both chemosensitization and chemoresistance in cancer cells upon therapeutic intervention. Recently the role of lncRNAs in the regulation of autophagy has also surfaced. Thus, lncRNAs can be used in cancer therapeutics to alleviate the challenges of chemoresistance by targeting the autophagosomal axis. In this chapter, we discuss about the role of lncRNAs in autophagy-mediated cancer drug resistance and its implication in targeted cancer therapy.
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Affiliation(s)
- Sandhik Nandi
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Atanu Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Aritra Ghosh
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Indian Institute of Science Education and Research, Kolkata, India
| | - Shravanti Mukherjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India.
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12
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Seydi H, Nouri K, Rezaei N, Tamimi A, Hassan M, Mirzaei H, Vosough M. Autophagy orchestrates resistance in hepatocellular carcinoma cells. Biomed Pharmacother 2023; 161:114487. [PMID: 36963361 DOI: 10.1016/j.biopha.2023.114487] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/26/2023] Open
Abstract
Treatment resistance is one of the major barriers for therapeutic strategies in hepatocellular carcinoma (HCC). Many studies have indicated that chemotherapy and radiotherapy induce autophagy machinery (cell protective autophagy) in HCC cells. In addition, many experiments report a remarkable crosstalk between treatment resistance and autophagy pathways. Thus, autophagy could be one of the key factors enabling tumor cells to hinder induced cell death after medical interventions. Therefore, extensive research on the molecular pathways involved in resistance induction and autophagy have been conducted to achieve the desired therapeutic response. The key molecular pathways related to the therapy resistance are TGF-β, MAPK, NRF2, NF-κB, and non-coding RNAs. In addition, EMT, drug transports, apoptosis evasion, DNA repair, cancer stem cells, and hypoxia could have considerable impact on the hepatoma cell's response to therapies. These mechanisms protect tumor cells against various treatments and many studies have shown that each of them is connected to the molecular pathways of autophagy induction in HCC. Hence, autophagy inhibition may be an effective strategy to improve therapeutic outcome in HCC patients. In this review, we further highlight how autophagy leads to poor response during treatment through a complex molecular network and how it enhances resistance in primary liver cancer. We propose that combinational regimens of approved HCC therapeutic protocols plus autophagy inhibitors may overcome drug resistance in HCC therapy.
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Affiliation(s)
- Homeyra Seydi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Kosar Nouri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Niloufar Rezaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Department of Biotechnology, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Islamic Republic of Iran
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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13
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Zhao X, Yin S, Shi J, Zheng M, He C, Meng H, Han Y, Chen J, Han J, Yuan Z, Wang Y. The association between several autophagy-related genes and their prognostic values in hepatocellular carcinoma: a study on the foundation of TCGA, GEPIA and HPA databases. Mol Biol Rep 2022; 49:10269-10277. [PMID: 36097121 DOI: 10.1007/s11033-022-07426-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND The purpose of this study was to investigate the relationship between the expression of autophagy-related genes and prognosis in hepatocellular carcinoma (HCC). METHODS AND RESULTS We selected three autophagy-related genes (ATG3, ATG7, and ATG9A) from gene expression data of liver cancer patients in The Cancer Genome Atlas (TCGA) database by Kaplan-Meier survival analysis, univariate and multivariate Cox regression analysis, and Gene Set Enrichment Analysis (GSEA). Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were applied to testify the credibility of our results. The expression levels of ATG3, ATG7, and ATG9A were verified by real-time quantitative PCR (RT-qPCR) in normal liver cells (L02) and three HCC cell lines (HepG2, Hep3b, and Li-7). Data analysis results from TCGA showed high ATG3, ATG7, ATG9A expression in HCC tumor tissues. Kaplan-Meier survival analysis showed that the survival rate of the high expression group of ATG3, ATG7, and ATG9A was all significantly lower than the low expression group. GSEA analysis showed that many signaling pathways (such as the regulation of autophagy, glycine serine and threonine metabolism, pathways in cancer, mitogen-activated protein kinase (MAPK) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway, as well as P53 signaling pathway) were differentially enriched in HCCs with ATG3, ATG7, and ATG9A expression. GEPIA and RT-qPCR also identified that the mRNA expression level of ATG3, ATG7, and ATG9A in normal liver cells were significantly lower than in HCC cells. High protein expression of ATG3, ATG7, and ATG9A was displayed in HCCs from the HPA database. CONCLUSIONS The ATG3, ATG7, ATG9A might be utilized as prognostic biomarkers for liver cancer.
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Affiliation(s)
- Xueying Zhao
- College of Biological Sciences and Biotechnology, Beijing Forestry University, 100083, Beijing, China
| | - Shangqi Yin
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Jingren Shi
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Mei Zheng
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Chaonan He
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Huan Meng
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Ying Han
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Jin Chen
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Jinyu Han
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Zhengrong Yuan
- College of Biological Sciences and Biotechnology, Beijing Forestry University, 100083, Beijing, China.
| | - Yajie Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China.
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14
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He Q, Guo P, Bo Z, Yu H, Yang J, Wang Y, Chen G. Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma. Cancer Cell Int 2022; 22:249. [PMID: 35945536 PMCID: PMC9361533 DOI: 10.1186/s12935-022-02643-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/27/2022] [Indexed: 11/10/2022] Open
Abstract
Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.
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Affiliation(s)
- Qikuan He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou No. 2 Hospital, Ningbo, 315199, Zhejiang, China
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Haitao Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Jinhuan Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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15
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Ghavami S, Zamani M, Ahmadi M, Erfani M, Dastghaib S, Darbandi M, Darbandi S, Vakili O, Siri M, Grabarek BO, Boroń D, Zarghooni M, Wiechec E, Mokarram P. Epigenetic regulation of autophagy in gastrointestinal cancers. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166512. [PMID: 35931405 DOI: 10.1016/j.bbadis.2022.166512] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 11/09/2022]
Abstract
The development of novel therapeutic approaches is necessary to manage gastrointestinal cancers (GICs). Considering the effective molecular mechanisms involved in tumor growth, the therapeutic response is pivotal in this process. Autophagy is a highly conserved catabolic process that acts as a double-edged sword in tumorigenesis and tumor inhibition in a context-dependent manner. Depending on the stage of malignancy and cellular origin of the tumor, autophagy might result in cancer cell survival or death during the GICs' progression. Moreover, autophagy can prevent the progression of GIC in the early stages but leads to chemoresistance in advanced stages. Therefore, targeting specific arms of autophagy could be a promising strategy in the prevention of chemoresistance and treatment of GIC. It has been revealed that autophagy is a cytoplasmic event that is subject to transcriptional and epigenetic regulation inside the nucleus. The effect of epigenetic regulation (including DNA methylation, histone modification, and expression of non-coding RNAs (ncRNAs) in cellular fate is still not completely understood. Recent findings have indicated that epigenetic alterations can modify several genes and modulators, eventually leading to inhibition or promotion of autophagy in different cancer stages, and mediating chemoresistance or chemosensitivity. The current review focuses on the links between autophagy and epigenetics in GICs and discusses: 1) How autophagy and epigenetics are linked in GICs, by considering different epigenetic mechanisms; 2) how epigenetics may be involved in the alteration of cancer-related phenotypes, including cell proliferation, invasion, and migration; and 3) how epidrugs modulate autophagy in GICs to overcome chemoresistance.
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Affiliation(s)
- Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland.
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Mehran Erfani
- Department of Biochemistry, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Sara Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morvarid Siri
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Beniamin Oskar Grabarek
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Maryam Zarghooni
- Department of Laboratory Medicine and Pathobiology, University of Toronto Alumni, Toronto, Canada
| | - Emilia Wiechec
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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16
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Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib. Int J Mol Sci 2021; 22:ijms222111770. [PMID: 34769197 PMCID: PMC8583804 DOI: 10.3390/ijms222111770] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/20/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.
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17
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The Role of Long Non-Coding RNA and microRNA Networks in Hepatocellular Carcinoma and Its Tumor Microenvironment. Int J Mol Sci 2021; 22:ijms221910630. [PMID: 34638971 PMCID: PMC8508708 DOI: 10.3390/ijms221910630] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/27/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common liver malignancy with high morbidity and poor prognosis. Long non-coding RNAs (lncRNAs) are involved in crucial biological processes of tumorigenesis and progression, and play four major regulatory roles, namely signal, decoy, guide, and scaffold, to regulate gene expression. Through these processes, lncRNAs can target microRNAs (miRNAs) to form lncRNA and miRNA networks, which regulate cancer cell proliferation, metastasis, drug resistance, and the tumor microenvironment. Here, we summarize the multifaceted functions of lncRNA and miRNA networks in the pathogenesis of HCC, the potential use of diagnostic or prognostic biomarkers, and novel therapeutic targets in HCC. This review also highlights the regulatory effects of lncRNA and miRNA networks in the tumor microenvironment of HCC.
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18
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Li L, Yu S, Hu Q, Hai Y, Li Y. Genome-scale CRISPRa screening identifies MTX1 as a contributor for sorafenib resistance in hepatocellular carcinoma by augmenting autophagy. Int J Biol Sci 2021; 17:3133-3144. [PMID: 34421355 PMCID: PMC8375235 DOI: 10.7150/ijbs.62393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/09/2021] [Indexed: 12/29/2022] Open
Abstract
Sorafenib is the standard first-line drug for the treatment of advanced hepatocellular carcinoma (HCC), however, its therapeutic efficacy is not satisfactory due to primary or secondary resistance of HCC cells. In the present study, we identified Metaxin 1 (MTX1) as a new regulator of sorafenib resistance in HCC through genome-scale CRISPR activation (CRISPRa) screening. We found that MTX1 was frequently upregulated in HCC tissues and overexpression of MTX1 promoted HCC cell proliferation in vitro and in vivo. As well, MTX1 overexpression increased cell growth rate and decreased cell apoptosis upon sorafenib treatment. Consistently, the resistance induced by MTX1 was also observed in subcutaneous xenograft tumor model. Clinically, high expression of MTX1 was closely related with poor outcomes in HCC patients who received sorafenib treatment. Mechanistically, overexpression of MTX1 could promote HCC cell autophagy via interacting with and inhibiting CDGSH iron sulfur domain 1 (CISD1), an autophagy negative regulator. Taken together, our findings suggest that MTX1 is upregulated in HCC and contributes to sorafenib resistance via a possible mechanism involving CISD1 mediated autophagy.
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Affiliation(s)
- Li Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Shijun Yu
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Qingqing Hu
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Yanan Hai
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Yandong Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
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19
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Hu X, Zhu H, Shen Y, Zhang X, He X, Xu X. The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma. Front Oncol 2021; 11:696705. [PMID: 34367979 PMCID: PMC8340683 DOI: 10.3389/fonc.2021.696705] [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: 04/17/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.
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Affiliation(s)
- Xinyao Hu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Shen
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoyu Zhang
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoqin He
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ximing Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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20
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Zeng Z, Lu Q, Liu Y, Zhao J, Zhang Q, Hu L, Shi Z, Tu Y, Xiao Z, Xu Q, Huang D. Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma. Front Oncol 2021; 11:641522. [PMID: 34307125 PMCID: PMC8292964 DOI: 10.3389/fonc.2021.641522] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
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Affiliation(s)
- Zhi Zeng
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Qiliang Lu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Yang Liu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Junjun Zhao
- Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.,Graduate Department, Bengbu Medical College, Bengbu, China
| | - Qian Zhang
- The Medical College of Qingdao University, Qingdao, China
| | - Linjun Hu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Zhan Shi
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yifeng Tu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zunqiang Xiao
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
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21
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Zhao H, Huang C, Luo Y, Yao X, Hu Y, Wang M, Chen X, Zeng J, Hu W, Wang J, Li R, Yao X. A Correlation Study of Prognostic Risk Prediction for Colorectal Cancer Based on Autophagy Signature Genes. Front Oncol 2021; 11:595099. [PMID: 34168974 PMCID: PMC8218632 DOI: 10.3389/fonc.2021.595099] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 04/26/2021] [Indexed: 01/07/2023] Open
Abstract
Autophagy plays a complex role in tumors, sometimes promoting cancer cell survival and sometimes inducing apoptosis, and its role in the colorectal tumor microenvironment is controversial. The purpose of this study was to investigate the prognostic value of autophagy-related genes (ARGs) in colorectal cancer. We identified 37 differentially expressed autophagy-related genes by collecting TCGA colorectal tumor transcriptome data. A single-factor COX regression equation was used to identify 11 key prognostic genes, and a prognostic risk prediction model was constructed based on multifactor COX analysis. We classified patients into high and low risk groups according to prognostic risk parameters (p <0.001) and determined the prognostic value they possessed by survival analysis and the receiver operating characteristic (ROC) curve in the training and test sets of internal tests. In a multifactorial independent prognostic analysis, this risk value could be used as an independent prognostic indicator (HR=1.167, 95% CI=1.078-1.264, P<0.001) and was a robust predictor without any staging interference. To make it more applicable to clinical procedures, we constructed nomogram based on risk parameters and parameters of key clinical characteristics. The area under ROC curve for 3-year and 5-year survival rates were 0.735 and 0.718, respectively. These will better enable us to monitor patient prognosis, thus improve patient outcomes.
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Affiliation(s)
- Haibi Zhao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China
| | - Chengzhi Huang
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| | - Yuwen Luo
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoya Yao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China
| | - Yong Hu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China
| | - Muqing Wang
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| | - Xin Chen
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China.,Medical College, Shantou University, Shantou, China
| | - Jun Zeng
- Department of General Surgery, Baoan Central Hospital, The Fifth Affiliated Hospital of Shen Zhen University, Shen Zhen, China
| | - Weixian Hu
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Junjiang Wang
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Rongjiang Li
- Department of General Surgery, Baoan Central Hospital, The Fifth Affiliated Hospital of Shen Zhen University, Shen Zhen, China
| | - Xueqing Yao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Ganzhou Hospital (Ganzhou Municipal Hospital), Guangdong Provincial People's Hospital, Ganzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Medical College, Shantou University, Shantou, China
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22
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Zhao G, Zhang A, Sun S, Ding Y. Long non-coding RNA LINC00173 enhances cisplatin resistance in hepatocellular carcinoma via the microRNA-641/RAB14 axis. Oncol Lett 2021; 21:371. [PMID: 33777195 PMCID: PMC7988719 DOI: 10.3892/ol.2021.12632] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 01/29/2021] [Indexed: 12/14/2022] Open
Abstract
A growing body of evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in the chemoresistance of human cancers. However, the molecular mechanisms underlying the functions of certain lncRNAs in the chemotherapeutic resistance of hepatocellular carcinoma (HCC) remain unclear. The aim of the present study was to investigate the function and potential mechanism of action of lncRNA LINC00173 in HCC cisplatin (DDP) resistance. Reverse transcription-quantitative PCR analysis indicated that LINC00173 was highly expressed in DDP-resistant HCC tissues and cell lines, and high expression levels of LINC00173 were found to be associated with poor prognosis in patients with HCC. Moreover, LINC00173-knockdown improved the DDP sensitivity of DDP-resistant HCC cells. A luciferase reporter assay also demonstrated that microRNA (miR)-641 was a direct target of LINC00173. miR-641 inhibition restored the promoting effect of LINC00173 knockdown on DDP sensitivity in HCC cells. Furthermore, RAB14 was identified as a target of miR-641, and RAB14 overexpression restrained the inducing effect of LINC00173 knockdown on HCC cell DDP sensitivity. The findings of the present study demonstrated that LINC00173 increased DDP resistance in HCC via the miR-641/RAB14 axis, which may represent a promising therapeutic strategy for HCC.
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Affiliation(s)
- Guangliang Zhao
- Department of Emergency General Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Anhua Zhang
- Department of Gastrointestinal Surgery, Gaomi People's Hospital, Gaomi, Shandong 261500, P.R. China
| | - Shufang Sun
- Department of Anesthesia, Weifang Maternal and Child Health Hospital, Weifang, Shandong 261000, P.R. China
| | - Yunlong Ding
- Department of Emergency General Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
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The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2020; 13:ph13120432. [PMID: 33260729 PMCID: PMC7760785 DOI: 10.3390/ph13120432] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
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Ashrafizadeh M, Zarrabi A, Orouei S, Kiavash Hushmandi, Hakimi A, Amirhossein Zabolian, Daneshi S, Samarghandian S, Baradaran B, Najafi M. MicroRNA-mediated autophagy regulation in cancer therapy: The role in chemoresistance/chemosensitivity. Eur J Pharmacol 2020; 892:173660. [PMID: 33310181 DOI: 10.1016/j.ejphar.2020.173660] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/10/2020] [Accepted: 10/20/2020] [Indexed: 12/20/2022]
Abstract
Chemoresistance has doubled the effort needed to reach an effective treatment for cancer. Now, scientists should consider molecular pathways and mechanisms involved in chemoresistance to overcome cancer. Autophagy is a "self-digestion" mechanism in which potentially toxic and aged organelles and macromolecules are degraded. Increasing evidence has shown that autophagy possesses dual role in cancer cells (onco-suppressor or oncogene). So, it is vital to identify its role in cancer progression and malignancy. MicroRNAs (miRs) are epigenetic factors capable of modulation of autophagy in cancer cells. In the current review, we emphasize on the relationship between miRs and autophagy in cancer chemotherapy. Besides, we discuss upstream mediators of miR/autophagy axis in cancer chemotherapy including long non-coding RNAs, circular RNAs, Nrf2 c-Myc, and HIF-1α. At the final section, we provide a discussion about how anti-tumor compounds affect miR/autophagy axis in ensuring chemosensitivity. These topics are described in this review to show how autophagy inhibition/induction can lead to chemosensitivity/chemoresistance, and miRs are considered as key players in these discussions.
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Affiliation(s)
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey
| | - Sima Orouei
- Department of Genetics, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Azadeh Hakimi
- Department of Anatomical Sciences, School of Medicine, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran; Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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25
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Yang C, Wang Y, Xue W, Xie Y, Dong Q, Zhu C. Competing Endogenous RNA (ceRNA) Network Analysis of Autophagy-Related Genes in Hepatocellular Carcinoma. Pharmgenomics Pers Med 2020; 13:445-462. [PMID: 33116760 PMCID: PMC7568685 DOI: 10.2147/pgpm.s267563] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Autophagy plays an important role in the occurrence and development of hepatocellular carcinoma (HCC). We aimed to develop an autophagy-related genes signature predicting the prognosis of HCC and to depict a competing endogenous RNA (ceRNA) network. METHODS Differentially expressed autophagy-related genes (DE-ATGs), miRNAs and lncRNAs and clinical data of HCC patients were extracted from TCGA. The GO and KEGG analysis were performed to investigate the gene function. Univariate and multivariate Cox regression analysis were used to identify a prognostic signature with the DE-ATGs. And a nomogram, adapted to the clinical characteristics, was established. Then, we established a ceRNA network related to autophagy genes. RESULTS We screened out 27 differentially expressed genes which were enriched in GO and KEGG pathways related to autophagy and cancers. In univariate and multivariate Cox regression analysis, BIRC5, HSPB8, and SQSTM1 were screened out to establish a prognostic risk score model (AUC=0.749, p<0.01). Kaplan-Meier survival analysis showed that the overall survival of high-risk patients was significantly worse. Furthermore, the signature was validated in the other two independent databases. The nomogram, including the autophagy-related risk signature, gender, stage and TNM, was constructed and validated (C-index=0.736). Finally, the ceRNA network was established based on DE-ATGs, differentially expressed miRNAs and lncRNAs. CONCLUSION We constructed a reliable prognostic model of HCC with autophagy-related genes and depicted a ceRNA network of DE-ATGs in HCC which provides a basis for the study of post-transcriptional modification and regulation of autophagy-related genes in HCC.
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Affiliation(s)
- Chenyu Yang
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-Assisted Surgery, Qingdao266003, People’s Republic of China
| | - Yixiu Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
| | - Weijie Xue
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
| | - Yuwei Xie
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
| | - Qian Dong
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-Assisted Surgery, Qingdao266003, People’s Republic of China
| | - Chengzhan Zhu
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-Assisted Surgery, Qingdao266003, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
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26
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Marin JJ, Macias RI, Monte MJ, Romero MR, Asensio M, Sanchez-Martin A, Cives-Losada C, Temprano AG, Espinosa-Escudero R, Reviejo M, Bohorquez LH, Briz O. Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12061663. [PMID: 32585893 PMCID: PMC7352164 DOI: 10.3390/cancers12061663] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/11/2022] Open
Abstract
The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.
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Affiliation(s)
- Jose J.G. Marin
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-923294674 (O.B.)
| | - Rocio I.R. Macias
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Marta R. Romero
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Anabel Sanchez-Martin
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Alvaro G. Temprano
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Ricardo Espinosa-Escudero
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Maria Reviejo
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Laura H. Bohorquez
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-923294674 (O.B.)
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