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1
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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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2
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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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3
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Yang Y, Liu L, Tian Y, Gu M, Wang Y, Ashrafizadeh M, Reza Aref A, Cañadas I, Klionsky DJ, Goel A, Reiter RJ, Wang Y, Tambuwala M, Zou J. Autophagy-driven regulation of cisplatin response in human cancers: Exploring molecular and cell death dynamics. Cancer Lett 2024; 587:216659. [PMID: 38367897 DOI: 10.1016/j.canlet.2024.216659] [Citation(s) in RCA: 67] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/29/2023] [Accepted: 01/17/2024] [Indexed: 02/19/2024]
Abstract
Despite the challenges posed by drug resistance and side effects, chemotherapy remains a pivotal strategy in cancer treatment. A key issue in this context is macroautophagy (commonly known as autophagy), a dysregulated cell death mechanism often observed during chemotherapy. Autophagy plays a cytoprotective role by maintaining cellular homeostasis and recycling organelles, and emerging evidence points to its significant role in promoting cancer progression. Cisplatin, a DNA-intercalating agent known for inducing cell death and cell cycle arrest, often encounters resistance in chemotherapy treatments. Recent studies have shown that autophagy can contribute to cisplatin resistance or insensitivity in tumor cells through various mechanisms. This resistance can be mediated by protective autophagy, which suppresses apoptosis. Additionally, autophagy-related changes in tumor cell metastasis, particularly the induction of Epithelial-Mesenchymal Transition (EMT), can also lead to cisplatin resistance. Nevertheless, pharmacological strategies targeting the regulation of autophagy and apoptosis offer promising avenues to enhance cisplatin sensitivity in cancer therapy. Notably, numerous non-coding RNAs have been identified as regulators of autophagy in the context of cisplatin chemotherapy. Thus, therapeutic targeting of autophagy or its associated pathways holds potential for restoring cisplatin sensitivity, highlighting an important direction for future clinical research.
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Affiliation(s)
- Yang Yang
- Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Lixia Liu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Yu Tian
- School of Public Health, Benedictine University, Lisle, IL, USA
| | - Miaomiao Gu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Yanan Wang
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding, China
| | - Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 440 Ji Yan Road, Jinan, Shandong, China
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc, 6, Tide Street, Boston, MA, 02210, USA
| | - Israel Cañadas
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA; Nuclear Dynamics and Cancer Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Arul Goel
- University of California Santa Barbara, Santa Barbara, CA, USA
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health, Long School of Medicine, San Antonio, TX, 78229, USA
| | - Yuzhuo Wang
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Murtaza Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln, LN6 7TS, UK.
| | - Jianyong Zou
- Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 510080, Guangzhou, China.
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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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Medda A, Compagnoni M, Spini G, Citro S, Croci O, Campaner S, Tagliabue M, Ansarin M, Chiocca S. c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer. Cell Death Dis 2023; 14:719. [PMID: 37925449 PMCID: PMC10625625 DOI: 10.1038/s41419-023-06248-3] [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: 01/25/2023] [Revised: 10/13/2023] [Accepted: 10/25/2023] [Indexed: 11/06/2023]
Abstract
Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.
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Affiliation(s)
- Alessandro Medda
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO Campus, Via Adamello 16, 20139, Milan, Italy
| | - Micaela Compagnoni
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO Campus, Via Adamello 16, 20139, Milan, Italy
| | - Giorgio Spini
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO Campus, Via Adamello 16, 20139, Milan, Italy
| | - Simona Citro
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO Campus, Via Adamello 16, 20139, Milan, Italy
| | - Ottavio Croci
- Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Stefano Campaner
- Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Marta Tagliabue
- Division of Otolaryngology Head & Neck Surgery, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Mohssen Ansarin
- Division of Otolaryngology Head & Neck Surgery, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy
| | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO Campus, Via Adamello 16, 20139, Milan, Italy.
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Wenhao R, Yali C, Shaoming L, Jingjing Z, Ling G, Keqian Z. circAP1M2 activates ATG9A-associated autophagy by inhibiting miR-1249-3p to promote cisplatin resistance in oral squamous cell carcinoma. J Cell Physiol 2023; 238:2612-2624. [PMID: 37661341 DOI: 10.1002/jcp.31116] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 08/14/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2023]
Abstract
Cisplatin (CDDP) is the first-line chemotherapeutic agent for oral squamous cell carcinoma (OSCC). Susceptibility to drug resistance during treatment is a significant challenge in enhancing the therapeutic efficacy of OSCC. Autophagy is an essential element to guarantee the cancer cells' survival under chemo-stress conditions. We established a cisplatin-resistant OSCC cell line (CAL27/CDDP) and showed that circAP1M2 is a remarkably upregulated circular RNA in OSCC. Knockdown of circAP1M2 contributes to reversing cisplatin chemoresistance in vivo, while enhanced autophagic activity in cisplatin-resistant OSCC cells contributes to chemoresistance. Mechanistically, we showed that circAP1M2 induces autophagy-associated cisplatin resistance via the miR-1249-3p-ATG9A axis in OSCC cells. This study provides insights into the specific influence of a newly identified circular RNA circAP1M2 in OSCC regarding drug abuse and the treatment of a broad range of cancers that can benefit from cisplatin.
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Affiliation(s)
- Ren Wenhao
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Cheng Yali
- Department of Stomatology, Huaian Hospital of Huaian City, Huaian, Jiangsu, China
| | - Li Shaoming
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- School of Stomatology of Qingdao University, Qingdao, Shandong, China
| | - Zheng Jingjing
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Gao Ling
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zhi Keqian
- Department of Oral and Maxillofacial Reconstruction, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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7
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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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9
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Tolue Ghasaban F, Maharati A, Akhlaghipour I, Moghbeli M. MicroRNAs as the critical regulators of autophagy-mediated cisplatin response in tumor cells. Cancer Cell Int 2023; 23:80. [PMID: 37098542 PMCID: PMC10127417 DOI: 10.1186/s12935-023-02925-7] [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: 03/03/2023] [Accepted: 04/12/2023] [Indexed: 04/27/2023] Open
Abstract
Chemotherapy is one of the most common therapeutic methods in advanced and metastatic tumors. Cisplatin (CDDP) is considered as one of the main first-line chemotherapy drugs in solid tumors. However, there is a high rate of CDDP resistance in cancer patients. Multi-drug resistance (MDR) as one of the main therapeutic challenges in cancer patients is associated with various cellular processes such as drug efflux, DNA repair, and autophagy. Autophagy is a cellular mechanism that protects the tumor cells toward the chemotherapeutic drugs. Therefore, autophagy regulatory factors can increase or decrease the chemotherapy response in tumor cells. MicroRNAs (miRNAs) have a pivotal role in regulation of autophagy in normal and tumor cells. Therefore, in the present review, we discussed the role of miRNAs in CDDP response through the regulation of autophagy. It has been reported that miRNAs mainly increased the CDDP sensitivity in tumor cells by inhibition of autophagy. PI3K/AKT signaling pathway and autophagy-related genes (ATGs) were the main targets of miRNAs in the regulation of autophagy-mediated CDDP response in tumor cells. This review can be an effective step to introduce the miRNAs as efficient therapeutic options to increase autophagy-mediated CDDP sensitivity in tumor cells.
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Affiliation(s)
- Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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10
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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: 16] [Impact Index Per Article: 8.0] [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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11
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de Ávila Narciso Gomes R, Marmolejo-Garza A, Haan FJ, García TM, Chen T, Mauthe M, Moreira Franco Parisotto YE, Murakami MM, Marie SKN, Baptista MS, Dolga AM, Trombetta-Lima M. Mitochondrial dysfunction mediates neuronal cell response to DMMB photodynamic therapy. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119429. [PMID: 36608805 DOI: 10.1016/j.bbamcr.2022.119429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 12/20/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023]
Abstract
Photodynamic therapy (PDT) is a process in which a photosensitizer (PS) is exposed to specific wavelengths and generates reactive oxygen species (ROS) which act within nanometers. The low invasive nature and directed cytotoxicity of this approach render it attractive to the treatment of different conditions, including the ones that affect the central nervous system (CNS). The effect of PDT on healthy neurons is one main concern over its use in the CNS, since neuronal-like cells were shown to be particularly sensitive to certain PSs. Among available PSs, 1,9-dimethyl-methylene blue (DMMB) stands out as being resistant to reduction to its inactive leuco form and by being able to produce high levels of singlet‑oxygen. In this study, we aimed to investigate DMMB photodamage mechanisms in the hippocampal cell line HT22. Our results demonstrate that DMMB-PDT decrease in cell viability was linked with an increase in cell death and overall ROS production. Besides, it resulted in a significant increase in mitochondrial ROS production and decreased mitochondria membrane potential. Furthermore, DMMB-PDT significantly increased the presence of acidic autolysosomes, which was accompanied by an increase in ATG1 and ATG8 homologue GaBarap1 expression, and decreased DRAM1 expression. Taken together our results indicated that mitochondrial and autophagic dysfunction underlie DMMB-PDT cytotoxicity in neuronal cells.
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Affiliation(s)
- Raphael de Ávila Narciso Gomes
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, the Netherlands; Chemistry Institute, Biochemistry Department, University of São Paulo (USP), 05508-000 São Paulo, Brazil
| | - Alejandro Marmolejo-Garza
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, the Netherlands; Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands
| | - Floris-Jan Haan
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, the Netherlands
| | - Teresa Mitchell García
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, the Netherlands
| | - Tingting Chen
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, the Netherlands
| | - Mario Mauthe
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands
| | | | - Mario Minor Murakami
- Medical School, Neurology Department, University of São Paulo (USP), 01246903 São Paulo, Brazil
| | | | - Maurício S Baptista
- Chemistry Institute, Biochemistry Department, University of São Paulo (USP), 05508-000 São Paulo, Brazil
| | - Amalia M Dolga
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, the Netherlands.
| | - Marina Trombetta-Lima
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, the Netherlands; Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
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12
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Tavakoli Pirzaman A, Ebrahimzadeh Pirshahid M, Babajani B, Rahmati A, Niknezhad S, Hosseinzadeh R, Taheri M, Ebrahimi-Zadeh F, Doostmohamadian S, Kazemi S. The Role of microRNAs in Regulating Cancer Cell Response to Oxaliplatin-Containing Regimens. Technol Cancer Res Treat 2023; 22:15330338231206003. [PMID: 37849311 PMCID: PMC10586010 DOI: 10.1177/15330338231206003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/18/2023] [Accepted: 10/18/2023] [Indexed: 10/19/2023] Open
Abstract
Oxaliplatin (cyclohexane-1,2-diamine; oxalate; platinum [2+]) is a third-generation chemotherapeutic drug with anticancer effects. Oxaliplatin has a role in the treatment of several cancers. It is one of the few drugs which can eliminate the neoplastic cells of colorectal cancer. Also, it has an influential role in breast cancer, lung cancer, bladder cancer, prostate cancer, and gastric cancer. Although oxaliplatin has many beneficial effects in cancer treatment, resistance to this drug is in the way to cure neoplastic cells and reduce treatment efficacy. microRNAs are a subtype of small noncoding RNAs with ∼22 nucleotides that exist among species. They have diverse roles in physiological processes, including cellular proliferation and cell death. Moreover, miRNAs have essential roles in resistance to cancer treatment and can strengthen sensitivity to chemotherapeutic drugs and regimens. In colorectal cancer, the co-treatment of oxaliplatin with anti-miR-19a can partially reverse the oxaliplatin resistance through the upregulation of phosphatase and tensin homolog (PTEN). Moreover, by preventing the spread of gastric cancer cells and downregulating glypican-3 (GPC3), MiR-4510 may modify immunosuppressive signals in the tumor microenvironment. Treatment with oxaliplatin may develop into a specialized therapeutic drug for patients with miR-4510 inhibition and glypican-3-expressing gastric cancer. Eventually, miR-122 upregulation or Wnt/β-catenin signaling suppression boosted the death of HCC cells and made them more sensitive to oxaliplatin. Herein, we have reviewed the role of microRNAs in regulating cancer cells' response to oxaliplatin, with particular attention to gastrointestinal cancers. We also discussed the role of these noncoding RNAs in the pathophysiology of oxaliplatin-induced neuropathic pain.
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Affiliation(s)
| | | | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Amirhossein Rahmati
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Shokat Niknezhad
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Rezvan Hosseinzadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Taheri
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Faezeh Ebrahimi-Zadeh
- Student Research Committee, school of Medicine, Jahrom University of Medical Science, Jahrom, Iran
| | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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13
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Zandieh MA, Farahani MH, Rajabi R, Avval ST, Karimi K, Rahmanian P, Razzazan M, Javanshir S, Mirzaei S, Paskeh MDA, Salimimoghadam S, Hushmandi K, Taheriazam A, Pandey V, Hashemi M. Epigenetic regulation of autophagy by non-coding RNAs in gastrointestinal tumors: Biological functions and therapeutic perspectives. Pharmacol Res 2023; 187:106582. [PMID: 36436707 DOI: 10.1016/j.phrs.2022.106582] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/26/2022]
Abstract
Cancer is the manifestation of changes and mutations in genetic and epigenetic levels. Non-coding RNAs (ncRNAs) are commonly dysregulated in disease pathogenesis, and their role in cancer has been well-documented. The ncRNAs regulate various molecular pathways and mechanisms in cancer that can lead to induction/inhibition of carcinogenesis. Autophagy is a molecular "self-digestion" mechanism its function can be pro-survival or pro-death in tumor cells. The aim of the present review is to evaluate the role of ncRNAs in regulating autophagy in gastrointestinal tumors. The role of the ncRNA/autophagy axis in affecting the progression of gastric, liver, colorectal, pancreatic, esophageal, and gallbladder cancers is investigated. Both ncRNAs and autophagy mechanisms can function as oncogenic or onco-suppressor and this interaction can determine the growth, invasion, and therapy response of gastrointestinal tumors. ncRNA/autophagy axis can reduce/increase the proliferation of gastrointestinal tumors via the glycolysis mechanism. Furthermore, related molecular pathways of metastasis, such as EMT and MMPs, are affected by the ncRNA/autophagy axis. The response of gastrointestinal tumors to chemotherapy and radiotherapy can be suppressed by pro-survival autophagy, and ncRNAs are essential regulators of this mechanism. miRNAs can regulate related genes and proteins of autophagy, such as ATGs and Beclin-1. Furthermore, lncRNAs and circRNAs down-regulate miRNA expression via sponging to modulate the autophagy mechanism. Moreover, anti-cancer agents can affect the expression level of ncRNAs regulating autophagy in gastrointestinal tumors. Therefore, translating these findings into clinics can improve the prognosis of patients.
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Affiliation(s)
- Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Melika Heydari Farahani
- Faculty of Veterinary Medicine, Islamic Azad University, Shahr-e kord Branch, Chaharmahal and Bakhtiari, Iran
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Kimia Karimi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Salar Javanshir
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, 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.
| | - Vijay Pandey
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, Guangdong, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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14
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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: 23] [Impact Index Per Article: 7.7] [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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15
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Behrouj H, Vakili O, Sadeghdoust A, Aligolighasemabadi N, Khalili P, Zamani M, Mokarram P. Epigenetic regulation of autophagy in coronavirus disease 2019 (COVID-19). Biochem Biophys Rep 2022; 30:101264. [PMID: 35469237 PMCID: PMC9021360 DOI: 10.1016/j.bbrep.2022.101264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 11/22/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has become the most serious global public health issue in the past two years, requiring effective therapeutic strategies. This viral infection is a contagious disease caused by new coronaviruses (nCoVs), also called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autophagy, as a highly conserved catabolic recycling process, plays a significant role in the growth and replication of coronaviruses (CoVs). Therefore, there is great interest in understanding the mechanisms that underlie autophagy modulation. The modulation of autophagy is a very complex and multifactorial process, which includes different epigenetic alterations, such as histone modifications and DNA methylation. These mechanisms are also known to be involved in SARS-CoV-2 replication. Thus, molecular understanding of the epigenetic pathways linked with autophagy and COVID-19, could provide novel therapeutic targets for COVID-19 eradication. In this context, the current review highlights the role of epigenetic regulation of autophagy in controlling COVID-19, focusing on the potential therapeutic implications.
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Affiliation(s)
- Hamid Behrouj
- Behbahan Faculty of Medical Sciences, Behbahan, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Adel Sadeghdoust
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Aligolighasemabadi
- Department of Internal Medicine, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Parnian Khalili
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Iran
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16
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Zitkute V, Kukcinaviciute E, Jonusiene V, Starkuviene V, Sasnauskiene A. Differential effects of 5‐fluorouracil and oxaliplatin on autophagy in chemoresistant colorectal cancer cells. J Cell Biochem 2022; 123:1103-1115. [DOI: 10.1002/jcb.30267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/30/2022] [Accepted: 04/20/2022] [Indexed: 12/22/2022]
Affiliation(s)
- Vilmante Zitkute
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Egle Kukcinaviciute
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Violeta Jonusiene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Vytaute Starkuviene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
- BioQuant Heidelberg University Heidelberg Germany
| | - Ausra Sasnauskiene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
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17
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Gou Y, Zheng X, Li W, Deng H, Qin S. Polysaccharides Produced by the Mushroom Trametes robiniophila Murr Boosts the Sensitivity of Hepatoma Cells to Oxaliplatin via the miR-224-5p/ABCB1/P-gp Axis. Integr Cancer Ther 2022; 21:15347354221090221. [PMID: 35426328 PMCID: PMC9014716 DOI: 10.1177/15347354221090221] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aim: To investigate the mechanisms employed by PS-T (polysaccharides of Trametes, PS-T), the main active ingredient of Huaier granules, to improve the susceptibility of hepatoma cells to oxaliplatin (OXA). Methods: Cell proliferation in response to PS-T was determined both in vitro and in vivo. The effects of PS-T on miRNAs were analyzed with the use of a microarray. MiRNAs were screened under specific conditions (P < .05, logFoldChange > ABS [1.5]) and further silenced or overexpressed by liposome transfection. Levels of ABCB1 mRNA and P-gp were detected by qRT-PCR and western blot analysis, respectively. A dual fluorescence assay was performed to determine whether miRNA directly targets ABCB1. Results: PS-T enhanced the inhibitory effect of OXA in human hepatoma cells and xenografts. Among 5 up-regulated miRNAs, overexpression of only miR-224-5p inhibited the expression of ABCB1 mRNA and P-gp, while silencing of miR-224-5p had an opposite effect. Moreover, miR-224-5p can directly target the 3′-UTR of ABCB1. Conclusion: PS-T increases the sensitivity of human hepatoma cells to OXA via the miR-224-5p/ABCB1/P-gp axis.
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Affiliation(s)
- Yudong Gou
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Xia Zheng
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenming Li
- Nanjing Jinling Hospital: East Region Military Command General Hospital, Nanjing, China
| | - Hongyu Deng
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shukui Qin
- Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing Jinling Hospital: East Region Military Command General Hospital, Nanjing, China
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18
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Szczepanek J, Skorupa M, Tretyn A. MicroRNA as a Potential Therapeutic Molecule in Cancer. Cells 2022; 11:1008. [PMID: 35326459 PMCID: PMC8947269 DOI: 10.3390/cells11061008] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/11/2022] [Accepted: 03/16/2022] [Indexed: 12/11/2022] Open
Abstract
Small noncoding RNAs, as post-translational regulators of many target genes, are not only markers of neoplastic disease initiation and progression, but also markers of response to anticancer therapy. Hundreds of miRNAs have been identified as biomarkers of drug resistance, and many have demonstrated the potential to sensitize cancer cells to therapy. Their properties of modulating the response of cells to therapy have made them a promising target for overcoming drug resistance. Several methods have been developed for the delivery of miRNAs to cancer cells, including introducing synthetic miRNA mimics, DNA plasmids containing miRNAs, and small molecules that epigenetically alter endogenous miRNA expression. The results of studies in animal models and preclinical studies for solid cancers and hematological malignancies have confirmed the effectiveness of treatment protocols using microRNA. Nevertheless, the use of miRNAs in anticancer therapy is not without limitations, including the development of a stable nanoconstruct, delivery method choices, and biodistribution. The aim of this review was to summarize the role of miRNAs in cancer treatment and to present new therapeutic concepts for these molecules. Supporting anticancer therapy with microRNA molecules has been verified in numerous clinical trials, which shows great potential in the treatment of cancer.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
| | - Monika Skorupa
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
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19
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Sadri Nahand J, Salmaninejad A, Mollazadeh S, Tamehri Zadeh SS, Rezaee M, Sheida AH, Sadoughi F, Dana PM, Rafiyan M, Zamani M, Taghavi SP, Dashti F, Mirazimi SMA, Bannazadeh Baghi H, Moghoofei M, Karimzadeh M, Vosough M, Mirzaei H. Virus, Exosome, and MicroRNA: New Insights into Autophagy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:97-162. [DOI: 10.1007/5584_2022_715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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20
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Abstract
Liver cancer is the fourth leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 80% of all liver cancers. The serum concentration of alpha-fetoprotein (AFP) is the only validated biomarker for HCC diagnosis. MicroRNAs (miRNAs) are small non-coding RNAs of 21–30 nucleotides playing a critical role in human carcinogenesis, with types of miRNAs with oncogenic (oncomiRs) or tumor suppressor features. The altered expression of miRNAs in HCC is associated with many pathological processes, such as cancer initiation, tumor growth, apoptosis escape, promotion of migration and invasion. Moreover, circulating miRNAs have been increasingly investigated as non-invasive biomarkers for HCC diagnosis. MiRNAs’ expression patterns are altered in HCC and several single miRNAs or miRNAs panels have been found significantly up or downregulated in HCC with respect to healthy controls or non-oncological patients (cirrhotic or with viral hepatitis). However, any of the investigated miRNAs or miRNAs panels has entered clinical practice so far. This has mostly to do with lack of protocols standardization, small sample size and discrepancies in the measurement techniques. This review summarizes the major findings regarding the diagnostic role of miRNAs in HCC and their possible use together with standard biomarkers in order to obtain an early diagnosis and easier differential diagnosis from non-cancerous liver disease.
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21
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Seebacher NA, Krchniakova M, Stacy AE, Skoda J, Jansson PJ. Tumour Microenvironment Stress Promotes the Development of Drug Resistance. Antioxidants (Basel) 2021; 10:1801. [PMID: 34829672 PMCID: PMC8615091 DOI: 10.3390/antiox10111801] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/29/2021] [Accepted: 11/08/2021] [Indexed: 01/18/2023] Open
Abstract
Multi-drug resistance (MDR) is a leading cause of cancer-related death, and it continues to be a major barrier to cancer treatment. The tumour microenvironment (TME) has proven to play an essential role in not only cancer progression and metastasis, but also the development of resistance to chemotherapy. Despite the significant advances in the efficacy of anti-cancer therapies, the development of drug resistance remains a major impediment to therapeutic success. This review highlights the interplay between various factors within the TME that collectively initiate or propagate MDR. The key TME-mediated mechanisms of MDR regulation that will be discussed herein include (1) altered metabolic processing and the reactive oxygen species (ROS)-hypoxia inducible factor (HIF) axis; (2) changes in stromal cells; (3) increased cancer cell survival via autophagy and failure of apoptosis; (4) altered drug delivery, uptake, or efflux and (5) the induction of a cancer stem cell (CSC) phenotype. The review also discusses thought-provoking ideas that may assist in overcoming the TME-induced MDR. We conclude that stressors from the TME and exposure to chemotherapeutic agents are strongly linked to the development of MDR in cancer cells. Therefore, there remains a vast area for potential research to further elicit the interplay between factors existing both within and outside the TME. Elucidating the mechanisms within this network is essential for developing new therapeutic strategies that are less prone to failure due to the development of resistance in cancer cells.
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Affiliation(s)
| | - Maria Krchniakova
- Department of Experimental Biology, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic;
- International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
| | - Alexandra E. Stacy
- Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia;
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic;
- International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
| | - Patric J. Jansson
- Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia;
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St. Leonards, NSW 2065, Australia
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22
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Mao C, Xu X, Ding Y, Xu N. Optimization of BCG Therapy Targeting Neutrophil Extracellular Traps, Autophagy, and miRNAs in Bladder Cancer: Implications for Personalized Medicine. Front Med (Lausanne) 2021; 8:735590. [PMID: 34660642 PMCID: PMC8514698 DOI: 10.3389/fmed.2021.735590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/05/2021] [Indexed: 01/07/2023] Open
Abstract
Bladder cancer (BC) is the ninth most common cancer and the thirteenth most common cause of mortality worldwide. Bacillus Calmette Guerin (BCG) instillation is a common treatment option for BC. BCG therapy is associated with the less adversary effects, compared to chemotherapy, radiotherapy, and other conventional treatments. BCG could inhibit the progression and recurrence of BC by triggering apoptosis pathways, arrest cell cycle, autophagy, and neutrophil extracellular traps (NETs) formation. However, BCG therapy is not efficient for metastatic cancer. NETs and autophagy were induced by BCG and help to suppress the growth of tumor cells especially in the primary stages of BC. Activated neutrophils can stimulate autophagy pathway and release NETs in the presence of microbial pathogenesis, inflammatory agents, and tumor cells. Autophagy can also regulate NETs formation and induce production of reactive oxygen species (ROS) and NETs. Moreover, miRNAs are important regulator of gene expression. These small non-coding RNAs are also considered as an essential factor to control the levels of tumor development. However, the interaction between BCG and miRNAs has not been well-understood yet. Therefore, the present study discusses the roles of miRNAs in regulations of autophagy and NETs formation in BCG therapy in the treatment of BC. The roles of autophagy and NETs formation in BC treatment and efficiency of BCG are also discussed.
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Affiliation(s)
- Chenyu Mao
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xin Xu
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yongfeng Ding
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Nong Xu
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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23
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Papaefthymiou A, Christodoulidis G, Koffas A, Doulberis M, Polyzos SA, Manolakis A, Potamianos S, Kapsoritakis A, Kountouras J. Role of autophagy in gastric carcinogenesis. World J Gastrointest Oncol 2021; 13:1244-1262. [PMID: 34721765 PMCID: PMC8529927 DOI: 10.4251/wjgo.v13.i10.1244] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/06/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer represents a common and highly fatal malignancy, and thus a pathophysiology-based reconsideration is necessary, given the absence of efficient therapeutic regimens. In this regard, emerging data reveal a significant role of autophagy in gastric oncogenesis, progression, metastasis and chemoresistance. Although autophagy comprises a normal primordial process, ensuring cellular homeostasis under energy depletion and stress conditions, alterations at any stage of the complex regulatory system could stimulate a tumorigenic and promoting cascade. Among others, Helicobacter pylori infection induces a variety of signaling molecules modifying autophagy, during acute infection or after chronic autophagy degeneration. Subsequently, defective autophagy allows malignant transformation and upon cancer establishment, an overactive autophagy is stimulated. This overexpressed autophagy provides energy supplies and resistance mechanisms to gastric cancer cells against hosts defenses and anticancer treatment. This review interprets the implicated autophagic pathways in normal cells and in gastric cancer to illuminate the potential preventive, therapeutic and prognostic benefits of understanding and intervening autophagy.
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Affiliation(s)
- Apostolis Papaefthymiou
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki 54642, Macedonia, Greece
| | | | - Apostolos Koffas
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Michael Doulberis
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki 54642, Macedonia, Greece
- Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau 5001, Switzerland
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
| | - Anastasios Manolakis
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Spyros Potamianos
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Andreas Kapsoritakis
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Jannis Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki 54642, Macedonia, Greece
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24
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Xu XF, Yang XK, Song Y, Chen BJ, Yu X, Xu T, Chen ZL. Dysregulation of Non-coding RNAs mediates Cisplatin Resistance in Hepatocellular Carcinoma and therapeutic strategies. Pharmacol Res 2021; 176:105906. [PMID: 34543740 DOI: 10.1016/j.phrs.2021.105906] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/06/2021] [Accepted: 09/14/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fourth major contributor to cancer-related deaths worldwide, and patients mostly have poor prognosis. Although several drugs have been approved for the treatment of HCC, cisplatin (CDDP) is still applied in treatment of HCC as a classical chemotherapeutic drug. Unfortunately, the emergence of CDDP resistance has caused HCC patients to exhibit poor drug response. How to mitigate or even reverse CDDP resistance is an urgent clinical issue to be solved. Because of critical roles in biological functional processes and disease developments, non-coding RNAs (ncRNAs) have been extensively studied in HCC in recent years. Importantly, ncRNAs have also been demonstrated to be involved in the development of HCC to CDDP resistance process. Therefore, this review highlighted the regulatory roles of ncRNAs in CDDP resistance of HCC, elucidated the multiple potential mechanisms by which HCC develops CDDP resistance, and attempted to propose multiple drug delivery systems to alleviate CDDP resistance. Recently, ncRNA-based therapy may be a feasible strategy to alleviate CDDP resistance in HCC. Meanwhile, nanoparticles can overcome the deficiencies in ncRNA-based therapy and make it possible to reverse tumor drug resistance. The combined use of these strategies provides clues for reversing CDDP resistance and overcoming the poor prognosis of HCC.
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Affiliation(s)
- Xu-Feng Xu
- Department of Hemorrhoid and Fistula of Traditional Chinese Medicine, Chaohu Hospital Affiliated to Anhui Medical University, Chaohu, Anhui, 238000, P.R. China.
| | - Xiao-Ke Yang
- Department of Rheumatology and Immunology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, P.R. China.
| | - Yang Song
- Department of Pain Treatment, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, P.R. China.
| | - Bang-Jie Chen
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, P.R. China.
| | - Xiao Yu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, P. R. China.
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, P. R. China; School of Pharmacy, Anhui Key Lab. of Bioactivity of Natural Products, Anhui Medical University, Hefei, Anhui, 230032, P. R. China.
| | - Zhao-Lin Chen
- Department of Pharmacy, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui, 230001, P.R. China.
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25
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Chaeichi-Tehrani N, Ferns GA, Hassanian SM, Khazaei M, Avan A. The Therapeutic Potential of Targeting Autophagy in The Treatment of Cancer. Curr Cancer Drug Targets 2021; 21:725-736. [PMID: 34077348 DOI: 10.2174/1568009621666210601113144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 03/02/2021] [Accepted: 03/12/2021] [Indexed: 11/22/2022]
Abstract
Autophagy is a mechanism by which unwanted cellular components are degraded through a pathway that involves the lysosomes and contributes to several pathological conditions such as cancer. Gastrointestinal cancers affect the digestive organs from the esophagus to the anus and are among the most commonly diagnosed cancers globally. The modulation of autophagy using pharmacologic agents potentially offers a great potential for cancer therapy. In this review, some commonly used compounds, together with their molecular target and the mechanism through which they stimulate or block the autophagy pathway as well as their therapeutic benefit in treating patients with gastrointestinal cancers, are summarized.
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Affiliation(s)
- Negin Chaeichi-Tehrani
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Seyed Mahdi Hassanian
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic syndrome Research centre, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Autophagy, an accomplice or antagonist of drug resistance in HCC? Cell Death Dis 2021; 12:266. [PMID: 33712559 PMCID: PMC7954824 DOI: 10.1038/s41419-021-03553-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 02/13/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal malignancy characterized by poor prognosis and a low 5-year survival rate. Drug treatment is proving to be effective in anti-HCC. However, only a small number of HCC patients exhibit sensitive responses, and drug resistance occurs frequently in advanced patients. Autophagy, an evolutionary process responsible for the degradation of cellular substances, is closely associated with the acquisition and maintenance of drug resistance for HCC. This review focuses on autophagic proteins and explores the intricate relationship between autophagy and cancer stem cells, tumor-derived exosomes, and noncoding RNA. Clinical trials involved in autophagy inhibition combined with anticancer drugs are also concerned.
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27
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Liu YF, Luo D, Li X, Li ZQ, Yu X, Zhu HW. PVT1 Knockdown Inhibits Autophagy and Improves Gemcitabine Sensitivity by Regulating the MiR-143/HIF-1α/VMP1 Axis in Pancreatic Cancer. Pancreas 2021; 50:227-234. [PMID: 33565800 DOI: 10.1097/mpa.0000000000001747] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Elucidation of the regulatory mechanisms of gemcitabine sensitivity is needed to improve the therapeutic effects of this drug in pancreatic cancer. METHODS PANC-1 cells were transfected with small hairpin RNA against PVT1 or microRNA (miR)-143 mimics or inhibitor. The gemcitabine sensitivity of pancreatic cancer was evaluated. Autophagosomes were analyzed with an immunofluorescence assay. Cell viability and proliferation were examined with MTT assays. Quantitative reverse transcription-polymerase chain reaction and Western blotting were used to analyze the expression of PVT1, miR-143, HIF-1α, VMP1, LC3I/II, p62, and Beclin-1. The interactions of PVT1/miR-143 and miR-143/HIF-1α were assessed by dual-luciferase reporter assays. RESULTS PVT1 was upregulated while miR-143 was downregulated in pancreatic cancer. Both PVT1 knockdown and miR-143 overexpression suppressed autophagy and improved gemcitabine sensitivity in pancreatic cancer. PVT1 directly sponged miR-143 to regulate HIF-1α expression. MiR-143 inhibitor reversed the effect of PVT1 knockdown on autophagy and gemcitabine sensitivity. CONCLUSIONS PVT1 knockdown inhibited autophagy and improved gemcitabine sensitivity via the miR-143/HIF-1α/VMP1 axis in pancreatic cancer. Our investigation elucidated a novel regulatory mechanism of gemcitabine sensitivity and may contribute to improve the therapeutic effects of chemotherapy drugs on pancreatic cancer.
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Affiliation(s)
- Yun-Fei Liu
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Dong Luo
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Xia Li
- Endocrinology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhi-Qiang Li
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Xiao Yu
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Hong-Wei Zhu
- From the Departments of Hepatobiliary and Pancreatic Surgery II
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28
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Wu J, Zheng C, Wang Y, Yang Z, Li C, Fang W, Jin Y, Hou K, Cheng Y, Qi J, Qu X, Liu Y, Che X, Hu X. LncRNA APCDD1L-AS1 induces icotinib resistance by inhibition of EGFR autophagic degradation via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis in lung adenocarcinoma. Biomark Res 2021; 9:9. [PMID: 33516270 PMCID: PMC7847171 DOI: 10.1186/s40364-021-00262-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Epidermal growth factor receptor-tyrosinase kinase inhibitor (EGFR-TKI) resistance is the major obstacle in the treatment of lung adenocarcinoma (LUAD) patients harboring EGFR-sensitive mutations. However, the long non-coding RNAs (lncRNAs) related to EGFR-TKIs resistance and their functional mechanisms are still largely unknown. This study aimed to investigate the role and regulatory mechanism of lncRNA APCDD1L-AS1 in icotinib resistance of lung cancer. METHODS Molecular approaches including qRT-PCR, MTT assay, colony formation, RNA interference and cell transfection, RNA immunoprecipitation (RIP), dual luciferase reporter assay, RNA fluorescence in situ hybridization, TUNEL assay, flow cytometry, immunoblotting, xenograft model and transcriptome sequencing were used to investigate the mechanism of APCDD1L-AS1 in icotinib resistance. RESULTS A novel lncRNA, APCDD1L-AS1 was identified as the most significantly upregulated lncRNA in icotinib-resistant LUAD cells by the transcriptome sequencing and differential lncRNA expression analysis. We found that APCDD1L-AS1 not only promoted icotinib resistance, but also upregulated the protein expression level of EGFR. Mechanistically, APCDD1L-AS1 promoted icotinib resistance and EGFR upregulation by sponging with miR-1322/miR-1972/miR-324-3p to remove the transcription inhibition of SIRT5. Furthermore, SIRT5 elevated EGFR expression and activation by inhibiting the autophagic degradation of EGFR, finally promoting icotinib resistance. Consistently, the autophagy initiator rapamycin could decrease EGFR levels and increase the sensitivity of icotinib-resistant LUAD cells to icotinib. CONCLUSION APCDD1L-AS1 could promote icotinib resistance by inhibiting autophagic degradation of EGFR via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis. The combination of autophagy initiator and EGFR-TKIs might serve as a potential new strategy for overcoming EGFR-TKIs resistance in LUAD patients.
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Affiliation(s)
- Jie Wu
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, No.155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, China
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, China
| | - Chunlei Zheng
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Yizhe Wang
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, No.155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, China
| | - Zichang Yang
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Ce Li
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Wanxia Fang
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Yue Jin
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Yang Cheng
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, No.155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, China
| | - Jianfei Qi
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China.
- Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, Liaoning, China.
| | - Xuejun Hu
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, No.155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, China.
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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30
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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Singh S, Raza W, Parveen S, Meena A, Luqman S. Flavonoid display ability to target microRNAs in cancer pathogenesis. Biochem Pharmacol 2021; 189:114409. [PMID: 33428895 DOI: 10.1016/j.bcp.2021.114409] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are non-coding, conserved, single-stranded nucleotide sequences involved in physiological and developmental processes. Recent evidence suggests an association between miRNAs' deregulation with initiation, promotion, progression, and drug resistance in cancer cells. Besides, miRNAs are known to regulate the epithelial-mesenchymal transition, angiogenesis, autophagy, and senescence in different cancer types. Previous reports proposed that apart from the antioxidant potential, flavonoids play an essential role in miRNAs modulation associated with changes in cancer-related proteins, tumor suppressor genes, and oncogenes. Thus, flavonoids can suppress proliferation, help in the development of drug sensitivity, suppress metastasis and angiogenesis by modulating miRNAs expression. In the present review, we summarize the role of miRNAs in cancer, drug resistance, and the chemopreventive potential of flavonoids mediated by miRNAs. The potential of flavonoids to modulate miRNAs expression in different cancer types demonstrate their selectivity and importance as regulators of carcinogenesis. Flavonoids as chemopreventive agents targeting miRNAs are extensively studied in vitro, in vivo, and pre-clinical studies, but their efficiency in targeting miRNAs in clinical studies is less investigated. The evidence presented in this review highlights the potential of flavonoids in cancer prevention/treatment by regulating miRNAs, although further investigations are required to validate and establish their clinical usefulness.
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Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Waseem Raza
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Jawahar Lal Nehru University, New Delhi 110067, India
| | - Shahnaz Parveen
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
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Shan C, Chen X, Cai H, Hao X, Li J, Zhang Y, Gao J, Zhou Z, Li X, Liu C, Li P, Wang K. The Emerging Roles of Autophagy-Related MicroRNAs in Cancer. Int J Biol Sci 2021; 17:134-150. [PMID: 33390839 PMCID: PMC7757044 DOI: 10.7150/ijbs.50773] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a conserved catabolic process involving the degradation and recycling of damaged biomacromolecules or organelles through lysosomal-dependent pathways and plays a crucial role in maintaining cell homeostasis. Consequently, abnormal autophagy is associated with multiple diseases, such as infectious diseases, neurodegenerative diseases and cancer. Currently, autophagy is considered to be a dual regulator in cancer, functioning as a suppressor in the early stage while supporting the growth and metastasis of cancer cells in the later stage and may also produce therapeutic resistance. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by silencing targeted mRNA. MiRNAs have great regulatory potential for several fundamental biological processes, including autophagy. In recent years, an increasing number of studies have linked miRNA dysfunction to the growth, metabolism, migration, metastasis, and responses of cancer cells to therapy. Therefore, the study of autophagy-related miRNAs in cancer will provide insights into cancer biology and lead to the development of novel anti-cancer strategies. In the present review, we summarise the current knowledge of miRNA dysregulation during autophagy in cancer, focusing on the relationship between autophagy and miRNAs, and discuss their involvement in cancer biology and cancer treatment.
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Affiliation(s)
- Chan Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinzhe Chen
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Hongjing Cai
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xiaodan Hao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jing Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yinfeng Zhang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jinning Gao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Zhixia Zhou
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinmin Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Cuiyun Liu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
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Guan Y, Zhang Y, Hao L, Nie Z. CircRNA_102272 Promotes Cisplatin-Resistance in Hepatocellular Carcinoma by Decreasing MiR-326 Targeting of RUNX2. Cancer Manag Res 2020; 12:12527-12534. [PMID: 33324096 PMCID: PMC7732977 DOI: 10.2147/cmar.s258230] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/30/2020] [Indexed: 12/22/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the leading cause of tumor-associated death in males and females worldwide. HCC is mostly diagnosed at advanced stages and the chemotherapeutic cisplatin is one of the major therapeutic options in the treatment of patients with treating advanced HCC. Despite several reports on HCC multidrug resistance, the underlying regulatory mechanisms are still unclear. Methods RT-PCR was performed to detect circRNA_102272, miR-326 and RUNX2 expression. The CCK8 assay was used to examine cell proliferation and cisplatin IC50 values. The luciferase reporter assay was performed to verify complementary combinations between circRNA_102272 and miR-326 and between miR-326 and RUNX2. Results CircRNA_102272 expression was upregulated in HCC tissues and cells. CircRNA_102272 knockdown suppressed HCC cell proliferation and decreased cisplatin-resistance. In addition, circRNA_102272 facilitated HCC cisplatin-resistance by regulating the miR-326/RUNX2 axis. Conclusion CircRNA_102272 is significantly increased in HCC tissues and cells and promotes HCC cell proliferation and cisplatin-resistance. More importantly, circRNA acts as a ceRNA to suppress the expression and activity of miR-326, leading to the increase in RUNX2 expression. By elucidating circRNA_102272 role and mechanism of action in HCC, our study provides insights and an opportunity to overcome cisplatin-resistance in HCC.
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Affiliation(s)
- Yonghai Guan
- Department of Infectious Diseases, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning, People's Republic of China
| | - Ying Zhang
- Sixth Department of Liver Diseases, The Sixth People's Hospital of Dalian, Dalian Medical University, Dalian 116031, Liaoning, People's Republic of China
| | - Lina Hao
- Department of Nephrology, The Third People's Hospital of Dalian, Dalian 116000, Liaoning, People's Republic of China
| | - Zhenwang Nie
- Department of Infectious Diseases, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning, People's Republic of China
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Autophagy modulates mesenchymal-to-endothelial transition via p53. Aging (Albany NY) 2020; 12:22112-22121. [PMID: 33186920 PMCID: PMC7695417 DOI: 10.18632/aging.104065] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022]
Abstract
Mesenchymal-to-endothelial transition (MEndT) is one of the mechanisms that influences cardiac fibrosis, which is a key process in cardiac remodeling. It has been reported that autophagy inhibits endothelial cell transition. However, whether autophagy could modulate MEndT in cardiac fibrosis has not yet been investigated. Here, we discussed the association between autophagy and MEndT and its possible mechanism. In this study, we induced endothelial-to-mesenchymal transition using transforming growth factor-β to generate mesenchymal cells and fibroblasts in wild-type human umbilical vein endothelial cells and cells with p53 knockout or overexpression. Then, autophagy was induced by Earle's balanced salt solution (EBSS) and was inhibited by bafilomycin A1 or lentivirus-ATG5-shRNA. The expression levels of MEndT and the autophagy markers CD31, VE-Cadherin, Vimentin, α-SMA, LC3, p62 and p53 were examined. We found that activation of autophagy could promote MEndT and increase cytoplasmic and total expression of p53, that but nuclear p53 expression was decreased, and that inhibition of autophagy activation could reverse the effect of EBSS. Moreover, after knockout of nuclear p53, autophagy promoted MEndT, while autophagy inhibited MEndT in p53 overexpressing cells. Our results demonstrate that autophagy modulate MEndT by nuclear p53 provide a new strategy for the treatment of fibrosis diseases.
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Bhol CS, Panigrahi DP, Praharaj PP, Mahapatra KK, Patra S, Mishra SR, Behera BP, Bhutia SK. Epigenetic modifications of autophagy in cancer and cancer therapeutics. Semin Cancer Biol 2020; 66:22-33. [DOI: 10.1016/j.semcancer.2019.05.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 05/09/2019] [Accepted: 05/30/2019] [Indexed: 12/30/2022]
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Pourhanifeh MH, Vosough M, Mahjoubin-Tehran M, Hashemipour M, Nejati M, Abbasi-Kolli M, Sahebkar A, Mirzaei H. Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers. Pharmacol Res 2020; 161:105133. [DOI: 10.1016/j.phrs.2020.105133] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/23/2020] [Accepted: 08/07/2020] [Indexed: 02/08/2023]
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Liu PF, Farooqi AA, Peng SY, Yu TJ, Dahms HU, Lee CH, Tang JY, Wang SC, Shu CW, Chang HW. Regulatory effects of noncoding RNAs on the interplay of oxidative stress and autophagy in cancer malignancy and therapy. Semin Cancer Biol 2020; 83:269-282. [PMID: 33127466 DOI: 10.1016/j.semcancer.2020.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/15/2020] [Accepted: 10/18/2020] [Indexed: 12/15/2022]
Abstract
Noncoding RNAs (ncRNAs) regulation of various diseases including cancer has been extensively studied. Reactive oxidative species (ROS) elevated by oxidative stress are associated with cancer progression and drug resistance, while autophagy serves as an ROS scavenger in cancer cells. However, the regulatory effects of ncRNAs on autophagy and ROS in various cancer cells remains complex. Here, we explore how currently investigated ncRNAs, mainly miRNAs and lncRNAs, are involved in ROS production through modulating antioxidant genes. The regulatory effects of miRNAs and lncRNAs on autophagy-related (ATG) proteins to control autophagy activity in cancer cells are discussed. Moreover, differential expression of ncRNAs in tumor and normal tissues of cancer patients are further analyzed using The Cancer Genome Atlas (TCGA) database. This review hypothesizes links between ATG genes- or antioxidant genes-modulated ncRNAs and ROS production, which might result in tumorigenesis, malignancy, and cancer recurrence. A better understanding of the regulation of ROS and autophagy by ncRNAs might advance the use of ncRNAs as diagnostic and prognostic markers as well as therapeutic targets in cancer therapy.
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Affiliation(s)
- Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
| | - Ammad Ahmad Farooqi
- Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
| | - Sheng-Yao Peng
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Tzu-Jung Yu
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Hans-Uwe Dahms
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
| | - Cheng-Hsin Lee
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Jen-Yang Tang
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Sheng-Chieh Wang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chih-Wen Shu
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
| | - Hsueh-Wei Chang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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Ashrafizadeh M, Zarrabi A, Orouei S, Kiavash Hushmandi, Hakimi A, Amirhossein Zabolian, Daneshi S, Samarghandian S, Baradaran B, Najafi M. MicroRNA-mediated autophagy regulation in cancer therapy: The role in chemoresistance/chemosensitivity. Eur J Pharmacol 2020; 892:173660. [PMID: 33310181 DOI: 10.1016/j.ejphar.2020.173660] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/10/2020] [Accepted: 10/20/2020] [Indexed: 12/20/2022]
Abstract
Chemoresistance has doubled the effort needed to reach an effective treatment for cancer. Now, scientists should consider molecular pathways and mechanisms involved in chemoresistance to overcome cancer. Autophagy is a "self-digestion" mechanism in which potentially toxic and aged organelles and macromolecules are degraded. Increasing evidence has shown that autophagy possesses dual role in cancer cells (onco-suppressor or oncogene). So, it is vital to identify its role in cancer progression and malignancy. MicroRNAs (miRs) are epigenetic factors capable of modulation of autophagy in cancer cells. In the current review, we emphasize on the relationship between miRs and autophagy in cancer chemotherapy. Besides, we discuss upstream mediators of miR/autophagy axis in cancer chemotherapy including long non-coding RNAs, circular RNAs, Nrf2 c-Myc, and HIF-1α. At the final section, we provide a discussion about how anti-tumor compounds affect miR/autophagy axis in ensuring chemosensitivity. These topics are described in this review to show how autophagy inhibition/induction can lead to chemosensitivity/chemoresistance, and miRs are considered as key players in these discussions.
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Affiliation(s)
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey
| | - Sima Orouei
- Department of Genetics, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Azadeh Hakimi
- Department of Anatomical Sciences, School of Medicine, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran; Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Shnaider PV, Ivanova OM, Malyants IK, Anufrieva KS, Semenov IA, Pavlyukov MS, Lagarkova MA, Govorun VM, Shender VO. New Insights into Therapy-Induced Progression of Cancer. Int J Mol Sci 2020; 21:E7872. [PMID: 33114182 PMCID: PMC7660620 DOI: 10.3390/ijms21217872] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/19/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.
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Affiliation(s)
- Polina V. Shnaider
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia
| | - Olga M. Ivanova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
| | - Irina K. Malyants
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Faculty of Chemical-Pharmaceutical Technologies and Biomedical Drugs, Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia
| | - Ksenia S. Anufrieva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Moscow Institute of Physics and Technology (State University), Dolgoprudny 141701, Russia
| | - Ilya A. Semenov
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
| | - Marat S. Pavlyukov
- Laboratory of Membrane Bioenergetics, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia;
| | - Maria A. Lagarkova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
| | - Vadim M. Govorun
- Laboratory of Simple Systems, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia;
| | - Victoria O. Shender
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Laboratory of Molecular Oncology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
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Overcoming cisplatin resistance in osteosarcoma through the miR-199a-modulated inhibition of HIF-1α. Biosci Rep 2020; 39:BSR20170080. [PMID: 28442599 PMCID: PMC6859113 DOI: 10.1042/bsr20170080] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 04/09/2017] [Accepted: 04/24/2017] [Indexed: 12/16/2022] Open
Abstract
Dysregulation of miRNAs has been shown to contribute to multiple tumorigenic processes, as well as to correlate with tumour progression and prognosis. miR-199a has been shown to be dysregulated in multiple tumour types. However, the association between miR-199a and the chemoresistance features of osteosarcoma are not well understood, the target genes for miR-199a and the regulatory mechanisms are also unknown. In the present study, we demonstrated that miR-199a is expressed at low levels in osteosarcoma cells and patient samples. By the selection and establishment of cisplatin resistant osteosarcoma cell line, we observed a correlation between miR-199a and cisplatin resistance in osteosarcoma cells: resistant cells exhibit attenuated miR-199a expressions and exogenous overexpression of miR-199a sensitizes osteosarcoma cells to cisplatin. Moreover, we identified HIF-1α as a direct target for miR-199a. Intriguingly, cisplatin resistant osteosarcoma cells display significantly elevated HIF-1α expression under hypoxia. We report here overexpression of miR-199a resensitizes cisplatin resistant cells to cisplatin through inhibition of HIF-1α in vitro and in vivo. Finally, by analysing the clinical osteosarcoma patient samples, we demonstrate a reverse correlation between miR-199a and HIF-1α mRNAs. Our study will provide mechanisms for the miRNA-mediated anticancer therapy and miR-199a may be considered a promising therapeutic agent for osteosarcoma patients who fail to respond to conventional chemotherapy.
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Fan J, Shi Y, Peng Y. Autophagy and Liver Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1207:497-528. [PMID: 32671772 DOI: 10.1007/978-981-15-4272-5_37] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autophagy plays an important role in the physiology and pathology of the liver. It is involved in the development of many liver diseases such as α-1-antitrypsin deficiency, chronic hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, and liver cancer. Autophagy has thus become a new target for the treatment of liver diseases. How to treat liver diseases by regulating autophagy has been a hot topic.
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Affiliation(s)
- Jia Fan
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China.
| | - Yinghong Shi
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China
| | - Yuanfei Peng
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China
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TAZ-regulated expression of IL-8 is involved in chemoresistance of hepatocellular carcinoma cells. Arch Biochem Biophys 2020; 693:108571. [PMID: 32898567 DOI: 10.1016/j.abb.2020.108571] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/30/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023]
Abstract
Chemotherapy resistance is one of the major challenges for the treatment of hepatocellular carcinoma (HCC). In order to investigate the mechanisms involved in chemoresistance of HCC, we established cisplatin (CDDP) and doxorubicin (Dox) resistant HCC cells. The expression of transcriptional coactivator with PDZ-binding motif (TAZ), one of the major downstream effectors of Hippo pathway, was upregulated in chemoresistant HCC cells. Targeted inhibition of TAZ via its siRNAs can restore CDDP and Dox sensitivity of chemoresistant HCC cells. The upregulation of TAZ increased the expression of IL-8 in HCC/CDDP and HCC/Dox cells. Recombinant IL-8 (rIL-8) antagonized the increased chemosensitivity mediated by TAZ knockdown. Mechanistically, TAZ can directly bind with the promoter of IL-8 to activate its transcription in chemoresistant HCC cells. Collectively, our data showed that TAZ-regulated expression of IL-8 was involved in chemoresistance of HCC cells. It indicated that targeted inhibition of TAZ/IL-8 axis might be helpful to improve chemotherapy efficiency for HCC.
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Zhao Y, Wu H, Xing X, Ma Y, Ji S, Xu X, Zhao X, Wang S, Jiang W, Fang C, Zhang L, Yan F, Wang X. CD13 Induces Autophagy to Promote Hepatocellular Carcinoma Cell Chemoresistance Through the P38/Hsp27/CREB/ATG7 Pathway. J Pharmacol Exp Ther 2020; 374:512-520. [PMID: 32571958 DOI: 10.1124/jpet.120.265637] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022] Open
Abstract
The chemoresistance of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutic agents. We previously reported that Aminopeptidase N (CD13) inhibition can enhance the cytotoxic efficacy of chemotherapy agents. In the present study, we use liver cancer cells to explore the molecular mechanism accounting for the relationship between CD13 and chemoresistance. We demonstrate that CD13 overexpression activates the P38/heat shock protein 27/cAMP response element-binding protein (CREB) signaling pathway to limit the efficacy of cytotoxic agents. Moreover, blockade of P38 or CREB sensitizes HCC cells to 5-fluorouracil. Then we reveal that CREB binds to the autophagy related 7 (ATG7) promoter to induce autophagy and promote HCC cell chemoresistance. CD13 inhibition also downregulates the expression of ATG7, autophagy, and tumor cell growth in vivo. Overall, the combination a CD13 inhibitor and chemotherapeutic agents may be a potential strategy for overcoming drug resistance in HCC. SIGNIFICANCE STATEMENT: Our study demonstrates that Aminopeptidase N (CD13) promotes hepatocellular carcinoma (HCC) cell chemoresistance via the P38/heat shock protein 27/cAMP response element-binding protein (CREB) pathway. CREB regulates autophagy related 7 transcription and expression to induce autophagy. Our results collectively suggest that CD13 may serve as a potential target for overcoming HCC resistance.
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Affiliation(s)
- Yan Zhao
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Huina Wu
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xiaoyan Xing
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Yuqian Ma
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Shengping Ji
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xinyue Xu
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xin Zhao
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Sensen Wang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Wenyan Jiang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Chunyan Fang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Lei Zhang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Fang Yan
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xuejian Wang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
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Autophagy-mediating microRNAs in cancer chemoresistance. Cell Biol Toxicol 2020; 36:517-536. [PMID: 32875398 DOI: 10.1007/s10565-020-09553-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/13/2020] [Indexed: 12/24/2022]
Abstract
Chemoresistance is a complex phenomenon responsible for failure in response to chemotherapy agents and more than 90% of deaths in cancer patients. MicroRNAs (miRNAs), as a subgroup of non-coding RNAs with lengths between 21 and 25 nucleotides, are involved in various cancer processes like chemoresistance via interacting with their target mRNAs and suppressing their expression. Autophagy is a greatly conserved procedure involving the lysosomal degradation of cytoplasmic contents and organelles to deal with environmental stresses like hypoxia and starvation. Autophagy contributes to response to chemotherapy agents: autophagy can act as a protective mechanism for mediating the resistance in response to chemotherapy or can induce autophagic cell death and mediate the sensitivity to chemotherapy. On the other hand, one of the processes targeted by microRNAs in the regulation of chemoresistance is autophagy. Hence, we studied the literatures on chemoresistance mechanisms, the miRNAs' role in cancer, and the miRNAs' role in chemoresistance by modulating autophagy. Graphical Abstract.
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Gao J, Dai C, Yu X, Yin XB, Zhou F. Long noncoding RNA LEF1-AS1 acts as a microRNA-10a-5p regulator to enhance MSI1 expression and promote chemoresistance in hepatocellular carcinoma cells through activating AKT signaling pathway. J Cell Biochem 2020; 122:86-99. [PMID: 32786108 DOI: 10.1002/jcb.29833] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 12/24/2019] [Accepted: 01/10/2020] [Indexed: 12/31/2022]
Abstract
Long noncoding RNAs (lncRNAs) contribute to the development of hepatocellular carcinoma (HCC), which could regulate various HCC biological characteristics. Here, the study seeks to investigate the role of lncRNA LEF1-AS1 in HCC cell chemoresistance by regulating microRNA (miR)-10a-5p and Musashi1 (MSI1). The microarray-based analysis was employed to identify the HCC-related lncRNA-miRNA-gene regulatory network. Expression patterns of LEF1-AS1, miR-10a-5p, and MSI1 in the HCC cell lines, tissues were accessed by means of reverse transcription-quantitative polymerase chain reaction. Next, the interaction among LEF1-AS1, miR-10a-5p, and MSI1 in HCC was accessed by bioinformatics and dual-luciferase reporter gene assay. Then, the cell line resistant to cisplatin was established, which was then treated with sh/oe-lncRNA LEF1-AS1, miR-10a-5p-mimic, and oe/sh-MSI1 vectors alone or in combination. Afterward, the effect of LEF1-AS1, miR-10a-5p, and MSI1 on HCC cell chemoresistance, proliferation, and apoptosis was assessed. At last, in vivo experiments confirmed the role of MSI1 in tumor growth and chemoresistance in HCC. LEF1-AS1 might potentially affect the growth and chemoresistance of HCC cells by regulating miR-10a-5p and MSI1. LEF1-AS1 and MSI1 expression patterns were elevated, while miR-10a-5p was repressed in HCC tissues and cell lines. LEF1-AS1 combined to miR-10a-5p and regulated MSI1, thereby activating the protein kinase B (AKT) signaling pathway. Knockdown of LEF1-AS1 and MSI1 or elevation of miR-10a-5p compromised the proliferation of Huh7 cell line resistant to DDP and promoted its chemosensitivity and apoptosis. At last, these in vitro findings were also confirmed in vivo. Our results unraveled LEF1-AS1 acts as a miR-10a-5p modulator to promote chemoresistance of HCC cells by stimulating MSI1 and activating the AKT signaling pathway, which might provide a novel therapeutic target for HCC.
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Affiliation(s)
- Jun Gao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chao Dai
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xin Yu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiang-Bao Yin
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fan Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Liang Y, Liang Q, Qiao L, Xiao F. MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma. Front Oncol 2020; 10:920. [PMID: 32695666 PMCID: PMC7338562 DOI: 10.3389/fonc.2020.00920] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open
Abstract
Primary liver cancer [hepatocellular carcinoma (HCC)] is one of the most common malignant tumors worldwide, causing serious health threats because of its high morbidity and mortality, rapid growth, and strong invasiveness. Patients with HCC frequently develop resistance to the current chemotherapeutic drugs, and this is largely attributed to the high-level heterogeneity of the tumor tissue. MicroRNAs (miRNAs) are a group of master regulators for multiple physiological and pathological processes and play important roles in the tumorigenesis. More recent studies have indicated that miRNAs also play a non-negligible role in the development of drug resistance in liver cancer. In this review, we summarize the data from the latest studies on the mechanisms of drug resistance in liver cancer, including autophagy, membrane transporters, epithelial-mesenchymal transitions (EMTs), tumor microenvironment, and genes and proteins that are associated with apoptosis. The data herein will provide valuable information for the development of novel approaches to tackle drug resistance in the management of liver cancer.
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Affiliation(s)
- Yuehui Liang
- Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha, China
| | - Qi Liang
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Liang Qiao
- Storr Liver Center, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Fang Xiao
- Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha, China
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Chi Q, Geng X, Xu K, Wang C, Zhao H. Potential targets and molecular mechanism of miR-331-3p in hepatocellular carcinoma identified by weighted gene coexpression network analysis. Biosci Rep 2020; 40:BSR20200124. [PMID: 32537629 PMCID: PMC7317601 DOI: 10.1042/bsr20200124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/27/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumor. miR-331-3p has been reported relevant to the progression of HCC, but the molecular mechanism of its regulation is still unclear. In the study, we comprehensively studied the role of miR-331-3p in HCC through weighted gene coexpression network analysis (WGCNA) based on The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Oncomine. WGCNA was applied to build gene co-expression networks to examine the correlation between gene sets and clinical characteristics, and to identify potential biomarkers. Five hundred one target genes of miR-331-3p were obtained by overlapping differentially expressed genes (DEGs) from the TCGA database and target genes predicted by miRWalk. The critical turquoise module and its eight key genes were screened by WGCNA. Enrichment analysis was implemented based on the genes in the turquoise module. Moreover, 48 genes with a high degree of connectivity were obtained by protein-protein interaction (PPI) analysis of the genes in the turquoise module. From overlapping genes analyzed by WGCNA and PPI, two hub genes were obtained, namely coatomer protein complex subunit zeta 1 (COPZ1) and elongation factor Tu GTP binding domain containing 2 (EFTUD2). In addition, the expression of both hub genes was also significantly higher in tumor tissues compared with normal tissues, as confirmed by analysis based on TCGA and Oncomine. Both hub genes were correlated with poor prognosis based on TCGA data. Receiver operating characteristic (ROC) curve validated that both hub genes exhibited excellent diagnostic efficiency for normal and tumor tissues.
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Affiliation(s)
- Qingjia Chi
- Department of Mechanics and Engineering Structure, Wuhan University of Technology, Wuhan 430070, China
| | - Xinge Geng
- Department of Mechanics and Engineering Structure, Wuhan University of Technology, Wuhan 430070, China
| | - Kang Xu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chunli Wang
- ‘111’ Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China
| | - Han Zhao
- Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
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Pourhanifeh MH, Mahjoubin-Tehran M, Karimzadeh MR, Mirzaei HR, Razavi ZS, Sahebkar A, Hosseini N, Mirzaei H, Hamblin MR. Autophagy in cancers including brain tumors: role of MicroRNAs. Cell Commun Signal 2020; 18:88. [PMID: 32517694 PMCID: PMC7285723 DOI: 10.1186/s12964-020-00587-w] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 04/27/2020] [Indexed: 12/14/2022] Open
Abstract
Autophagy has a crucial role in many cancers, including brain tumors. Several types of endogenous molecules (e.g. microRNAs, AKT, PTEN, p53, EGFR, and NF1) can modulate the process of autophagy. Recently miRNAs (small non-coding RNAs) have been found to play a vital role in the regulation of different cellular and molecular processes, such as autophagy. Deregulation of these molecules is associated with the development and progression of different pathological conditions, including brain tumors. It was found that miRNAs are epigenetic regulators, which influence the level of proteins coded by the targeted mRNAs with any modification of the genetic sequences. It has been revealed that various miRNAs (e.g., miR-7-1-3p, miR-340, miR-17, miR-30a, miR-224-3p, and miR-93), as epigenetic regulators, can modulate autophagy pathways within brain tumors. A deeper understanding of the underlying molecular targets of miRNAs, and their function in autophagy pathways could contribute to the development of new treatment methods for patients with brain tumors. In this review, we summarize the various miRNAs, which are involved in regulating autophagy in brain tumors. Moreover, we highlight the role of miRNAs in autophagy-related pathways in different cancers.
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