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Zhang R, Wu Z, Wang H, Ji M, Shen T, Yang L, Li Y, Yu J, Huang Y, Li L, Xu Z, Sheng Y, Li X, Wang F, Xiao W. Structural optimization and pharmacological evaluation of diphenyl amine esters as anti-hepatocellular carcinoma agents by targeting TAR RNA-binding protein 2. Eur J Med Chem 2025; 291:117676. [PMID: 40279767 DOI: 10.1016/j.ejmech.2025.117676] [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: 12/09/2024] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
Hepatocellular Carcinoma (HCC), a leading cause of cancer-related death in the world, urgently requires novel therapeutic strategies and drug targets. The TRBP-Dicer complex plays a critical role in miRNA biosynthesis, which can be regulated by small molecules to exert anti-cancer effects. This study presented the structural modification of the natural product (-)-Gomisin M1(GM), resulting in the synthesis of 37 derivatives with a diphenyl amine ester scaffold. Several of these derivatives exhibited enhanced modulation of miRNA biogenesis compared to GM. Notably, derivative 13j displayed improved binding affinity to TRBP and greater efficacy in modulating miRNA biosynthesis, as well as anti-HCC activity in vitro and in vivo. Further investigation revealed that 13j induced apoptosis and pyroptosis while inhibiting the epithelial-to-mesenchymal transition process in HCC cells. In terms of druggability, 13j possesses favorable drug-likeness and a promising safety profile. These findings provide a promising scaffold with potent activity and low toxicity, offering a foundation for the development of miRNA-based therapeutic strategies for HCC.
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Affiliation(s)
- Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Zhao Wu
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hairong Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Minghui Ji
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Tianze Shen
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Linhan Yang
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yiming Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Jialing Yu
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yinqiao Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Lingyu Li
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zihan Xu
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Yuwen Sheng
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
| | - Xiaoli Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Fei Wang
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China.
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Bandyopadhyay A, Sinha S, Roy R, Biswas N. Autophagy mediated immune response regulation and drug resistance in cancer. Mol Biol Rep 2025; 52:492. [PMID: 40402380 DOI: 10.1007/s11033-025-10573-5] [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: 02/14/2025] [Accepted: 05/02/2025] [Indexed: 05/23/2025]
Abstract
Autophagy is a critical regulator of cellular homeostasis. The proteins involved in autophagy orchestrate the functions to strike the balance between cell survival and cell death in context-specific situations like aging, infections, inflammation and most importantly carcinogenesis. One of the major dead-locks in cancer treatment is the development of resistance to the available drugs (multi-drug resistance) as well as immune-suppressions in patients. Different studies over time have shown that autophagy is being involved in chemotherapy by working hand in hand with apoptosis or drug resistance through proliferative signals. Resistance to various drugs, such as, Cisplatin, Vincristine, Tamoxifen (TAM) occurs by epigenetic modifications, changed expression levels of microRNAs (miRNAs/miRs), and long non-coding RNAs (lncRNAs), which are regulated by the aberrant autophagy levels in lung, and breast cancers. More interestingly in the tumour microenvironment the immune suppressor cells also bring in autophagy in different pathway regulations either helping or opposing the whole carcinogenesis process. Macrophages, T cells, B cells, dendritic cells (DCs), neutrophils, and fibroblasts show involvement of autophagy in their differentiation and development in the tumor microenvironment (TME). Here, this extensive review for the first time tries to bring under a single canopy, several recent examples of autophagy-mediated immune regulations and autophagy-mediated epigenetically regulated drug resistance in different types of cancers.
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Affiliation(s)
- Anupriya Bandyopadhyay
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, India
| | - Samraj Sinha
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, India
| | - Rajdeep Roy
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, India
| | - Nabendu Biswas
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, India.
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Chen Y, Wang J, Gu L, Chen H, Gai Z, Hu R, Qing B, Yuan Y, Xia Z. lncRNA NR_146969 promotes the progression of lung adenocarcinoma. Exp Cell Res 2025; 447:114535. [PMID: 40147711 DOI: 10.1016/j.yexcr.2025.114535] [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: 02/15/2025] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Emerging research suggests that dysregulation of long non-coding RNAs (lncRNAs) is closely linked to the onset and progression of cancer. In this study, we used lncRNA array technology to identify differentially expressed lncRNAs in lung adenocarcinoma patients and normal lung tissues. The study further explored the clinical significance and function of candidate lncRNAs in lung adenocarcinoma (LUAD). The results showed that lncRNA NR_146969 was upregulated in LAUD specimens and was associated with lymph node metastasis and clinical staging in LUAD patients. METHODS The biological functions of lncRNA NR_146969 were observed using CCK-8, colony formation, transwell assay and xenograft tumor model. Explore the potential mechanism of action of lncRNA NR_146969 by FISH, dual luciferase reporter assay and recovery assay. RESULTS Overall, lncRNA NR_146969 plays an oncogenic role in LUAD. Mechanically, lncRNA NR_146969 targets SLC6A14 via miR-26a-1-3p, leading to phosphorylation of the AKT/mTOR pathway, which promotes LUAD growth and metastasis. CONCLUSION Therefore, targeting lncRNA NR_146969 may provide a new therapeutic strategy for LUAD.
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Affiliation(s)
- Ying Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Juan Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Linguo Gu
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Hongzuo Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Zhengling Gai
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Rui Hu
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Bei Qing
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Yunchang Yuan
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Zhenkun Xia
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Hunan Provincial Key Laboratory of Early Diagnosis and Precision Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
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Zhang D, Zuo M, Zhou J, Ouyang S, Liu S, Yuan J, Ou C, Chen Q, Yu D, Cheng D, Wang J. A facile combined therapy of chemotherapeutic agent and microRNA for hepatocellular carcinoma using non-cationic nanogel. J Mater Chem B 2025; 13:2753-2766. [PMID: 39868422 DOI: 10.1039/d4tb02256d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
High drug resistance remains a challenge for chemotherapy against hepatocellular carcinoma (HCC). Combining chemotherapeutic agents with microRNA (miRNA), which simultaneously regulates multiple pathways, offers a promising approach to improve therapeutic efficacy against HCC. Although cationic amphiphilic copolymers have been used to co-deliver these agents, their effectiveness is often limited by low co-encapsulation efficiency and inherent cationic toxicity. In this study, we developed a facile approach to co-deliver doxorubicin (DOX) and miRNA-26a (miR-26a) using a non-cationic nanogel. The incorporation of an amphiphilic monomer and a lysosomal enzyme-sensitive crosslinker endows the nanomedicine with several advantages, including high co-encapsulation efficiency, lysosomal escape, and minimal toxicity. miR-26a significantly increased the sensitivity of HCC to DOX by 3.35-fold through targeting multiple pathways, and promoted DOX penetration within tumor tissue through reducing type I collagen content, thereby showing significant synergistic anticancer effects. This study provides a facile and biosafe nanoplatform for the efficient co-delivery of DOX and miRNA with synergistic drug effect.
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Affiliation(s)
- Dingyue Zhang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
| | - Mingxiang Zuo
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Jinhui Zhou
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
| | - Siyu Ouyang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
| | - Shuang Liu
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Jianming Yuan
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Chiyi Ou
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Qinghua Chen
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Dongsheng Yu
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Du Cheng
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Jin Wang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
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Niu X, You Q, Hou K, Tian Y, Wei P, Zhu Y, Gao B, Ashrafizadeh M, Aref AR, Kalbasi A, Cañadas I, Sethi G, Tergaonkar V, Wang L, Lin Y, Kang D, Klionsky DJ. Autophagy in cancer development, immune evasion, and drug resistance. Drug Resist Updat 2025; 78:101170. [PMID: 39603146 DOI: 10.1016/j.drup.2024.101170] [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: 07/16/2024] [Revised: 10/22/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024]
Abstract
Macroautophagy/autophagy is a highly conserved evolutionary mechanism involving lysosomes for the degradation of cytoplasmic components including organelles. The constitutive, basal level of autophagy is fundamental for preserving cellular homeostasis; however, alterations in autophagy can cause disease pathogenesis, including cancer. The role of autophagy in cancer is particularly complicated, since this process acts both as a tumor suppressor in precancerous stages but facilitates tumor progression during carcinogenesis and later stages of cancer progression. This shift between anti-tumor and pro-tumor roles may be influenced by genetic and environmental factors modulating key pathways such as those involving autophagy-related proteins, the PI3K-AKT-MTOR axis, and AMPK, which often show dysregulation in tumors. Autophagy regulates various cellular functions, including metabolism of glucose, glutamine, and lipids, cell proliferation, metastasis, and several types of cell death (apoptosis, ferroptosis, necroptosis and immunogenic cell death). These multifaceted roles demonstrate the potential of autophagy to affect DNA damage repair, cell death pathways, proliferation and survival, which are critical in determining cancer cells' response to chemotherapy. Therefore, targeting autophagy pathways presents a promising strategy to combat chemoresistance, as one of the major reasons for the failure in cancer patient treatment. Furthermore, autophagy modulates immune evasion and the function of immune cells such as T cells and dendritic cells, influencing the tumor microenvironment and cancer's biological behavior. However, the therapeutic targeting of autophagy is complex due to its dual role in promoting survival and inducing cell death in cancer cells, highlighting the need for strategies that consider both the beneficial and detrimental effects of autophagy modulation in cancer therapy. Hence, both inducers and inhibitors of autophagy have been introduced for the treatment of cancer. This review emphasizes the intricate interplay between autophagy, tumor biology, and immune responses, offering insights into potential therapeutic approaches that deploy autophagy in the cancer suppression.
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Affiliation(s)
- Xuegang Niu
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Qi You
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Kaijian Hou
- School of Public Health（Long Hu people hospital), Shantou University, Shantou, 515000, Guangdong, China
| | - Yu Tian
- School of Public Health, Benedictine University, Lisle, IL 60532, USA
| | - Penghui Wei
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Yang Zhu
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Bin Gao
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Amir Reza Aref
- VitroVision Department, DeepkinetiX, Inc, Boston, MA, USA
| | - Alireza Kalbasi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Israel Cañadas
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Gautam Sethi
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A⁎STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Lingzhi Wang
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore
| | - Yuanxiang Lin
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
| | - Dezhi Kang
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
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Schütz F, Longo L, Keingeski MB, Filippi-Chiela E, Uribe-Cruz C, Álvares-da-Silva MR. Lipophagy and epigenetic alterations are related to metabolic dysfunction-associated steatotic liver disease progression in an experimental model. World J Hepatol 2024; 16:1468-1479. [DOI: 10.4254/wjh.v16.i12.1468] [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: 05/07/2024] [Revised: 08/31/2024] [Accepted: 09/19/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Genetic and epigenetic alterations are related to metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis.
AIM To evaluate micro (mi)RNAs and lipophagy markers in an experimental model of metabolic dysfunction-associated steatohepatitis (MASH).
METHODS Adult male Sprague Dawley rats were randomized into two groups: Control group (n = 10) fed a standard diet; and intervention group (n = 10) fed a high-fat-choline-deficient diet for 16 weeks. Molecular evaluation of lipophagy markers in liver tissue [sirtuin-1, p62/sequestosome-1, transcription factor-EB, perilipin-2 (Plin2), Plin3, Plin5, lysosome-associated membrane proteins-2, rubicon, and Cd36], and serum miRNAs were performed.
RESULTS Animals in the intervention group developed MASH and showed a significant decrease in sirtuin-1 (P = 0.020) and p62/sequestosome-1 (P < 0.001); the opposite was reported for transcription factor-EB (P = 0.020), Plin2 (P = 0.003), Plin3 (P = 0.031), and Plin5 (P = 0.005) compared to the control group. There was no significant difference between groups for lysosome-associated membrane proteins-2 (P = 0.715), rubicon (P = 0.166), and Cd36 (P = 0.312). The intervention group showed a significant increase in miR-34a (P = 0.005) and miR-21 (P = 0.043) compared to the control. There was no significant difference between groups for miR-375 (P = 0.905), miR-26b (P = 0.698), and miR-155 (P = 0.688).
CONCLUSION Animals with MASH presented expression changes in markers related to lysosomal stress and autophagy as well as in miRNAs related to inflammation and fibrogenesis, processes that promote MASLD progression.
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Affiliation(s)
- Felipe Schütz
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Larisse Longo
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Melina Belén Keingeski
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Eduardo Filippi-Chiela
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
- Department of Morphological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
| | - Carolina Uribe-Cruz
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Facultad de Ciencias de la Salud, Universidad Católica de las Misiones, Posadas 3300, Misiones, Argentina
| | - Mário Reis Álvares-da-Silva
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasilia 71.605-001, Distrito Federal, Brazil
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Wei J, Wang X, Yu D, Tu Y, Yu Y. MicroRNA-mediated autophagy and drug resistance in cancer: mechanisms and therapeutic strategies. Discov Oncol 2024; 15:662. [PMID: 39549162 PMCID: PMC11569378 DOI: 10.1007/s12672-024-01525-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024] Open
Abstract
This paper provides an exhaustive overview of the intricate interplay between microRNAs (miRNAs) and autophagy in the context of human cancers, underscoring the pivotal role these non-coding RNAs play in modulating autophagic pathways and their implications for cancer development, progression, and resistance to therapy. MiRNAs, as critical regulators of gene expression post-transcription, influence various biological processes, including autophagy, a catabolic mechanism essential for cellular homeostasis, stress response, and survival. The review meticulously delineates the mechanisms through which miRNAs impact autophagy by targeting specific genes and signaling pathways, thereby affecting cancer cell proliferation, metastasis, and response to chemotherapy. It highlights several miRNAs with dual roles, acting either as oncogenes or tumor suppressors based on the cellular context and the specific autophagic pathways they regulate. The paper further explores the therapeutic potential of targeting miRNA-autophagy axis, offering insights into novel strategies for cancer treatment through modulation of this axis. Emphasizing the complexity of the miRNA-autophagy relationship, the review calls for more in-depth studies to unravel the nuanced regulatory networks between miRNAs and autophagy in cancer, which could pave the way for the development of innovative therapeutic interventions and diagnostic tools.
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Affiliation(s)
- Jinxing Wei
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Xianghui Wang
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Duo Yu
- Department of Biopharmaceutics School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People's Hospital, Guangdong Medical University, No. 41 Eling North Road, Huizhou, Guangdong, China.
| | - Yaoyu Yu
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China.
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Ghionescu AV, Sorop A, Linioudaki E, Coman C, Savu L, Fogarasi M, Lixandru D, Dima SO. A predicted epithelial-to-mesenchymal transition-associated mRNA/miRNA axis contributes to the progression of diabetic liver disease. Sci Rep 2024; 14:27678. [PMID: 39532948 PMCID: PMC11557572 DOI: 10.1038/s41598-024-77416-4] [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: 06/05/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Despite public health measures, type 2 diabetes (T2D) is still a significant concern worldwide, given its associated complications, including hepatic alterations. The role of epithelial-to-mesenchymal transition (EMT) in liver fibrosis is well established. However, its effects on the progression of diabetic liver diseases are not well understood. Therefore, this study aims to investigate the mRNA/miRNA axes involved in this process. Bioinformatic analysis revealed new EMT-associated genes (CDH2, ITGB1, COL4A1, COL1A1, TNC, CCN2, and JUN), which showed higher expression in obese T2D and hepatocellular carcinoma (HCC) patients. In addition, six miRNAs (miR-21-5p, miR-26a-5p, miR-34a-5p, miR-106a-5p, miR-320a-3p and miR-424-5p) have been found as potential targets. Among them, miR-26a-5p and miR-424-5p were significantly downregulated in nonalcoholic steatohepatitis (NASH) and HCC (p < 0.05), being considered potential negative regulators of the EMT process. In our hepatic mesenchymal culture model, miR-26a-5p negatively regulated cadherin 2 (also known as N-cadherin, CDH2) and promoted the cadherin 1 (also known as E-cadherin, CDH1) expression. Our results reveal potential molecules involved in liver tumor development. Moreover, we observe that miR-26a-5p impairs EMT in the initial stages of diabetic liver disease by inhibiting CDH2 and could be a valuable target in this pathology.
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Grants
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 28571/02.10.2023 UMFCD
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Affiliation(s)
- Alina-Veronica Ghionescu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
| | - Ekaterini Linioudaki
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Cristin Coman
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- "Cantacuzino" National Medico-Military Institute for Research and Development, Bucharest, Romania
| | - Lorand Savu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Marton Fogarasi
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Daniela Lixandru
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania.
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania.
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
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9
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Liu B, Liu L, Liu Y. Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy. Front Immunol 2024; 15:1450487. [PMID: 39315094 PMCID: PMC11416969 DOI: 10.3389/fimmu.2024.1450487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.
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Affiliation(s)
- Beibei Liu
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ling Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Liu
- Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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10
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Mahboobnia K, Beveridge DJ, Yeoh GC, Kabir TD, Leedman PJ. MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities. Int J Mol Sci 2024; 25:9393. [PMID: 39273339 PMCID: PMC11395074 DOI: 10.3390/ijms25179393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.
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Affiliation(s)
- Khadijeh Mahboobnia
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - George C Yeoh
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Tasnuva D Kabir
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
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11
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Poggio P, Rocca S, Fusella F, Ferretti R, Ala U, D'Anna F, Giugliano E, Panuzzo C, Fontana D, Palumbo V, Carrà G, Taverna D, Gambacorti-Passerini C, Saglio G, Fava C, Piazza R, Morotti A, Orso F, Brancaccio M. miR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia. Sci Rep 2024; 14:15089. [PMID: 38956394 PMCID: PMC11220062 DOI: 10.1038/s41598-024-65404-7] [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: 01/24/2024] [Accepted: 06/19/2024] [Indexed: 07/04/2024] Open
Abstract
Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients' bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.
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MESH Headings
- Animals
- Humans
- Mice
- Bone Marrow/metabolism
- Bone Marrow/pathology
- Down-Regulation
- Gene Expression Regulation, Leukemic
- HSP90 Heat-Shock Proteins/metabolism
- HSP90 Heat-Shock Proteins/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Molecular Chaperones/metabolism
- Molecular Chaperones/genetics
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Affiliation(s)
- Pietro Poggio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Stefania Rocca
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Federica Fusella
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Roberta Ferretti
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Ugo Ala
- Department of Veterinary Sciences, University of Turin, Grugliasco, TO, Italy
| | - Flora D'Anna
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Emilia Giugliano
- Division of Internal Medicine and Hematology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | - Cristina Panuzzo
- Department of Clinical and Biological Science, University of Turin, Orbassano, Italy
| | - Diletta Fontana
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Valeria Palumbo
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Giovanna Carrà
- Department of Clinical and Biological Science, University of Turin, Orbassano, Italy
| | - Daniela Taverna
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Carlo Gambacorti-Passerini
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Hematology Division and Bone Marrow Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Giuseppe Saglio
- Department of Clinical and Biological Science, University of Turin, Orbassano, Italy
| | - Carmen Fava
- Department of Clinical and Biological Science, University of Turin, Orbassano, Italy
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Hematology Division and Bone Marrow Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Alessandro Morotti
- Department of Clinical and Biological Science, University of Turin, Orbassano, Italy
| | - Francesca Orso
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Department of Translational Medicine (DIMET), University of Piemonte Orientale, Novara, Italy
| | - Mara Brancaccio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
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12
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Azam HMH, Rößling RI, Geithe C, Khan MM, Dinter F, Hanack K, Prüß H, Husse B, Roggenbuck D, Schierack P, Rödiger S. MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review. Front Mol Neurosci 2024; 17:1386735. [PMID: 38883980 PMCID: PMC11177777 DOI: 10.3389/fnmol.2024.1386735] [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: 02/15/2024] [Accepted: 04/12/2024] [Indexed: 06/18/2024] Open
Abstract
Neurodegenerative diseases (NDs) are characterized by abnormalities within neurons of the brain or spinal cord that gradually lose function, eventually leading to cell death. Upon examination of affected tissue, pathological changes reveal a loss of synapses, misfolded proteins, and activation of immune cells-all indicative of disease progression-before severe clinical symptoms become apparent. Early detection of NDs is crucial for potentially administering targeted medications that may delay disease advancement. Given their complex pathophysiological features and diverse clinical symptoms, there is a pressing need for sensitive and effective diagnostic methods for NDs. Biomarkers such as microRNAs (miRNAs) have been identified as potential tools for detecting these diseases. We explore the pivotal role of miRNAs in the context of NDs, focusing on Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Huntington's disease, and Amyotrophic Lateral Sclerosis. The review delves into the intricate relationship between aging and NDs, highlighting structural and functional alterations in the aging brain and their implications for disease development. It elucidates how miRNAs and RNA-binding proteins are implicated in the pathogenesis of NDs and underscores the importance of investigating their expression and function in aging. Significantly, miRNAs exert substantial influence on post-translational modifications (PTMs), impacting not just the nervous system but a wide array of tissues and cell types as well. Specific miRNAs have been found to target proteins involved in ubiquitination or de-ubiquitination processes, which play a significant role in regulating protein function and stability. We discuss the link between miRNA, PTM, and NDs. Additionally, the review discusses the significance of miRNAs as biomarkers for early disease detection, offering insights into diagnostic strategies.
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Affiliation(s)
- Hafiz Muhammad Husnain Azam
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Rosa Ilse Rößling
- German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
- Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Christiane Geithe
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus - Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Berlin, Germany
| | - Muhammad Moman Khan
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Franziska Dinter
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- PolyAn GmbH, Berlin, Germany
| | - Katja Hanack
- Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany
| | - Harald Prüß
- German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
- Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Britta Husse
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Stefan Rödiger
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus - Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Berlin, Germany
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13
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Jiang MJ, Lin CJ, Liu FR, Mei Z, Gu DN, Tian L. Pancreatic cancer cells hijack tumor suppressive microRNA-26a to promote radioresistance and potentiate tumor repopulation. Heliyon 2024; 10:e31346. [PMID: 38807872 PMCID: PMC11130661 DOI: 10.1016/j.heliyon.2024.e31346] [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: 07/04/2023] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/30/2024] Open
Abstract
Pancreatic cancer is one of the most lethal cancers with significant radioresistance and tumor repopulation after radiotherapy. As a type of short non-coding RNA that regulate various biological and pathological processes, miRNAs might play vital role in radioresistance. We found by miRNA sequencing that microRNA-26a (miR-26a) was upregulated in pancreatic cancer cells after radiation, and returned to normal state after a certain time. miR-26a was defined as a tumor suppressive miRNA by conventional tumor biology experiments. However, transient upregulation of miR-26a after radiation significantly promoted radioresistance, while stable overexpression inhibited radioresistance, highlighting the importance of molecular dynamic changes after treatment. Mechanically, transient upregulation of miR-26a promoted cell cycle arrest and DNA damage repair to promote radioresistance. Further experiments confirmed HMGA2 as the direct functional target, which is an oncogene but enhances radiosensitivity. Moreover, PTGS2 was also the target of miR-26a, which might potentiate tumor repopulation via delaying the synthesis of PGE2. Overall, this study revealed that transient upregulation of miR-26a after radiation promoted radioresistance and potentiated tumor repopulation, highlighting the importance of dynamic changes of molecules upon radiotherapy.
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Affiliation(s)
- Ming-jie Jiang
- Department of Head and Neck Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Chen-jing Lin
- Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Fu-rao Liu
- Department of Oncology, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200032, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Zhu Mei
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Dian-na Gu
- Department of Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Ling Tian
- Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
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14
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Tian Y, Zhang M, Liu LX, Wang ZC, Liu B, Huang Y, Wang X, Ling YZ, Wang F, Feng X, Tu Y. Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis. Front Immunol 2024; 15:1400744. [PMID: 38799446 PMCID: PMC11116607 DOI: 10.3389/fimmu.2024.1400744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.
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Affiliation(s)
- Yu Tian
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
- School of Public Health, Benedictine University, Lisle, IL, United States
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Li-xia Liu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Zi-chao Wang
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Youcai Huang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoling Wang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Yun-zhi Ling
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Furong Wang
- Department of Pathology, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People’s Hospital, Gaozhou, Guangdong, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
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15
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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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16
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Arefnezhad R, Ashna S, Rezaei-Tazangi F, Arfazadeh SM, Seyedsalehie SS, Yeganeafrouz S, Aghaei M, Sanandaji M, Davoodi R, Abadi SRK, Vosough M. Noncoding RNAs and programmed cell death in hepatocellular carcinoma: Significant role of epigenetic modifications in prognosis, chemoresistance, and tumor recurrence rate. Cell Biol Int 2024; 48:556-576. [PMID: 38411312 DOI: 10.1002/cbin.12145] [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: 05/30/2023] [Revised: 01/26/2024] [Accepted: 02/09/2024] [Indexed: 02/28/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high death rate in the world. The molecular mechanisms related to the pathogenesis of HCC have not been precisely defined so far. Hence, this review aimed to address the potential cross-talk between noncoding RNAs (ncRNAs) and programmed cell death in HCC. All related papers in the English language up to June 2023 were collected and screened. The searched keywords in scientific databases, including Scopus, PubMed, and Google Scholar, were HCC, ncRNAs, Epigenetic, Programmed cell death, Autophagy, Apoptosis, Ferroptosis, Chemoresistance, Tumor recurrence, Prognosis, and Prediction. According to the reports, ncRNAs, comprising long ncRNAs, microRNAs, circular RNAs, and small nucleolar RNAs can affect cell proliferation, migration, invasion, and metastasis, as well as cell death-related processes, such as autophagy, ferroptosis, necroptosis, and apoptosis in HCC by regulating cancer-associated genes and signaling pathways, for example, phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase/MAPK, and Wnt/β-catenin signaling pathways. It seems that ncRNAs, as epigenetic regulators, can be utilized as biomarkers in diagnosis, prognosis, survival and recurrence rates prediction, chemoresistance, and evaluation of therapeutic response in HCC patients. However, more scientific evidence is suggested to be accomplished to confirm these results.
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Affiliation(s)
- Reza Arefnezhad
- Coenzyme R Research Institute, Tehran, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Ashna
- Student Research Committee, Islamic Azad University Science and Research Branch, Tehran, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Seyede Shabnam Seyedsalehie
- Department of Pediatrics, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Ahvaz, Iran
| | - Shaghayegh Yeganeafrouz
- Department of Medical Science, Faculty of Medicine, Islamic Azad University, Medical branch, Tehran, Iran
| | - Melika Aghaei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mandana Sanandaji
- Department of Physical Education and Sport Sciences, Tehran University, Tehran, Iran
| | | | | | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Institution for Laboratory Medicine, Karolinska Institutet, Experimental Cancer Medicine, Huddinge, Sweden
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17
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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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18
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Chakraborty S, Nandi P, Mishra J, Niharika, Roy A, Manna S, Baral T, Mishra P, Mishra PK, Patra SK. Molecular mechanisms in regulation of autophagy and apoptosis in view of epigenetic regulation of genes and involvement of liquid-liquid phase separation. Cancer Lett 2024; 587:216779. [PMID: 38458592 DOI: 10.1016/j.canlet.2024.216779] [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: 01/13/2024] [Revised: 02/19/2024] [Accepted: 02/29/2024] [Indexed: 03/10/2024]
Abstract
Cellular physiology is critically regulated by multiple signaling nexuses, among which cell death mechanisms play crucial roles in controlling the homeostatic landscape at the tissue level within an organism. Apoptosis, also known as programmed cell death, can be induced by external and internal stimuli directing the cells to commit suicide in unfavourable conditions. In contrast, stress conditions like nutrient deprivation, infection and hypoxia trigger autophagy, which is lysosome-mediated processing of damaged cellular organelle for recycling of the degraded products, including amino acids. Apparently, apoptosis and autophagy both are catabolic and tumor-suppressive pathways; apoptosis is essential during development and cancer cell death, while autophagy promotes cell survival under stress. Moreover, autophagy plays dual role during cancer development and progression by facilitating the survival of cancer cells under stressed conditions and inducing death in extreme adversity. Despite having two different molecular mechanisms, both apoptosis and autophagy are interconnected by several crosslinking intermediates. Epigenetic modifications, such as DNA methylation, post-translational modification of histone tails, and miRNA play a pivotal role in regulating genes involved in both autophagy and apoptosis. Both autophagic and apoptotic genes can undergo various epigenetic modifications and promote or inhibit these processes under normal and cancerous conditions. Epigenetic modifiers are uniquely important in controlling the signaling pathways regulating autophagy and apoptosis. Therefore, these epigenetic modifiers of both autophagic and apoptotic genes can act as novel therapeutic targets against cancers. Additionally, liquid-liquid phase separation (LLPS) also modulates the aggregation of misfolded proteins and provokes autophagy in the cytosolic environment. This review deals with the molecular mechanisms of both autophagy and apoptosis including crosstalk between them; emphasizing epigenetic regulation, involvement of LLPS therein, and possible therapeutic approaches against cancers.
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Affiliation(s)
- Subhajit Chakraborty
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Piyasa Nandi
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Jagdish Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Soumen Manna
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Tirthankar Baral
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Prahallad Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Pradyumna Kumar Mishra
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462 030, MP, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India.
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Xu J, Bian L, You D, Li Z, Wang T, Li Y, Ren X, He Y. PDGF-BB accelerates TSCC via fibroblast lactates limiting miR-26a-5p and boosting mitophagy. Cancer Cell Int 2024; 24:5. [PMID: 38169376 PMCID: PMC10763357 DOI: 10.1186/s12935-023-03172-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/03/2023] [Indexed: 01/05/2024] Open
Abstract
The tumor microenvironment and cancer-associated fibroblasts (CAFs) play crucial roles in tumor development, and their metabolic coupling remains unclear. Clinical data showed a positive correlation between PDGF-BB, CAFs, and glycolysis in the tumor microenvironment of oral tongue squamous cell carcinoma patients. In vitro, CAFs are derived from hOMF cells treated with PDGF-BB, which induces their formation and promotes aerobic glycolysis. Mitophagy increased the PDGF-BB-induced formation of CAF phenotypes and aerobic glycolysis, while autophagy inhibition blocked PDGF-BB-induced effects. Downregulation of miR-26a-5p was observed in CAFs; upregulation of miR-26a-5p inhibited the expression of mitophagy-related proteins ULKI, Parkin, PINK1, and LC3 and aerobic glycolysis in PDGF-BB-induced CAFs. PDGF-BB-induced CAFs promoted tumor cell proliferation, invasion, metastasis, NF-κB signaling pathway activation, and PDGF-BB secretion. Thus, PDGF-BB is associated with lactate-induced CAF formation and glucose metabolism reprogramming. These findings indicate potential therapeutic targets in oral tongue squamous cell carcinoma.
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Affiliation(s)
- Jianguo Xu
- Department of Oral and Maxillofacial Surgery, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China
- Yunnan Key Laboratory of Stomatology, Kunming, 650106, China
| | - Li Bian
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650106, China
| | - Dingyun You
- School of Public Health, Kunming Medical University, Kunming, 650500, China
| | - Ziliang Li
- Department of oral Implantology, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China
| | - Tingting Wang
- Department of Stomatology, The First People's Hospital of Yunnan Province, Kunming, 650032, China
| | - Yiting Li
- Department of Oral and Maxillofacial Surgery, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China
| | - Xiaobin Ren
- Department of Periodontology, Kunming Medical University School and Hospital of Stomatology, 1088 Haiyuan Central Road, Kunming, Yunnan, 650106, China.
| | - Yongwen He
- Department of Dental Research, Kunming Medical University School and Hospital of Stomatology, 1088 Haiyuan Central Road, Kunming, Yunnan, 650106, China.
- Qujing Medical College, Qujing, 655011, China.
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20
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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21
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Hajizadeh M, Hajizadeh F, Ghaffarei S, Amin Doustvandi M, Hajizadeh K, Yaghoubi SM, Mohammadnejad F, Khiabani NA, Mousavi P, Baradaran B. MicroRNAs and their vital role in apoptosis in hepatocellular carcinoma: miRNA-based diagnostic and treatment methods. Gene 2023; 888:147803. [PMID: 37716587 DOI: 10.1016/j.gene.2023.147803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 08/03/2023] [Accepted: 09/13/2023] [Indexed: 09/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies with high invasive and metastatic capability. Although significant advances have been made in the treatment of HCC, the overall survival rate of patients is still low. It is essential to explore accurate biomarkers for early diagnosis and prognosis along with therapeutic procedures to increase the survival rate of these patients. Anticancer therapies can contribute to induce apoptosis for the elimination of cancerous cells. However, dysregulated apoptosis and proliferation signaling pathways lead to treatment resistance, a significant challenge in improving efficient therapies. MiRNAs, short non-coding RNAs, play crucial roles in the progression of HCC, which regulate gene expression through post-transcriptional inhibition and targeting mRNA degradation in cancers. Dysregulated expression of multiple miRNAs is associated with numerous biological processes, including cell proliferation, apoptosis, invasion and metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and drug resistance in HCC. This review summarizes the role and potential efficacy of miRNAs in promoting and inhibiting cell proliferation and apoptosis in HCC, as well as the role of miRNAs in therapy resistance in HCC.
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Affiliation(s)
- Masoumeh Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnaz Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sevil Ghaffarei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Khadijeh Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyed Mohammad Yaghoubi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | | | - Pegah Mousavi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Yerukala Sathipati S, Aimalla N, Tsai MJ, Carter T, Jeong S, Wen Z, Shukla SK, Sharma R, Ho SY. Prognostic microRNA signature for estimating survival in patients with hepatocellular carcinoma. Carcinogenesis 2023; 44:650-661. [PMID: 37701974 DOI: 10.1093/carcin/bgad062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/01/2023] [Accepted: 09/08/2023] [Indexed: 09/14/2023] Open
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is one of the leading cancer types with increasing annual incidence and high mortality in the USA. MicroRNAs (miRNAs) have emerged as valuable prognostic indicators in cancer patients. To identify a miRNA signature predictive of survival in patients with HCC, we developed a machine learning-based HCC survival estimation method, HCCse, using the miRNA expression profiles of 122 patients with HCC. METHODS The HCCse method was designed using an optimal feature selection algorithm incorporated with support vector regression. RESULTS HCCse identified a robust miRNA signature consisting of 32 miRNAs and obtained a mean correlation coefficient (R) and mean absolute error (MAE) of 0.87 ± 0.02 and 0.73 years between the actual and estimated survival times of patients with HCC; and the jackknife test achieved an R and MAE of 0.73 and 0.97 years between actual and estimated survival times, respectively. The identified signature has seven prognostic miRNAs (hsa-miR-146a-3p, hsa-miR-200a-3p, hsa-miR-652-3p, hsa-miR-34a-3p, hsa-miR-132-5p, hsa-miR-1301-3p and hsa-miR-374b-3p) and four diagnostic miRNAs (hsa-miR-1301-3p, hsa-miR-17-5p, hsa-miR-34a-3p and hsa-miR-200a-3p). Notably, three of these miRNAs, hsa-miR-200a-3p, hsa-miR-1301-3p and hsa-miR-17-5p, also displayed association with tumor stage, further emphasizing their clinical relevance. Furthermore, we performed pathway enrichment analysis and found that the target genes of the identified miRNA signature were significantly enriched in the hepatitis B pathway, suggesting its potential involvement in HCC pathogenesis. CONCLUSIONS Our study developed HCCse, a machine learning-based method, to predict survival in HCC patients using miRNA expression profiles. We identified a robust miRNA signature of 32 miRNAs with prognostic and diagnostic value, highlighting their clinical relevance in HCC management and potential involvement in HCC pathogenesis.
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Affiliation(s)
| | - Nikhila Aimalla
- Department of Internal Medicine-Pediatrics, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - Ming-Ju Tsai
- Hinda and Arthur Marcus Institute for Aging Research at Hebrew Senior Life, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Tonia Carter
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Sohyun Jeong
- Hinda and Arthur Marcus Institute for Aging Research at Hebrew Senior Life, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Zhi Wen
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Sanjay K Shukla
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Rohit Sharma
- Department of Surgical Oncology, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
- Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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23
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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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24
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Wang HL, Li JN, Kan WJ, Xu GY, Luo GH, Song N, Wu WB, Feng B, Fu JF, Tu YT, Liu MM, Xu R, Zhou YB, Wei G, Li J. Chloroquine enhances the efficacy of chemotherapy drugs against acute myeloid leukemia by inactivating the autophagy pathway. Acta Pharmacol Sin 2023; 44:2296-2306. [PMID: 37316630 PMCID: PMC10618541 DOI: 10.1038/s41401-023-01112-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 05/16/2023] [Indexed: 06/16/2023]
Abstract
Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.
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Affiliation(s)
- Han-Lin Wang
- School of Pharmacy, Fudan University, Shanghai, 210023, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jia-Nan Li
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wei-Juan Kan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Gao-Ya Xu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Guang-Hao Luo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
| | - Ning Song
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Wen-Biao Wu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
| | - Bo Feng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jing-Feng Fu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yu-Tong Tu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Min-Min Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China
| | - Ran Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yu-Bo Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
| | - Gang Wei
- School of Pharmacy, Fudan University, Shanghai, 210023, China.
| | - Jia Li
- School of Pharmacy, Fudan University, Shanghai, 210023, China.
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China.
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
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Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G. Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming. Mol Aspects Med 2023; 93:101205. [PMID: 37515939 DOI: 10.1016/j.mam.2023.101205] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/15/2023] [Accepted: 07/17/2023] [Indexed: 07/31/2023]
Abstract
Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance.
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Affiliation(s)
- Roberto Mattioli
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy
| | - Beatrice Colotti
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Luciana Mosca
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy.
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Murata M, Bilim V, Shirono Y, Kazama A, Hiruma K, Tasaki M, Tomita Y. MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma. Curr Issues Mol Biol 2023; 45:7432-7448. [PMID: 37754254 PMCID: PMC10529713 DOI: 10.3390/cimb45090470] [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: 07/03/2023] [Revised: 09/07/2023] [Accepted: 09/09/2023] [Indexed: 09/28/2023] Open
Abstract
The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3β in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3β. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3' untranslated region of GSK-3β, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3β protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3β expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field.
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Affiliation(s)
- Masaki Murata
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (V.B.); (Y.S.); (A.K.); (K.H.); (M.T.); (Y.T.)
| | - Vladimir Bilim
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (V.B.); (Y.S.); (A.K.); (K.H.); (M.T.); (Y.T.)
- Department of Urology, Kameda Daiichi Hospital, Niigata 950-0165, Japan
| | - Yuko Shirono
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (V.B.); (Y.S.); (A.K.); (K.H.); (M.T.); (Y.T.)
| | - Akira Kazama
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (V.B.); (Y.S.); (A.K.); (K.H.); (M.T.); (Y.T.)
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Kaede Hiruma
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (V.B.); (Y.S.); (A.K.); (K.H.); (M.T.); (Y.T.)
| | - Masayuki Tasaki
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (V.B.); (Y.S.); (A.K.); (K.H.); (M.T.); (Y.T.)
| | - Yoshihiko Tomita
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (V.B.); (Y.S.); (A.K.); (K.H.); (M.T.); (Y.T.)
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El-Aziz MKA, Dawoud A, Kiriacos CJ, Fahmy SA, Hamdy NM, Youness RA. Decoding hepatocarcinogenesis from a noncoding RNAs perspective. J Cell Physiol 2023; 238:1982-2009. [PMID: 37450612 DOI: 10.1002/jcp.31076] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/11/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Being a leading lethal malignancy worldwide, the pathophysiology of hepatocellular carcinoma (HCC) has gained a lot of interest. Yet, underlying mechanistic basis of the liver tumorigenesis is poorly understood. The role of some coding genes and their respective translated proteins, then later on, some noncoding RNAs (ncRNAs) such as microRNAs have been extensively studied in context of HCC pathophysiology; however, the implication of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in HCC is indeed less investigated. As a subclass of the ncRNAs which has been elusive for long time ago, lncRNAs was found to be involved in plentiful cellular functions such as DNA, RNA, and proteins regulation. Hence, it is undisputed that lncRNAs dysregulation profoundly contributes to HCC via diverse etiologies. Accordingly, lncRNAs represent a hot research topic that requires prime focus in HCC. In this review, the authors discuss breakthrough discoveries involving lncRNAs and circRNAs dysregulation that have contributed to the contemporary concepts of HCC pathophysiology and how these concepts could be leveraged as potential novel diagnostic and prognostic HCC biomarkers. Further, this review article sheds light on future trends, thereby discussing the pathological roles of lncRNAs and circRNAs in HCC proliferation, migration, and epithelial-to-mesenchymal transition. Along this line of reasoning, future recommendations of how these targets could be exploited to achieve effective HCC-related drug development is highlighted.
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Affiliation(s)
- Mostafa K Abd El-Aziz
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Alyaa Dawoud
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Caroline J Kiriacos
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Sherif Ashraf Fahmy
- Chemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Rana A Youness
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Landry J, Shows K, Jagdeesh A, Shah A, Pokhriyal M, Yakovlev V. Regulatory miRNAs in cancer cell recovery from therapy exposure and its implications as a novel therapeutic strategy for preventing disease recurrence. Enzymes 2023; 53:113-196. [PMID: 37748835 DOI: 10.1016/bs.enz.2023.07.007] [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] [Indexed: 09/27/2023]
Abstract
The desired outcome of cancer therapies is the eradication of disease. This can be achieved when therapy exposure leads to therapy-induced cancer cell death as the dominant outcome. Theoretically, a permanent therapy-induced growth arrest could also contribute to a complete response, which has the potential to lead to remission. However, preclinical models have shown that therapy-induced growth arrest is not always durable, as recovering cancer cell populations can contribute to the recurrence of cancer. Significant research efforts have been expended to develop strategies focusing on the prevention of recurrence. Recovery of cells from therapy exposure can occur as a result of several cell stress adaptations. These include cytoprotective autophagy, cellular quiescence, a reversable form of senescence, and the suppression of apoptosis and necroptosis. It is well documented that microRNAs regulate the response of cancer cells to anti-cancer therapies, making targeting microRNAs therapeutically a viable strategy to sensitization and the prevention of recovery. We propose that the use of microRNA-targeting therapies in prolonged sequence, that is, a significant period after initial therapy exposure, could reduce toxicity from the standard combination strategy, and could exploit new epigenetic states essential for cancer cells to recover from therapy exposure. In a step toward supporting this strategy, we survey the available scientific literature to identify microRNAs which could be targeted in sequence to eliminate residual cancer cell populations that were arrested as a result of therapy exposure. It is our hope that by successfully identifying microRNAs which could be targeted in sequence we can prevent disease recurrence.
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Affiliation(s)
- Joseph Landry
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
| | - Kathryn Shows
- Department of Biology, Virginia State University, Petersburg, VA, United States
| | - Akash Jagdeesh
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Aashka Shah
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Mihir Pokhriyal
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Vasily Yakovlev
- Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, United States.
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Gupta J, Suliman M, Ali R, Margiana R, Hjazi A, Alsaab HO, Qasim MT, Hussien BM, Ahmed M. Double-edged sword role of miRNA-633 and miRNA-181 in human cancers. Pathol Res Pract 2023; 248:154701. [PMID: 37542859 DOI: 10.1016/j.prp.2023.154701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 08/07/2023]
Abstract
Understanding the function and mode of operation of microRNAs (miRNAs) in cancer is of growing interest. The short non-coding RNAs known as miRNAs, which target mRNA in multicellular organisms, are described as controlling essential cellular processes. The miR-181 family and miR-633 are well-known miRNAs that play a key role in the development and metastasis of tumor cells. They may facilitate either tumor-suppressive or oncogenic function in malignant cells, according to mounting evidence. Metastatic cells that are closely linked to cancer cell migration, invasion, and angiogenesis can be identified by abnormal levels of miR-181 and miR-633. Numerous studies have demonstrated their capacity to control drug resistance, cell growth, apoptosis, and the epithelial-mesenchymal transition (EMT) and metastasis process. Interestingly, the levels of miR-181 and miR-633 and their potential target genes in the basic cellular process can vary depending on the type of cancer cells and their gene expression profile. Such miRNAs' interactions with other non-coding RNAs such as long non-coding RNAs and circular RNAs can influence tumor behaviors. Herein, we concentrated on the multifaceted roles of miR-181 and miR-633 and potential targets in human tumorigenesis, ranging from cell growth and metastasis to drug resistance.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U. P., India.
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Rida Ali
- Rawalpindi Medical University, Rawalpindi, Pakistan
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Muhja Ahmed
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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Li J, Bao H, Huang Z, Liang Z, Wang M, Lin N, Ni C, Xu Y. Little things with significant impact: miRNAs in hepatocellular carcinoma. Front Oncol 2023; 13:1191070. [PMID: 37274242 PMCID: PMC10235484 DOI: 10.3389/fonc.2023.1191070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/09/2023] [Indexed: 06/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has developed into one of the most lethal, aggressive, and malignant cancers worldwide. Although HCC treatment has improved in recent years, the incidence and lethality of HCC continue to increase yearly. Therefore, an in-depth study of the pathogenesis of HCC and the search for more reliable therapeutic targets are crucial to improving the survival quality of HCC patients. Currently, miRNAs have become one of the hotspots in life science research, which are widely present in living organisms and are non-coding RNAs involved in regulating gene expression. MiRNAs exert their biological roles by suppressing the expression of downstream genes and are engaged in various HCC-related processes, including proliferation, apoptosis, invasion, and metastasis. In addition, the expression status of miRNAs is related to the drug resistance mechanism of HCC, which has important implications for the systemic treatment of HCC. This paper reviews the regulatory role of miRNAs in the pathogenesis of HCC and the clinical applications of miRNAs in HCC in recent years.
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Affiliation(s)
- Jiehan Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Haolin Bao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Zixin Liang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Mei Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Ning Lin
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian, China
| | - Chunjie Ni
- Jiangsu Province Engineering Research Center of Tumor Targeted Nano Diagnostic and Therapeutic Materials, Yancheng Teachers University, Yancheng, Jiangsu, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian, China
- Jiangsu Province Engineering Research Center of Tumor Targeted Nano Diagnostic and Therapeutic Materials, Yancheng Teachers University, Yancheng, Jiangsu, China
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui, China
- Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People’s Hospital, Changxing, Zhejiang, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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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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Ait-Ahmed Y, Lafdil F. Novel insights into the impact of liver inflammatory responses on primary liver cancer development. LIVER RESEARCH 2023; 7:26-34. [PMID: 39959704 PMCID: PMC11791919 DOI: 10.1016/j.livres.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/05/2022] [Accepted: 01/27/2023] [Indexed: 03/10/2023]
Abstract
Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.
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Affiliation(s)
- Yeni Ait-Ahmed
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
- Institut Universitaire de France (IUF), Paris, France
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Oura K, Morishita A, Hamaya S, Fujita K, Masaki T. The Roles of Epigenetic Regulation and the Tumor Microenvironment in the Mechanism of Resistance to Systemic Therapy in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:2805. [PMID: 36769116 PMCID: PMC9917861 DOI: 10.3390/ijms24032805] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/29/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita 761-0793, Kagawa, Japan
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Hepatoprotective Effect of Kaempferol: A Review of the Dietary Sources, Bioavailability, Mechanisms of Action, and Safety. Adv Pharmacol Pharm Sci 2023; 2023:1387665. [PMID: 36891541 PMCID: PMC9988374 DOI: 10.1155/2023/1387665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/27/2022] [Accepted: 02/03/2023] [Indexed: 03/02/2023] Open
Abstract
The liver is the body's most critical organ that performs vital functions. Hepatic disorders can affect the physiological and biochemical functions of the body. Hepatic disorder is a condition that describes the damage to cells, tissues, structures, and functions of the liver, which can cause fibrosis and ultimately result in cirrhosis. These diseases include hepatitis, ALD, NAFLD, liver fibrosis, liver cirrhosis, hepatic failure, and HCC. Hepatic diseases are caused by cell membrane rupture, immune response, altered drug metabolism, accumulation of reactive oxygen species, lipid peroxidation, and cell death. Despite the breakthrough in modern medicine, there is no drug that is effective in stimulating the liver function, offering complete protection, and aiding liver cell regeneration. Furthermore, some drugs can create adverse side effects, and natural medicines are carefully selected as new therapeutic strategies for managing liver disease. Kaempferol is a polyphenol contained in many vegetables, fruits, and herbal remedies. We use it to manage various diseases such as diabetes, cardiovascular disorders, and cancers. Kaempferol is a potent antioxidant and has anti-inflammatory effects, which therefore possesses hepatoprotective properties. The previous research has studied the hepatoprotective effect of kaempferol in various hepatotoxicity protocols, including acetaminophen (APAP)-induced hepatotoxicity, ALD, NAFLD, CCl4, HCC, and lipopolysaccharide (LPS)-induced acute liver injury. Therefore, this report aims to provide a recent brief overview of the literature concerning the hepatoprotective effect of kaempferol and its possible molecular mechanism of action. It also provides the most recent literature on kaempferol's chemical structure, natural source, bioavailability, and safety.
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35
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Li L, Xun C, Yu CH. Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma. World J Hepatol 2022; 14:1985-1996. [PMID: 36618329 PMCID: PMC9813843 DOI: 10.4254/wjh.v14.i12.1985] [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: 09/05/2022] [Revised: 10/24/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Among the most common cancers, hepatocellular carcinoma (HCC) has a high rate of tumor recurrence, tumor dormancy, and drug resistance after initial successful chemotherapy or radiotherapy. A small subset of cancer cells, cancer stem cells (CSCs), exhibit stem cell characteristics and are present in various cancers, including HCC. The dysregulation of microRNAs (miRNAs) often accompanies the occurrence and development of HCC. miRNAs can influence tumorigenesis, progression, recurrence, and drug resistance by regulating CSCs properties, which supports their clinical utility in managing and treating HCC. This review summarizes the regulatory effects of miRNAs on CSCs in HCC with a special focus on their impact on HCC recurrence.
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Affiliation(s)
- Lei Li
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Chen Xun
- Department of Hepatobiliary Surgery, Zhuzhou Central Hospital, Zhuzhou 412000, Hunan Province, China
| | - Chun-Hong Yu
- School of Engineering Medicine, Beihang University, Beijing 100191, China.
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Serra M, Pal R, Puliga E, Sulas P, Cabras L, Cusano R, Giordano S, Perra A, Columbano A, Kowalik MA. mRNA-miRNA networks identify metabolic pathways associated to the anti-tumorigenic effect of thyroid hormone on preneoplastic nodules and hepatocellular carcinoma. Front Oncol 2022; 12:941552. [PMID: 36203462 PMCID: PMC9530455 DOI: 10.3389/fonc.2022.941552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
Background Thyroid hormones (THs) inhibit hepatocellular carcinoma (HCC) through different mechanisms. However, whether microRNAs play a role in the antitumorigenic effect of THs remains unknown. Methods By next generation sequencing (NGS) we performed a comprehensive comparative miRNomic and transcriptomic analysis of rat hepatic preneoplastic lesions exposed or not to a short-term treatment with triiodothyronine (T3). The expression of the most deregulated miRs was also investigated in rat HCCs, and in human hepatoma cell lines, treated or not with T3. Results Among miRs down-regulated in preneoplastic nodules following T3, co-expression networks revealed those targeting thyroid hormone receptor-β (Thrβ) and deiodinase1, and Oxidative Phosphorylation. On the other hand, miRs targeting members of the Nrf2 Oxidative Pathway, Glycolysis, Pentose Phosphate Pathway and Proline biosynthesis – all involved in the metabolic reprogramming displayed by preneoplastic lesions– were up-regulated. Notably, while the expression of most miRs deregulated in preneoplastic lesions was not altered in HCC or in hepatoma cells, miR-182, a miR known to target Dio1 and mitochondrial complexes, was down-deregulated by T3 treatment at all stages of hepatocarcinogenesis and in hepatocarcinoma cell lines. In support to the possible critical role of miR-182 in hepatocarcinogenesis, exogenous expression of this miR significantly impaired the inhibitory effect of T3 on the clonogenic growth capacity of human HCC cells. Conclusions This work identified several miRNAs, so far never associated to T3. In addition, the precise definition of the miRNA-mRNA networks elicited by T3 treatment gained in this study may provide a better understanding of the key regulatory events underlying the inhibitory effect of T3 on HCC development. In this context, T3-induced down-regulation of miR-182 appears as a promising tool.
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Affiliation(s)
- Marina Serra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Rajesh Pal
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Elisabetta Puliga
- Department of Oncology, University of Turin, Turin, Italy
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy
| | - Pia Sulas
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Lavinia Cabras
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Roberto Cusano
- Centro di Ricerca, Sviluppo e Studi Superiori in Sardegna (CRS4), Pula, Italy
| | - Silvia Giordano
- Department of Oncology, University of Turin, Turin, Italy
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Amedeo Columbano
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
- *Correspondence: Amedeo Columbano, ; Marta Anna Kowalik,
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
- *Correspondence: Amedeo Columbano, ; Marta Anna Kowalik,
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Abdu S, Juaid N, Amin A, Moulay M, Miled N. Therapeutic Effects of Crocin Alone or in Combination with Sorafenib against Hepatocellular Carcinoma: In Vivo & In Vitro Insights. Antioxidants (Basel) 2022; 11:antiox11091645. [PMID: 36139719 PMCID: PMC9495549 DOI: 10.3390/antiox11091645] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/13/2022] [Accepted: 08/24/2022] [Indexed: 12/24/2022] Open
Abstract
This study investigated the therapeutic effects of the phytochemical crocin alone or in combination with sorafenib both in rats chemically induced with hepatocellular carcinoma (HCC) and in human liver cancer cell line (HepG2). Male rats were randomly divided into five groups, namely, control group, HCC induced group, and groups treated with sorafenib, crocin or both crocin and sorafenib. HCC was induced in rats with a single intraperitoneal injection of diethylnitrosamine (DEN), then 2-acetylaminofluorene (2-AAF). The HCC-induced rats showed a significant decrease in body weight compared to animals treated with either or both examined drugs. Serum inflammatory markers (C-reactive protein (CRP); interleukin-6 (IL-6); lactate dehydrogenase (LDH), and oxidative stress markers were significantly increased in the HCC group and were restored upon treatment with either or both of therapeutic molecules. Morphologically, the HCC-induced rats manifested most histopathological features of liver cancer. Treatment with either or both of crocin and sorafenib successfully restored normal liver architecture. The expression of key genes involved in carcinogenesis (TNFα, p53, VEGF and NF-κB) was highly augmented upon HCC induction and was attenuated post-treatment with either or both examined drugs. Treatment with both crocin and sorafenib improved the histopathological and inflammation parameters as compared to single treatments. The in vivo anti-cancer effects of crocin and/or sorafenib were supported by their respective cytotoxicity on HepG2 cells. Crocin and sorafenib displayed an anti-tumor synergetic effect on HepG2 cells. The present findings demonstrated that a treatment regimen with crocin and sorafenib reduced liver toxicity, impeded HCC development, and improved the liver functions.
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Affiliation(s)
- Suzan Abdu
- Department of Biological Sciences, University of Jeddah, Jeddah 23445, Saudi Arabia
| | - Nouf Juaid
- Department of Biological Sciences, University of Jeddah, Jeddah 23445, Saudi Arabia
- Correspondence: (N.J.); (N.M.)
| | - Amr Amin
- Biology Department, UAE University, Al Ain 15551, United Arab Emirates
- The College, The University of Chicago, Chicago, IL 60637, USA
| | - Mohamed Moulay
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdul Aziz University, Jeddah 22252, Saudi Arabia
| | - Nabil Miled
- Department of Biological Sciences, University of Jeddah, Jeddah 23445, Saudi Arabia
- Functional Genomics and Plant Physiology Research Unit, Higher Institute of Biotechnology Sfax, University of Sfax, BP261 Road Soukra Km4, Sfax 3038, Tunisia
- Correspondence: (N.J.); (N.M.)
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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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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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Sritharan S, Guha S, Hazarika S, Sivalingam N. Meta analysis of bioactive compounds, miRNA, siRNA and cell death regulators as sensitizers to doxorubicin induced chemoresistance. Apoptosis 2022; 27:622-646. [PMID: 35716277 DOI: 10.1007/s10495-022-01742-z] [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: 05/30/2022] [Indexed: 11/02/2022]
Abstract
Cancer has presented to be the most challenging disease, contributing to one in six mortalities worldwide. The current treatment regimen involves multiple rounds of chemotherapy administration, alone or in combination. The treatment has adverse effects including cardiomyopathy, hepatotoxicity, and nephrotoxicity. In addition, the development of resistance to chemo has been attributed to cancer relapse and low patient overall survivability. Multiple drug resistance development may be through numerous factors such as up-regulation of drug transporters, drug inactivation, alteration of drug targets and drug degradation. Doxorubicin is a widely used first line chemotherapeutic drug for a myriad of cancers. It has multiple intracellular targets, DNA intercalation, adduct formation, topoisomerase inhibition, iron chelation, reactive oxygen species generation and promotes immune mediated clearance of the tumor. Agents that can sensitize the resistant cancer cells to the chemotherapeutic drug are currently the focus to improve the clinical efficiency of cancer therapy. This review summarizes the recent 10-year research on the use of natural phytochemicals, inhibitors of apoptosis and autophagy, miRNAs, siRNAs and nanoformulations being investigated for doxorubicin chemosensitization.
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Affiliation(s)
- Sruthi Sritharan
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, Chengalpattu District, Chennai, Tamil Nadu, 603203, India
| | - Sampurna Guha
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, Chengalpattu District, Chennai, Tamil Nadu, 603203, India
| | - Snoopy Hazarika
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, Chengalpattu District, Chennai, Tamil Nadu, 603203, India
| | - Nageswaran Sivalingam
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, Chengalpattu District, Chennai, Tamil Nadu, 603203, India.
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Cheng Y, Mao M, Lu Y. The biology of YAP in programmed cell death. Biomark Res 2022; 10:34. [PMID: 35606801 PMCID: PMC9128211 DOI: 10.1186/s40364-022-00365-5] [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: 11/06/2021] [Accepted: 03/18/2022] [Indexed: 02/08/2023] Open
Abstract
In the last few decades, YAP has been shown to be critical in regulating tumor progression. YAP activity can be regulated by many kinase cascade pathways and proteins through phosphorylation and promotion of cytoplasmic localization. Other factors can also affect YAP activity by modulating its binding to different transcription factors (TFs). Programmed cell death (PCD) is a genetically controlled suicide process present with the scope of eliminating cells unnecessary or detrimental for the proper development of the organism. In some specific states, PCD is activated and facilitates the selective elimination of certain types of tumor cells. As a candidate oncogene correlates with many regulatory factors, YAP can inhibit or induce different forms of PCD, including apoptosis, autophagy, ferroptosis and pyroptosis. Furthermore, YAP may act as a bridge between different forms of PCD, eventually leading to different outcomes regarding tumor development. Researches on YAP and PCD may benefit the future development of novel treatment strategies for some diseases. Therefore, in this review, we provide a general overview of the cellular functions of YAP and the relationship between YAP and PCD.
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Affiliation(s)
- Yifan Cheng
- Department of Gastrointestinal Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, Zhejiang, China
| | - Misha Mao
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yong Lu
- Department of Gastrointestinal Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, Zhejiang, China.
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Xu LL, Chen YK, Zhang QY, Chen LJ, Zhang KK, Li JH, Liu JL, Wang Q, Xie XL. Gestational exposure to GenX induces hepatic alterations by the gut-liver axis in maternal mice: A similar mechanism as PFOA. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 820:153281. [PMID: 35066053 DOI: 10.1016/j.scitotenv.2022.153281] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/09/2022] [Accepted: 01/16/2022] [Indexed: 05/27/2023]
Abstract
GenX is an alternative to perfluorooctanoic acid (PFOA) and was included in the accession list of Substances of Very High Concern in 2019. Gestational GenX exposure induces maternal hepatotoxicity in animals. However, the mechanisms of GenX toxicity have not been explored. In the present study, pregnant Balb/c mice were administered with PFOA (1 mg/kg BW/day), GenX (2 mg/kg BW/day), or Milli-Q water by gavage during gestation. Similar hepatic pathological changes, including enlargement of hepatocytes, cytoplasm loss, nucleus migration, inflammatory cell infiltration, and reduction of glycogen storage, were observed in PFOA and GenX groups. Increased expression levels of indicators of the TLR4 pathway indicated activation of inflammation in the liver of maternal mice after exposure to PFOA or GenX, consistent with the pathological changes. Overexpression of cleaved PARP-1, cleaved caspase 3, Bax and decreased Bcl-2 proteins indicated activation of apoptosis, whereas overexpression of ULK-1, p62, beclin-1, LC3-II proteins and downregulation of p-mTOR implied that PFOA and GenX exposure initiated autophagy. Decreased secretion of mucus, reduced expression levels of tight junction proteins, and higher serum levels of lipopolysaccharide indicated disruption of the intestinal barrier. Translocation of lipopolysaccharide may be recognized by TLR4, thus triggering inflammatory pathway in the maternal liver. In summary, gestational exposure to PFOA or GenX induced maternal hepatic alterations through the gut-liver axis.
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Affiliation(s)
- Ling-Ling Xu
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Yu-Kui Chen
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Qin-Yao Zhang
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Li-Jian Chen
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Kai-Kai Zhang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Jia-Hao Li
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Jia-Li Liu
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Qi Wang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
| | - Xiao-Li Xie
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
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Gao S, Bu X, Gao Y, Bao Z, Shi W, Luan L, Chen H, Zhang B, Tian Q, Guan W, Yang L. The miR-532-E2F1 feedback loop contributes to gastric cancer progression. Cell Death Dis 2022; 13:376. [PMID: 35440106 PMCID: PMC9018701 DOI: 10.1038/s41419-022-04832-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 03/27/2022] [Accepted: 04/04/2022] [Indexed: 11/12/2022]
Abstract
Gastric cancer (GC) ranks fourth in incidence and mortality worldwide, ascertaining the pathogenesis of GC is crucial for its treatment. E2F1, which regulates the transcription of genes encoding proteins involved in DNA repair, DNA replication, mitosis and survival of cancer patients, functions as a key regulator in GC progression. However, the underneath mechanism of these processes is not fully elucidated. Here, TCGA database analysis, microarray immunohistochemical technique and western blot showed that E2F1 was highly upregulated in clinical GC tissues and correlated with tumor malignancy. In vitro and in vivo assays confirmed the oncogenic function of E2F1. MiR-532 was decreased and negatively correlated with E2F1 in GC tissues. MiR-532 directly targeted and inhibited E2F1 expression, leading to the decrease of ASK1 and elevation of TXNIP, and affected proliferation, cell cycle, apoptosis and DNA damage in vitro and tumor growth in vivo. Moreover, E2F1 serves as a transcriptional repressor to suppress miR-532 expression and a double-negative feedback loop was formed between them. This study demonstrates the significant roles of the E2F1-miR-532 double-negative feedback loop in GC progression and may represent a potential target for GC therapy.
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Affiliation(s)
- Shanting Gao
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China
| | - Xiaomin Bu
- Department of Clinical Laboratory, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Yongyue Gao
- Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital Nanjing University Medicine School, Nanjing, China
| | - Zengtao Bao
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China
| | - Wenchao Shi
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China
| | - Lipeng Luan
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China
| | - Huiyu Chen
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China
| | - Baoming Zhang
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China.
| | - Qingshui Tian
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China.
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
| | - Liuqing Yang
- Department of Infectious Diseases, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China.
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Development an Immune-Related MicroRNA Risk Index in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:5224434. [PMID: 35466321 PMCID: PMC9019458 DOI: 10.1155/2022/5224434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 03/30/2022] [Indexed: 12/24/2022]
Abstract
Purpose Hepatocellular carcinoma (HC) has emerged as one of the most prevalent malignancies on a global scale. Recently, immunotherapy has achieved favorable effectiveness in the management of multiple cancers. However, there are limited therapeutic options for advanced HC. As the liver is a special immune organ, we intend to uncover potential and effective immunotherapeutic modalities for HC. Our study was designed to develop specific immune-related miRNAs (IRMs) for outcome assessment and individualized strategies for the management of HC. Methods The miRNA-seq and survival data of TCGA-LIHC dataset was enrolled into this program. We first collected IRMs from Immune-miR website. Differentially expression analysis was applied to screen aberrantly expressed IRMs. In order to set up an IRM-related index (IRMRI) in HC, we conducted the Cox relevant methods. Next, the statistical approaches (survival curve and ROC curve analyses) were utilized to detect the evaluation capacity of our IRMRI. Subsequently, we obtained the target genes of hub miRNAs from IRMRI through three miRNA-related predictive online tools (miRDB, miRTarBase, and TargetScan websites). Results Five IRMs were determined to develop the IRMRI. It can effectively segregate all HC cases from two different risk subgroups. We identified a marked discrepancy in survival outcome between the two groups by survival analysis and confirmed the reliability of IRMRI in two testing sets. Moreover, we collected 10 hub target genes (ESR1, IGF1, PDGFRB, JUN, MYC, ZWINT, MAD2L1, TOP2A, KIF11, and CDCA8) which were strongly linked to HC progression and malignant behavior. Conclusion We screened out five hub IRMs with clinical value and constructed a risk index model in HC, which can precisely assess the risk status and outcome of patients to a certain extent.
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El-Mahdy HA, Sallam AAM, Ismail A, Elkhawaga SY, Elrebehy MA, Doghish AS. miRNAs inspirations in hepatocellular carcinoma: Detrimental and favorable aspects of key performers. Pathol Res Pract 2022; 233:153886. [PMID: 35405621 DOI: 10.1016/j.prp.2022.153886] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. HCC initiation, progression, and therapy failure are all influenced by various variables, including microRNAs (miRNAs). miRNAs are short non-coding RNA sequences that modulate target mRNA expression by deteriorating or repressing translation. miRNAs play an imperative role in HCC pathogenesis by triggering the induction of cancer stem cells (CSCs) and their proliferation, while also delaying apoptosis, sustaining the cell cycle, and inspiring angiogenesis, invasion, and metastasis. Additionally, miRNAs modulate crucial HCC-related molecular pathways such as the p53 pathway, the Wnt/β-catenin pathway, VEGFR2, and PTEN/PI3K/AKT pathway. Consequently, the goal of this review was to give an up-to-date overview of oncogenic and tumor suppressor (TS) miRNAs, as well as their potential significance in HCC pathogenesis and treatment responses, highlighting their underpinning molecular pathways in HCC initiation and progression. Similarly, the biological importance and clinical application of miRNAs in HCC are summarized.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
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Lei Y, Chen L, Liu J, Zhong Y, Deng L. The MicroRNA-Based Strategies to Combat Cancer Chemoresistance via Regulating Autophagy. Front Oncol 2022; 12:841625. [PMID: 35211417 PMCID: PMC8861360 DOI: 10.3389/fonc.2022.841625] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance frequently occurs in cancer treatment, which results in chemotherapy failure and is one of the most leading causes of cancer-related death worldwide. Understanding the mechanism of chemoresistance and exploring strategies to overcome chemoresistance have become an urgent need. Autophagy is a highly conserved self-degraded process in cells. The dual roles of autophagy (pro-death or pro-survival) have been implicated in cancers and chemotherapy. MicroRNA (miRNA) is a class of small non-coding molecules that regulate autophagy at the post-transcriptional level in cancer cells. The association between miRNAs and autophagy in cancer chemoresistance has been emphasized. In this review, we focus on the dual roles of miRNA-mediated autophagy in facilitating or combating chemoresistance, aiming to shed lights on the potential role of miRNAs as targets to overcome chemoresistance.
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Affiliation(s)
- Yuhe Lei
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lei Chen
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Junshan Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yinqin Zhong
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lijuan Deng
- Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
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He X, Cheng X, Ding J, Xiong M, Chen B, Cao G. Hyperglycemia induces miR-26-5p down-regulation to overexpress PFKFB3 and accelerate epithelial–mesenchymal transition in gastric cancer. Bioengineered 2022; 13:2902-2917. [PMID: 35094634 PMCID: PMC8974024 DOI: 10.1080/21655979.2022.2026730] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Gastric cancer (GC) is one of the most deadly malignancies with high morbidity worldwide. Cancer cells exhibited higher level of glucose catabolism than normal cells to meet the needs for rapid growth. Emerging evidences indicated that hyperglycemia has positive effects on the progression of tumor. As a vital regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) was confirmed to have a higher expression level in tumor tissue and correlated with the prognosis of GC patients. However, the role of PFKFB3 in GC patients with hyperglycemia remains unclear. The data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were utilized to analyze the expression level of PFKFB3 and conducted survival analysis of GC patients. Western blot assay was used to detect gene expression at the protein level. Small interfering RNA (siRNA) transfection assay was conducted to down-regulate the expression of PFKFB3. Cell functional assays were carried out to reflect the ability of cell proliferation and migration. The results indicated that PFKFB3 was significantly upregulated and its overexpression was associated with poor prognosis of GC patients. Besides, hyperglycemia stimulated the higher expression of PFKFB3 along with the enhanced proliferation, migration and epithelial–mesenchymal transition (EMT) in GC cells. Knocking down of PFKFB3 effectively reversed the effects of high glucose concentration on GC malignant phenotype and the opposite results were gained when miR-26-5p was inhibited. Therefore, PFKFB3 down-regulated by miR-26-5p inhibited the malignant phenotype of GC with hyperglycemia.
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Affiliation(s)
- Xiaobo He
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiao Cheng
- Department of Pathology, Ningbo Diagnostic Pathology Center, Ningbo, China
| | - Jianfeng Ding
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Maoming Xiong
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bo Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guodong Cao
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
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Feng X, Zou B, Nan T, Zheng X, Zheng L, Lan J, Chen W, Yu J. MiR-25 enhances autophagy and promotes sorafenib resistance of hepatocellular carcinoma via targeting FBXW7. Int J Med Sci 2022; 19:257-266. [PMID: 35165511 PMCID: PMC8795798 DOI: 10.7150/ijms.67352] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/07/2021] [Indexed: 12/25/2022] Open
Abstract
Sorafenib resistance is a major challenge in the treatment of patients with advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are a large family of non-coding RNA molecules, which is an important mechanism of drug resistance. We previously found that knockdown of miR-25 increased the sensitivity of TRAIL-induced apoptosis in liver cancer stem cells. We aimed to study the effects of miR-25 on sorafenib resistance of HCC and the underlying mechanisms. In the present study, we analyzed the expression of miR-25 between HCC and normal tissues and predicted miR-25 target genes through databases. After transfecting miR-25 mimics, inhibitor or FBXW7 Plasmid, CCK-8 and flow cytometry assay was performed to determine the sorafenib resistance. We performed LC3-dual-fluorescence assay and Western blotting to detect the autophagy levels. The expression of miR-25 was upregulated in human HCC tissues and was associated with tumor pathological grade, clinic staging, and lymphatic metastasis. MiR-25 enhanced sorafenib resistance of HCC cells and autophagy. FBXW7 is the direct target of miR-25. Overexpression of FBXW7 could reverse the increase of sorafenib resistance caused by miR-25 mimics. Our results suggested that miR-25 increased the sorafenib resistance of HCC via inducing autophagy. In addition, miR-25 decreases the expression of FBXW7 protein to regulate autophagy. Therefore, miR-25 may represent a novel therapeutic target for the treatment of HCC.
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Affiliation(s)
- Xiaoning Feng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Bei Zou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Tianhao Nan
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiaoxiao Zheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Li Zheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Jiahua Lan
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Jun Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Qu J, Lin Z. Autophagy Regulation by Crosstalk between miRNAs and Ubiquitination System. Int J Mol Sci 2021; 22:ijms222111912. [PMID: 34769343 PMCID: PMC8585084 DOI: 10.3390/ijms222111912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes with ~22 nucleotides which are involved in the regulation of post-transcriptional gene expression. Ubiquitination and deubiquitination are common post-translational modifications in eukaryotic cells and important pathways in regulating protein degradation and signal transduction, in which E3 ubiquitin ligases and deubiquitinases (DUBs) play a decisive role. MiRNA and ubiquitination are involved in the regulation of most biological processes, including autophagy. Furthermore, in recent years, the direct interaction between miRNA and E3 ubiquitin ligases or deubiquitinases has attracted much attention, and the cross-talk between miRNA and ubiquitination system has been proved to play key regulatory roles in a variety of diseases. In this review, we summarized the advances in autophagy regulation by crosstalk between miRNA and E3 ubiquitin ligases or deubiquitinases.
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