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Topcu KSB, Cacan E. Twist1 Regulates the Immune Checkpoint VISTA and Promotes the Proliferation, Migration and Progression of Pancreatic Cancer Cells. J Cell Mol Med 2025; 29:e70586. [PMID: 40344465 PMCID: PMC12061639 DOI: 10.1111/jcmm.70586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 04/20/2025] [Accepted: 04/28/2025] [Indexed: 05/11/2025] Open
Abstract
Pancreatic cancer is one of the deadliest malignant tumours worldwide. Despite the developments in the treatments of pancreatic cancer, survival rates remain at a low level, and the mechanisms underlying the aggressive course of the cancer are not fully understood. VISTA is an immune checkpoint and has recently become a significant target in cancer treatment; however, the roles of VISTA in the development of pancreatic cancer have largely remained unknown. Histone deacetylase inhibitors (HDACi) have been reported to reverse the epithelial-mesenchymal transition (EMT) and may enhance the efficacy of anti-PD-1 therapy. The PD-L1/PD-1 immune checkpoint targeted by this therapy shares structural similarity with VISTA. Moreover, combination therapy of vorinostat and anti-PD-1 has been shown to significantly reduce tumour growth by suppressing the transcription factor c-Myc. Therefore, in this study, we aim to investigate the genes that are associated with EMT and explore the potential mechanism involving Twist1, a proto-oncogene, and VISTA in pancreatic cancer. We also sought to determine the synergistic effects of an HDACi, vorinostat, in combination with Twist1-siRNA on VISTA expression in pancreatic cancer cells' viability and proliferation. Our results revealed that Twist1 blockade in combination with vorinostat in pancreatic cancer cells suppresses EMT-associated genes and the immune checkpoint VISTA compared to treatments administered alone. As a result, identifying the genes associated with EMT in pancreatic cancer and understanding the role of Twist1 in this process is a crucial step to contribute to the identification of new targets for pancreatic cancer treatment and the improvement of existing treatment strategies.
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Affiliation(s)
- Kubra Sena Bas Topcu
- Department of Molecular Biology and Genetics, Faculty of ScienceBartin UniversityBartinTürkiye
- Department of Molecular Biology and Genetics, Faculty of art and ScienceTokat Gaziosmanpasa UniversityTokatTürkiye
| | - Ercan Cacan
- Department of Molecular Biology and Genetics, Faculty of art and ScienceTokat Gaziosmanpasa UniversityTokatTürkiye
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Attia YM, Tadros SA, Fahim SA, Badr DM. Role of noncoding RNA as a pacemaker in cancer stem cell regulation: a review article. J Egypt Natl Canc Inst 2025; 37:9. [PMID: 40122959 DOI: 10.1186/s43046-025-00266-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/10/2025] [Indexed: 03/25/2025] Open
Abstract
Accumulated evidence supported the crucial role of a tiny population of cells within the tumor called cancer stem cells (CSCs) in cancer origination, and proliferation. Additionally, these cells are distinguished by their self-renewal, differentiation, and therapeutic resistance capabilities. Interestingly, many studies recorded dysregulation of different types of noncoding RNAs, such as microRNA (miRNA) and long non-coding RNA (LncRNA), in cancer cells as well as CSCs. Moreover, several studies also supported the regulation of the transcription factors and signaling pathways required for CSC progression by these noncoding RNAs. However, the exact biological functions of all these noncoding RNAs are not well understood yet. These findings are of great interest, implying usage of noncoding RNA as therapeutic tool to target these cells. In this review, we provide an insight into how noncoding RNAs regulate CSCs and how this correlation is manipulated to develop new therapies to eradicate cancer cells successfully.
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Affiliation(s)
- Yasmin M Attia
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Kasr Al Eini Street, Fom El Khalig, Cairo, 11796, Egypt
| | - Samer A Tadros
- Department of Biochemistry, Faculty of Pharmacy, 110123october University for Modern Sciences and Arts (MSA), 6th of October City, Egypt
| | - Sally A Fahim
- Department of Biochemistry, School of Pharmacy, Newgiza University (NGU), Newgiza, Km 22 Cairo-Alexandria Desert Road, Giza, 12577, Egypt.
| | - Doaa M Badr
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Kasr Al Eini Street, Fom El Khalig, Cairo, 11796, Egypt
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Cao XC, Peng J, Qiu YB, Zhu W, Cao JG, Zou H, Yu ZZ, Wu D, Lu SS, Huang W, Yi H, Xiao ZQ. FVTF inhibits hepatocellular carcinoma stem properties via targeting DNMT1/miR-34a-5p/FoxM1 axis. Chin Med 2025; 20:32. [PMID: 40050970 PMCID: PMC11884036 DOI: 10.1186/s13020-025-01084-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/23/2025] [Indexed: 03/10/2025] Open
Abstract
BACKGROUND Fructus Viticis Total Flavonoids (FVTF) is a novel candidate preparation that possesses anticancer activity. However, the role and mechanism of FVTF-inhibiting human hepatocellular carcinoma (HCC) cell stem properties is unclear. METHODS Liquid chromatography (LC) in conjugation with mass spectrometer (MS) was used to identify the compounds of FVTF. Tumorsphere and soft agar colony formation ability, cancer stem marker expression levels, CD133+ cell percentage, and a xenograft model were utilized to investigate the impact of FVTF on HCC cells stemness. PCR array and qRT-PCR were conducted to identify differentially expressed cancer stem-related genes and miRNAs between FVTF-treated and untreated HCC cells, respectively. Pyrosequencing was conducted to assess the DNA methylation level of the miR-34a-5p promoter. A luciferase reporter assay was performed to verify whether FoxM1 serves as a direct target of miR-34a-5p. Additionally, immunohistochemistry of an HCC tissue microarray was carried out to assess the expression levels of DNMT1, FoxM1, and miR-34a-5p. RESULTS A total of 26 compounds, including 10 flavones, in FVTF were identified. FVTF significantly reduced the ability of tumorsphere and soft agar colony formation, the levels of CD44 protein and BMI1, OCT4 and SOX2 mRNAs in HCC cells, and in vivo tumor initiation ability of HCC cells. Mechanistically, FVTF inhibited HCC cell stem properties via targeting DNMT1/miR-34a-5p/FoxM1 axis. Clinically, DNMT1 expression was inversely correlated with miR-34a-5p expression, whereas a positive correlation was noted between DNMT1 and FoxM1 expression levels, and high DNMT1 levels, low miR-34a-5p levels, and high FoxM1 levels were associated with cancer recurrence. Furthermore, a combination of DNMT1, miR-34a-5p and FoxM1 served as an independent prognostic indicator influencing both DFS and OS in patients with HCC. CONCLUSIONS FVTF inhibits HCC cell stem properties by targeting DNMT1/miR-34a-5p/FoxM1 axis, which is associated with HCC recurrence and prognosis, and FVTF is a prospective treatment drug for human HCC.
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Affiliation(s)
- Xiao-Cheng Cao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jinwu Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ye-Bei Qiu
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Wei Zhu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jian-Guo Cao
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Hui Zou
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Zheng-Zheng Yu
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Di Wu
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Shan-Shan Lu
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wei Huang
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Hong Yi
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China.
- The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Zhi-Qiang Xiao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China.
- The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Amer H, Kampan NC, Itsiopoulos C, Flanagan KL, Scott CL, Kartikasari AER, Plebanski M. Interleukin-6 Modulation in Ovarian Cancer Necessitates a Targeted Strategy: From the Approved to Emerging Therapies. Cancers (Basel) 2024; 16:4187. [PMID: 39766086 PMCID: PMC11674514 DOI: 10.3390/cancers16244187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/27/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025] Open
Abstract
Despite significant advances in treatments, ovarian cancer (OC) remains one of the most prevalent and lethal gynecological cancers in women. The frequent detection at the advanced stages has contributed to low survival rates, resistance to various treatments, and disease recurrence. Thus, a more effective approach is warranted to combat OC. The cytokine Interleukin-6 (IL6) has been implicated in various stages of OC development. High IL6 levels are also correlated with a lower survival rate in OC patients. In this current review, we summarized the pivotal roles of IL6 in OC, including the initiation, development, invasion, metastasis, and drug resistance mechanisms. This article systematically highlights how targeting IL6 improves OC outcomes by altering various cancer processes and reports the ongoing clinical trials that would further shape the IL6-based targeted therapies. This review also suggests how combining IL6-targeted therapies with other therapeutic strategies could further enhance their efficacy to combat OC.
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Affiliation(s)
- Hina Amer
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
| | - Nirmala C. Kampan
- Department of Obstetrics and Gynecology, Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Catherine Itsiopoulos
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
| | - Katie L. Flanagan
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
- School of Medicine and School of Health Sciences, University of Tasmania, Launceston, TAS 7250, Australia
- Tasmanian Vaccine Trial Centre, Clifford Craig Foundation, Launceston General Hospital, Launceston, TAS 7250, Australia
| | - Clare L. Scott
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Faculty of Medicine, Dentistry, and Health Sciences, The University of Melbourne, Parkville, VIC 3052, Australia
- The Royal Women’s Hospital, Parkville, VIC 3052, Australia
| | - Apriliana E. R. Kartikasari
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
| | - Magdalena Plebanski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
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Gao W, Zhou J, Morshedi M. MicroRNA-34 and gastrointestinal cancers: a player with big functions. Cancer Cell Int 2024; 24:163. [PMID: 38725047 PMCID: PMC11084024 DOI: 10.1186/s12935-024-03338-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a's molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.
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Affiliation(s)
- Wei Gao
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Jianping Zhou
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China.
| | - Mohammadamin Morshedi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Oda T, Tsutsumi K, Obata T, Ueta E, Kikuchi T, Ako S, Fujii Y, Yamazaki T, Uchida D, Matsumoto K, Horiguchi S, Kato H, Okada H, Chijimatsu R, Otsuka M. MicroRNA-34a-5p: A pivotal therapeutic target in gallbladder cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200765. [PMID: 38596294 PMCID: PMC10963938 DOI: 10.1016/j.omton.2024.200765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 11/04/2023] [Accepted: 01/18/2024] [Indexed: 04/11/2024]
Abstract
Gallbladder cancer incidence has been increasing globally, and it remains challenging to expect long prognosis with the current systemic chemotherapy. We identified a novel nucleic acid-mediated therapeutic target against gallbladder cancer by using innovative organoid-based gallbladder cancer models generated from KrasLSL-G12D/+; Trp53f/f mice. Using comprehensive microRNA expression analyses and a bioinformatics approach, we identified significant microRNA-34a-5p downregulation in both murine gallbladder cancer organoids and resected human gallbladder cancer specimens. In three different human gallbladder cancer cell lines, forced microRNA-34a-5p expression inhibited cell proliferation and induced cell-cycle arrest at the G1 phase by suppressing direct target (CDK6) expression. Furthermore, comprehensive RNA sequencing revealed the significant enrichment of gene sets related to the cell-cycle regulators after microRNA-34a-5p expression in gallbladder cancer cells. In a murine xenograft model, locally injected microRNA-34a-5p mimics significantly inhibited gallbladder cancer progression and downregulated CDK6 expression. These results provide a rationale for promising therapeutics against gallbladder cancer by microRNA-34a-5p injection, as well as a strategy to explore therapeutic targets against cancers using organoid-based models, especially for those lacking useful genetically engineered murine models, such as gallbladder cancer.
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Affiliation(s)
- Takashi Oda
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Koichiro Tsutsumi
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Taisuke Obata
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Eijiro Ueta
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Tatsuya Kikuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Soichiro Ako
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Yuki Fujii
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Tatsuhiro Yamazaki
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Daisuke Uchida
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Kazuyuki Matsumoto
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Shigeru Horiguchi
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Hironari Kato
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Ryota Chijimatsu
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
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Sipos F, Műzes G. Sirtuins Affect Cancer Stem Cells via Epigenetic Regulation of Autophagy. Biomedicines 2024; 12:386. [PMID: 38397988 PMCID: PMC10886574 DOI: 10.3390/biomedicines12020386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Sirtuins (SIRTs) are stress-responsive proteins that regulate several post-translational modifications, partly by acetylation, deacetylation, and affecting DNA methylation. As a result, they significantly regulate several cellular processes. In essence, they prolong lifespan and control the occurrence of spontaneous tumor growth. Members of the SIRT family have the ability to govern embryonic, hematopoietic, and other adult stem cells in certain tissues and cell types in distinct ways. Likewise, they can have both pro-tumor and anti-tumor effects on cancer stem cells, contingent upon the specific tissue from which they originate. The impact of autophagy on cancer stem cells, which varies depending on the specific circumstances, is a very intricate phenomenon that has significant significance for clinical and therapeutic purposes. SIRTs exert an impact on the autophagy process, whereas autophagy reciprocally affects the activity of certain SIRTs. The mechanism behind this connection in cancer stem cells remains poorly understood. This review presents the latest findings that position SIRTs at the point where cancer cells and autophagy interact. Our objective is to highlight the various roles of distinct SIRTs in cancer stem cell-related functions through autophagy. This would demonstrate their significance in the genesis and recurrence of cancer and offer a more precise understanding of their treatment possibilities in relation to autophagy.
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Affiliation(s)
- Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary;
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Tewari AB, Saini A, Sharma D. Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy. Clin Exp Med 2023; 23:3125-3145. [PMID: 37093450 DOI: 10.1007/s10238-023-01066-5] [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: 12/09/2022] [Accepted: 04/02/2023] [Indexed: 04/25/2023]
Abstract
Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy.
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Affiliation(s)
- Amit B Tewari
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Anamika Saini
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Deepika Sharma
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India.
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Fu J, Imani S, Wu MY, Wu RC. MicroRNA-34 Family in Cancers: Role, Mechanism, and Therapeutic Potential. Cancers (Basel) 2023; 15:4723. [PMID: 37835417 PMCID: PMC10571940 DOI: 10.3390/cancers15194723] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
MicroRNA (miRNA) are small noncoding RNAs that play vital roles in post-transcriptional gene regulation by inhibiting mRNA translation or promoting mRNA degradation. The dysregulation of miRNA has been implicated in numerous human diseases, including cancers. miR-34 family members (miR-34s), including miR-34a, miR-34b, and miR-34c, have emerged as the most extensively studied tumor-suppressive miRNAs. In this comprehensive review, we aim to provide an overview of the major signaling pathways and gene networks regulated by miR-34s in various cancers and highlight the critical tumor suppressor role of miR-34s. Furthermore, we will discuss the potential of using miR-34 mimics as a novel therapeutic approach against cancer, while also addressing the challenges associated with their development and delivery. It is anticipated that gaining a deeper understanding of the functions and mechanisms of miR-34s in cancer will greatly contribute to the development of effective miR-34-based cancer therapeutics.
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Affiliation(s)
- Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China
| | - Saber Imani
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310022, China
| | - Mei-Yi Wu
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201, USA
| | - Ray-Chang Wu
- Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20052, USA
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10
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Joshi G, Basu A. Epigenetic control of cell signalling in cancer stem cells. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 383:67-88. [PMID: 38359971 DOI: 10.1016/bs.ircmb.2023.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
The self-renewing cancer stem cells (CSCs) represent one of the distinct cell populations occurring in a tumour that can differentiate into multiple lineages. This group of sparsely abundant cells play a vital role in tumour survival and resistance to different treatments during cancer. The lack of exclusive markers associated with CSCs makes diagnosis and prognosis in cancer patients extremely difficult. This calls for the identification of unique regulators and markers for CSCs. Various signalling pathways like the Wnt/β-catenin pathway, Hedgehog pathway, Notch pathway, and TGFβ/BMP play a major role in the regulation and maintenance of CSCs. Epigenetic regulatory mechanisms add another layer of complexity to control these signalling pathways. In this chapter, we discuss about the role of epigenetic mechanisms in regulating the cellular signalling pathways in CSCs. The epigenetic regulatory mechanisms such as DNA methylation, histone modification and microRNAs can modulate the diverse effectors of signalling pathways and consequently the growth, differentiation and tumorigenicity of CSCs. In the end, we briefly discuss the therapeutic potential of targeting these epigenetic regulators and their target genes in CSCs.
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Affiliation(s)
- Gaurav Joshi
- Institute of Molecular Biology (IMB), Mainz, Germany.
| | - Amitava Basu
- Institute of Molecular Biology (IMB), Mainz, Germany.
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11
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Jin ML, Jeong KW. Histone modifications in drug-resistant cancers: From a cancer stem cell and immune evasion perspective. Exp Mol Med 2023; 55:1333-1347. [PMID: 37394580 PMCID: PMC10394043 DOI: 10.1038/s12276-023-01014-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/25/2023] [Accepted: 03/20/2023] [Indexed: 07/04/2023] Open
Abstract
The development and immune evasion of cancer stem cells (CSCs) limit the efficacy of currently available anticancer therapies. Recent studies have shown that epigenetic reprogramming regulates the expression of characteristic marker proteins and tumor plasticity associated with cancer cell survival and metastasis in CSCs. CSCs also possess unique mechanisms to evade external attacks by immune cells. Hence, the development of new strategies to restore dysregulated histone modifications to overcome cancer resistance to chemotherapy and immunotherapy has recently attracted attention. Restoring abnormal histone modifications can be an effective anticancer strategy to increase the therapeutic effect of conventional chemotherapeutic and immunotherapeutic drugs by weakening CSCs or by rendering them in a naïve state with increased sensitivity to immune responses. In this review, we summarize recent findings regarding the role of histone modifiers in the development of drug-resistant cancer cells from the perspectives of CSCs and immune evasion. In addition, we discuss attempts to combine currently available histone modification inhibitors with conventional chemotherapy or immunotherapy.
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Affiliation(s)
- Ming Li Jin
- Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea
| | - Kwang Won Jeong
- Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea.
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12
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Chattopadhyay S, Sarkar SS, Saproo S, Yadav S, Antil D, Das B, Naidu S. Apoptosis-targeted gene therapy for non-small cell lung cancer using chitosan-poly-lactic-co-glycolic acid -based nano-delivery system and CASP8 and miRs 29A-B1 and 34A. Front Bioeng Biotechnol 2023; 11:1188652. [PMID: 37346791 PMCID: PMC10281530 DOI: 10.3389/fbioe.2023.1188652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/29/2023] [Indexed: 06/23/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with resistance to apoptosis being a major driver of therapeutic resistance and aggressive phenotype. This study aimed to develop a novel gene therapy approach for NSCLC by targeting resistance to apoptosis. Loss of function mutations of caspase 8 (CASP8) and downregulation of microRNAs (miRs) 29A-B1 and 34A were identified as key contributors to resistance to apoptosis in NSCLC. A biodegradable polymeric nano-gene delivery system composed of chitosan-poly-lactic-co-glycolic acid was formulated to deliver initiator CASP8 and miRs 29A-B1 and 34A. The nano-formulation efficiently encapsulated the therapeutic genes effectively internalized into NSCLC cells and induced significant apoptosis. Evaluation of the nano-formulation in A549 tumor spheroids showed a significant increase in apoptosis within the core of the spheroids, suggesting effective penetration into the spheroid structures. We provide a novel nano-formulation that demonstrate therapeutic potential for suicidal gene therapy in NSCLC.
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13
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Zhao Y, Qin C, Zhao B, Wang Y, Li Z, Li T, Yang X, Wang W. Pancreatic cancer stemness: dynamic status in malignant progression. J Exp Clin Cancer Res 2023; 42:122. [PMID: 37173787 PMCID: PMC10182699 DOI: 10.1186/s13046-023-02693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Xiaoying Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China.
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14
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Bubin R, Uljanovs R, Strumfa I. Cancer Stem Cells in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:ijms24087030. [PMID: 37108193 PMCID: PMC10138709 DOI: 10.3390/ijms24087030] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
The first discovery of cancer stem cells (CSCs) in leukaemia triggered active research on stemness in neoplastic tissues. CSCs represent a subpopulation of malignant cells, defined by unique properties: a dedifferentiated state, self-renewal, pluripotency, an inherent resistance to chemo- and radiotherapy, the presence of certain epigenetic alterations, as well as a higher tumorigenicity in comparison with the general population of cancer cells. A combination of these features highlights CSCs as a high-priority target during cancer treatment. The presence of CSCs has been confirmed in multiple malignancies, including pancreatic ductal adenocarcinoma, an entity that is well known for its dismal prognosis. As the aggressive course of pancreatic carcinoma is partly attributable to treatment resistance, CSCs could contribute to adverse outcomes. The aim of this review is to summarize the current information regarding the markers and molecular features of CSCs in pancreatic ductal adenocarcinoma and the therapeutic options to remove them.
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Affiliation(s)
- Roman Bubin
- Faculty of Medicine, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
| | - Romans Uljanovs
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
| | - Ilze Strumfa
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
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15
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Yin JY, Lu XT, Hou ML, Cao T, Tian Z. Sirtuin1-p53: a potential axis for cancer therapy. Biochem Pharmacol 2023; 212:115543. [PMID: 37037265 DOI: 10.1016/j.bcp.2023.115543] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/12/2023]
Abstract
Sirtuin1 (SIRT1) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that plays key roles in a range of cellular events, including the maintenance of genome stability, gene regulation, cell proliferation, and apoptosis. P53 is one of the most studied tumor suppressors and the first identified non-histone target of SIRT1. SIRT1 deacetylates p53 in a NAD+-dependent manner and inhibits its transcriptional activity, thus exerting action on a series of pathways related to tissue homeostasis and various pathological states. The SIRT1-p53 axis is thought to play a central role in tumorigenesis. Although SIRT1 was initially identified as a tumor promoter, evidence now indicates that SIRT1 may also act as a tumor suppressor. This seemingly contradictory evidence indicates that the functionality of SIRT1 may be dictated by different cell types and intracellular localization patterns. In this review, we summarize recent evidence relating to the interactions between SIRT1 and p53 and discuss the relative roles of these two molecules with regards to cancer-associated cellular events. We also provide an overview of current knowledge of SIRT1-p53 signaling in tumorigenesis. Given the vital role of the SIRT1-p53 pathway, targeting this axis may provide promising strategies for the treatment of cancer.
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Affiliation(s)
- Jia-Yi Yin
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Xin-Tong Lu
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Meng-Ling Hou
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Ting Cao
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Zhen Tian
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
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16
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Bernardo BC, Yildiz GS, Kiriazis H, Harmawan CA, Tai CMK, Ritchie RH, McMullen JR. In Vivo Inhibition of miR-34a Modestly Limits Cardiac Enlargement and Fibrosis in a Mouse Model with Established Type 1 Diabetes-Induced Cardiomyopathy, but Does Not Improve Diastolic Function. Cells 2022; 11:cells11193117. [PMID: 36231079 PMCID: PMC9563608 DOI: 10.3390/cells11193117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/21/2022] [Accepted: 09/28/2022] [Indexed: 12/02/2022] Open
Abstract
MicroRNA 34a (miR-34a) is elevated in the heart in a setting of cardiac stress or pathology, and we previously reported that inhibition of miR-34a in vivo provided protection in a setting of pressure overload-induced pathological cardiac hypertrophy and dilated cardiomyopathy. Prior work had also shown that circulating or cardiac miR-34a was elevated in a setting of diabetes. However, the therapeutic potential of inhibiting miR-34a in vivo in the diabetic heart had not been assessed. In the current study, type 1 diabetes was induced in adult male mice with 5 daily injections of streptozotocin (STZ). At 8 weeks post-STZ, when mice had established type 1 diabetes and diastolic dysfunction, mice were administered locked nucleic acid (LNA)-antimiR-34a or saline-control with an eight-week follow-up. Cardiac function, cardiac morphology, cardiac fibrosis, capillary density and gene expression were assessed. Diabetic mice presented with high blood glucose, elevated liver and kidney weights, diastolic dysfunction, mild cardiac enlargement, cardiac fibrosis and reduced myocardial capillary density. miR-34a was elevated in the heart of diabetic mice in comparison to non-diabetic mice. Inhibition of miR-34a had no significant effect on diastolic function or atrial enlargement, but had a mild effect on preventing an elevation in cardiac enlargement, fibrosis and ventricular gene expression of B-type natriuretic peptide (BNP) and the anti-angiogenic miRNA (miR-92a). A miR-34a target, vinculin, was inversely correlated with miR-34a expression, but other miR-34a targets were unchanged. In summary, inhibition of miR-34a provided limited protection in a mouse model with established type 1 diabetes-induced cardiomyopathy and failed to improve diastolic function. Given diabetes represents a systemic disorder with numerous miRNAs dysregulated in the diabetic heart, as well as other organs, strategies targeting multiple miRNAs and/or earlier intervention is likely to be required.
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Affiliation(s)
- Bianca C. Bernardo
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC 3800, Australia
- Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia
| | - Gunes S. Yildiz
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC 3010, Australia
| | | | | | - Rebecca H. Ritchie
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Monash Institute of Pharmaceutical Sciences, Monash University, Royal Parade, Parkville, VIC 3052, Australia
| | - Julie R. McMullen
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC 3800, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC 3010, Australia
- Department of Physiology, Monash University, Clayton, VIC 3800, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia
- Correspondence: ; Tel.: +61-3-8532-1194
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17
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Xu L, Zhang J, Sun J, Hou K, Yang C, Guo Y, Liu X, Kalvakolanu DV, Zhang L, Guo B. Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers. Biochem Pharmacol 2022; 202:115110. [PMID: 35640714 DOI: 10.1016/j.bcp.2022.115110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/05/2023]
Abstract
The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.
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Affiliation(s)
- Libo Xu
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jinghua Zhang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jicheng Sun
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Kunlin Hou
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Chenxin Yang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Ying Guo
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Xiaorui Liu
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Dhan V Kalvakolanu
- Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Maryland School Medicine, Baltimore, MD, USA
| | - Ling Zhang
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China.
| | - Baofeng Guo
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China.
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18
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Sahoo OS, Pethusamy K, Srivastava TP, Talukdar J, Alqahtani MS, Abbas M, Dhar R, Karmakar S. The metabolic addiction of cancer stem cells. Front Oncol 2022; 12:955892. [PMID: 35957877 PMCID: PMC9357939 DOI: 10.3389/fonc.2022.955892] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg's aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate "onco-metabolites" that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.
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Affiliation(s)
- Om Saswat Sahoo
- Department of Biotechnology, National Institute of technology, Durgapur, India
| | - Karthikeyan Pethusamy
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | | | - Joyeeta Talukdar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
- Computers and communications Department, College of Engineering, Delta University for Science and Technology, Gamasa, Egypt
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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19
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Sukocheva OA, Lukina E, Friedemann M, Menschikowski M, Hagelgans A, Aliev G. The crucial role of epigenetic regulation in breast cancer anti-estrogen resistance: Current findings and future perspectives. Semin Cancer Biol 2022; 82:35-59. [PMID: 33301860 DOI: 10.1016/j.semcancer.2020.12.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/22/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.
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Affiliation(s)
- Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia.
| | - Elena Lukina
- Discipline of Biology, College of Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia
| | - Markus Friedemann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Mario Menschikowski
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Federal State Budgetary Institution «Research Institute of Human Morphology», 3, Tsyurupy Str., Moscow, 117418, Russian Federation; GALLY International Research Institute, San Antonio, TX, 78229, USA.
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20
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Li QH, Ge ZW, Xiang Y, Tian D, Tang Y, Zhang YC. Upregulation of microRNA-34a enhances myocardial ischemia-reperfusion injury via the mitochondrial apoptotic pathway. Free Radic Res 2022; 56:229-244. [PMID: 35703738 DOI: 10.1080/10715762.2021.1953004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Mitochondrial oxidative injury can result in many cardiovascular diseases including cardiac ischemia-reperfusion (I/R) injury. This study was designed to investigate whether microRNA-34a (miR-34a) influences cardiac I/R or hypoxia/reoxygenation (H/R) injury by regulating the mitochondrial apoptotic pathway from oxidative injury.In vivo, myocardial infarction size was examined by Evan blue/TTC staining. Apoptosis was assessed by TUNEL assay. Heart function was measured by echocardiography. Lactate dehydrogenase (LDH) and creatine kinase (CK) were evaluated. In vitro, H9c2 cardiomyocytes were exposed to H/R stimulation. Cell viability was assessed by the CCK-8 assay and apoptosis was detected by Annexin V/PI staining. Mitochondrial superoxide, mitochondrial membrane potential (MMP) and ATP production was evaluated by detection kits, and related proteins were detected by western blotting analysis. We observed that the level of miR-34a was significantly upregulated in I/R rats compared to the sham group. Injection of adenovirus inhibiting miR-34a into the left ventricular anterior wall improved heart function and decreased I/R injury. H9c2 cardiomyocytes exposed to H/R stimulation displayed an obvious increase in miR-34a expression. In addition, miR-34a inhibitor alleviated, whereas miR-34a mimic aggravated H/R-induced mitochondrial injury. Bcl-2 was identified as a target gene of miR-34a by dual-luciferase reporter gene detection. Knockdown of Bcl-2 abolished the cardioprotection of the miR-34a inhibitor in H9c2 cells. In summary,our study demonstrates that inhibition of miR-34a exhibits therapeutic potential in treatment of myocardial I/R injury by restraining mitochondrial apoptosis.
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Affiliation(s)
- Qian-Hui Li
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhuo-Wang Ge
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yin Xiang
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ding Tian
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yong Tang
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ya-Chen Zhang
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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21
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Adhikari S, Bhattacharya A, Adhikary S, Singh V, Gadad S, Roy S, Das C. The paradigm of drug resistance in cancer: an epigenetic perspective. Biosci Rep 2022; 42:BSR20211812. [PMID: 35438143 PMCID: PMC9069444 DOI: 10.1042/bsr20211812] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Innate and acquired resistance towards the conventional therapeutic regimen imposes a significant challenge for the successful management of cancer for decades. In patients with advanced carcinomas, acquisition of drug resistance often leads to tumor recurrence and poor prognosis after the first therapeutic cycle. In this context, cancer stem cells (CSCs) are considered as the prime drivers of therapy resistance in cancer due to their 'non-targetable' nature. Drug resistance in cancer is immensely influenced by different properties of CSCs such as epithelial-to-mesenchymal transition (EMT), a profound expression of drug efflux pump genes, detoxification genes, quiescence, and evasion of apoptosis, has been highlighted in this review article. The crucial epigenetic alterations that are intricately associated with regulating different mechanisms of drug resistance, have been discussed thoroughly. Additionally, special attention is drawn towards the epigenetic mechanisms behind the interaction between the cancer cells and their microenvironment which assists in tumor progression and therapy resistance. Finally, we have provided a cumulative overview of the alternative treatment strategies and epigenome-modifying therapies that show the potential of sensitizing the resistant cells towards the conventional treatment strategies. Thus, this review summarizes the epigenetic and molecular background behind therapy resistance, the prime hindrance of present day anti-cancer therapies, and provides an account of the novel complementary epi-drug-based therapeutic strategies to combat drug resistance.
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Affiliation(s)
- Swagata Adhikari
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
| | - Apoorva Bhattacharya
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
| | - Santanu Adhikary
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India
| | - Vipin Singh
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
| | - Shrikanth S. Gadad
- Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, TX, U.S.A
- Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX 78229, U.S.A
| | - Siddhartha Roy
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
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22
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Wang B, Li D, Cherkasova V, Gerasymchuk M, Narendran A, Kovalchuk I, Kovalchuk O. Cannabinol Inhibits Cellular Proliferation, Invasion, and Angiogenesis of Neuroblastoma via Novel miR-34a/tRiMetF31/PFKFB3 Axis. Cancers (Basel) 2022; 14:cancers14081908. [PMID: 35454815 PMCID: PMC9027424 DOI: 10.3390/cancers14081908] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 03/24/2022] [Accepted: 03/31/2022] [Indexed: 11/21/2022] Open
Abstract
Simple Summary The prognosis of high-risk neuroblastoma is poor due to its high relapse rate. To date, no effective treatment for this disease has been developed. In this study, we utilized two neuroblastoma cell lines (IMR-5 and SK-N-AS) as a model system to explore the effects of cannabinol (CBN) on neuroblastoma and elucidate the potential mechanisms of action. We reveal an inhibitory role of CBN on neuroblastoma cell proliferation, invasion, and angiogenesis through miR-34a-mediated targeting. We identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a direct target of a novel 31 nt tRNAiMet fragment tRiMetF31 generated from miR-34a-guided cleavage, highlighting the crucial role of the miR-34a/tRiMetF31/PFKFB3 axis in CBN-mediated suppression in neuroblastoma biology. Abstract High-risk neuroblastoma is an aggressive pediatric tumor. Despite great advances in neuroblastoma therapy and supportive care protocols, no curative treatment is available for most patients with this disease. Here, we uncover that CBN attenuated the cell proliferation, invasion, and angiogenesis of neuroblastoma cell lines in a dose-dependent manner via the inhibition of the AKT pathway and the upregulation of miR-34a that targets E2F1. Both miR-34a and a 31-nt tRNAiMet fragment (tRiMetF31) derived from miR-34a-guided cleavage were downregulated in 4 examined neuroblastoma cell lines inversely correlated with the levels of its direct target, the PFKFB3 protein. Moreover, ectopic tRiMetF31 suppressed proliferation, migration, and angiogenesis in the studied neuroblastoma cell lines. Conversely, tRiMetF31 knockdown promoted PFKFB3 expression, resulting in enhanced angiogenesis. Our findings reveal a suppressive role of CBN in neuroblastoma tumorigenesis, highlighting a novel and crucial miR-34a tumor suppressor network in CBN’s antineuroblastoma actions.
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Affiliation(s)
- Bo Wang
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; (B.W.); (D.L.); (V.C.); (M.G.)
| | - Dongping Li
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; (B.W.); (D.L.); (V.C.); (M.G.)
| | - Viktoriia Cherkasova
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; (B.W.); (D.L.); (V.C.); (M.G.)
| | - Marta Gerasymchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; (B.W.); (D.L.); (V.C.); (M.G.)
| | - Aru Narendran
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada;
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; (B.W.); (D.L.); (V.C.); (M.G.)
- Correspondence: (I.K.); (O.K.)
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; (B.W.); (D.L.); (V.C.); (M.G.)
- Correspondence: (I.K.); (O.K.)
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23
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Gujrati H, Ha S, Mohamed A, Wang BD. MicroRNA-mRNA Regulatory Network Mediates Activation of mTOR and VEGF Signaling in African American Prostate Cancer. Int J Mol Sci 2022; 23:ijms23062926. [PMID: 35328346 PMCID: PMC8949405 DOI: 10.3390/ijms23062926] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/25/2022] [Accepted: 03/05/2022] [Indexed: 12/11/2022] Open
Abstract
African American (AA) men exhibit 1.6-fold higher prostate cancer (PCa) incidence and 2.4-fold higher mortality rates compared to European American (EA) men. In addition to socioeconomic factors, emerging evidence suggests that intrinsic biological differences may explain part of PCa disparities. In this study, we applied microRNA (miRNA)-driven bioinformatics to evaluate whether differential miRNA-mRNA regulatory networks play a role in promoting the AA PCa disparities. 10 differentially expressed miRNAs were imported to mirPath V.3 algorithm, leading to identification of 58 signaling pathways differentially regulated in AA PCa versus EA PCa. Among these pathways, we particularly focused on mTOR and VEGF signaling, where we identified 5 reciprocal miRNA-mRNA pairings: miR-34a-5p/HIF1A, miR-34a-5p/PIK3CB, miR-34a-5p/IGFBP2, miR-99b-5p/MTOR and miR-96-5p/MAPKAPK2 in AA PCa versus EA PCa. RT-qPCR validation confirmed that miR-34a-5p, miR-99b-5p and MAPKAPK2 were downregulated, while miR-96-5p, IGFBP2, HIF1A, PIK3CB and MTOR were upregulated in AA PCa versus EA PCa cells. Transfection of miRNA mimics/antagomir followed by RT-qPCR and Western blot analysis further verified that IGFBP2, HIF1A and PIK3CB are negatively regulated by miR-34a-5p, whereas MTOR and MAPKAPK2 are negatively regulated by miR-99b-5p and miR-96-5p, respectively, at mRNA and protein levels. Targeting reciprocal pairings by miR-34a-5p mimic, miR-99b-5p mimic or miR-96-5p antagomir downregulates HIF1α, PI3Kβ, mTOR, IGFBP2 but upregulates MAPKAPK2, subsequently reducing cell proliferation and sensitizing docetaxel-induced cytotoxicity in PCa cells. These results suggest that miRNA-mRNA regulatory network plays a critical role in AA PCa disparities, and targeting these core miRNA-mRNA pairings may reduce PCa aggressiveness and overcome the chemoresistance in AA patients.
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Affiliation(s)
- Himali Gujrati
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA; (H.G.); (S.H.)
| | - Siyoung Ha
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA; (H.G.); (S.H.)
| | - Azah Mohamed
- Toxicology Program, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA;
| | - Bi-Dar Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA; (H.G.); (S.H.)
- Hormone Related Cancers Program, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
- Correspondence:
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24
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Xiang XS, Li PC, Wang WQ, Liu L. Histone deacetylases: A novel class of therapeutic targets for pancreatic cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188676. [PMID: 35016922 DOI: 10.1016/j.bbcan.2022.188676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is the seventh leading cause of cancer death worldwide, with a low 5-year survival rate. Novel agents are urgently necessary to treat the main pathological type, known as pancreatic ductal carcinoma (PDAC). The dysregulation of histone deacetylases (HDACs) has been identified in association with PDAC, which can be more easily targeted by small molecular inhibitors than gene mutations and may represent a therapeutic breakthrough for PDAC. However, the contributions of HDACs to PDAC remain controversial, and pharmacokinetic challenges have limited the application of HDAC inhibitors (HDACis) in PDAC. This review summarizes the mechanisms associated with success and failure of HDACis in PDAC and discusses the recent progress made in HDACi development and application, such as combination therapies designed to enhance efficacy. More precise strategies involving HDACis might eventually improve the outcomes of PDAC treatment.
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Affiliation(s)
- Xue-Song Xiang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peng-Cheng Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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25
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Wang C, Jia Q, Guo X, Li K, Chen W, Shen Q, Xu C, Fu Y. microRNA-34 Family: From Mechanism to Potential Applications. Int J Biochem Cell Biol 2022; 144:106168. [DOI: 10.1016/j.biocel.2022.106168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/04/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023]
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26
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Yu W, Ma Y, Roy SK, Srivastava R, Shankar S, Srivastava RK. Ethanol exposure of human pancreatic normal ductal epithelial cells induces EMT phenotype and enhances pancreatic cancer development in KC (Pdx1-Cre and LSL-Kras G12D ) mice. J Cell Mol Med 2021; 26:399-409. [PMID: 34859959 PMCID: PMC8743655 DOI: 10.1111/jcmm.17092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/20/2022] Open
Abstract
Alcohol is a risk factor for pancreatic cancer. However, the molecular mechanism by which chronic alcohol consumption influences pancreatic cancer development is not well understood. We have recently demonstrated that chronic ethanol exposure of pancreatic normal ductal epithelial cells (HPNE) induces cellular transformation by generating cancer stem cells (CSCs). Here, we examined whether chronic ethanol treatment induces epithelial–mesenchymal transition in HPNE cells and promotes pancreatic cancer development in KC (Pdx1‐Cre, and LSL‐KrasG12D) mice. Our data demonstrate that chronic ethanol exposure of HPNE cells induces SATB2 gene and those cells became highly motile. Ethanol treatment of HPNE cells results in downregulation of E‐Cadherin and upregulation of N‐Cadherin, Snail, Slug, Zeb1, Nanog and BMI‐1. Suppression of SATB2 expression in ethanol‐transformed HPNE cells inhibits EMT phenotypes. KC mice fed with an ethanol‐containing diet show enhanced pancreatic cancer growth and development than those fed with a control diet. Pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of stem cell markers (CD133, CD44, CD24), pluripotency‐maintaining factors (cMyc, KLF4, SOX‐2, and Oct‐4), N‐Cadherin, EMT‐transcription factors (Snail, Slug, and Zeb1), and lower expression of E‐cadherin than those isolated from mice fed with a control diet. Furthermore, pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of inflammatory cytokines (TNF‐α, IL‐6, and IL‐8) and PTGS‐2 (COX‐2) gene than those isolated from mice fed with a control diet. These data suggest that chronic alcohol consumption may contribute to pancreatic cancer development by generating inflammatory signals and CSCs.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center, Kansas City, Missouri, USA
| | - Yuming Ma
- Kansas City VA Medical Center, Kansas City, Missouri, USA
| | - Sanjit K Roy
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA
| | - Rashmi Srivastava
- Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA
| | - Sharmila Shankar
- Kansas City VA Medical Center, Kansas City, Missouri, USA.,Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisina, USA.,Southeast Louisiana Veterans Health Care System, New Orleans, Louisina, USA
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, Kansas City, Missouri, USA.,Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,Southeast Louisiana Veterans Health Care System, New Orleans, Louisina, USA
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27
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Amiri S, Rabbani-Chadegani A, Davoodi J, Fakhrabadi HG. Restoration of MiR-34a Expression by 5-Azacytidine Augments Alimta -Induced Cell Death in Non-Small Lung Cancer Cells by Downregulation of HMG B1, A2 and Bcl-2 Pathway. CELL JOURNAL 2021; 23:674-683. [PMID: 34939761 PMCID: PMC8665979 DOI: 10.22074/cellj.2021.7332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 03/16/2020] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Alimta (Pemetrexed) as an antifolate drug has been approved for the treatment of lung cancer. The aim of the present study was to investigate the combination effect of 5-Azacytidine (5-aza) and Alimta on the miR-34a and its target genes expression and induction of apoptotic cell death in non-small lung cancer A549 cells. MATERIALS AND METHODS In this experimental study, lung cancer A549 cells were treated with various concentrations of Alimta alone and combined with 5-Aza. Then, viability was assessed by trypan blue and MTT assays. mRNA expressions were performed by real time-polymerase chain reaction (PCR) and western blot. Flow cytometry used to detect apoptotic/ necrotic cells and cell cycle arrest. RESULTS Alimta alone reduced viability of the cells in a dose dependent manner with the half-maximal inhibitory concentration (IC50) value of 12 μM. Pretreatment of the cells with 5-aza (5 μM) induced a synergistic cytotoxic effect with IC50 of 3 μM. Sequential exposure of the cells to 5-aza and Alimta enhanced miR-34a expression and significantly downregulated HMGB1, HMGA2 and BCL-2 expressions. Also, it was associated with reduction of nuclear HMGB1 and HMGA2 content. Caspase-3 activation, HMGB1 release into extracellular space and staining of the cells with annexine V/PI suggested that 5-aza reduced late apoptotic/necrotic cell death induced by Alimta. In addition, combination of 5-aza and Alimta arrested the cells at S and sub-G1 phases and inhibited colony formation. CONCLUSION 5-aza synergistically enhances Alimta induced apoptotic cell death through HMG proteins regulation, MIR34A gene expression and intrinsic apoptosis mechanism, providing a promising combination therapy in clinical lung cancer therapy.
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Affiliation(s)
| | - Azra Rabbani-Chadegani
- P.O.Box: 13145-1384Department of BiochemistryInstitute of Biochemistry and BiophysicsUniversity of TehranTehranIran
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28
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MicroRNAs in Pancreatic Cancer and Chemoresistance. Pancreas 2021; 50:1334-1342. [PMID: 35041330 DOI: 10.1097/mpa.0000000000001934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading malignancies affecting human health, largely because of the development of resistance to chemotherapy/radiotherapy. There are many mechanisms that mediate the development of drug resistance, such as the transport of antineoplastic agents into cells, shifts in energy metabolism and environment, antineoplastic agent-induced DNA damage, and genetic mutations. MicroRNAs are short, noncoding RNAs that are 20 to 24 nucleotides in length and serve several biological functions. They bind to the 3'-untranslated regions of target genes and induce target degradation or translational inhibition. MicroRNAs can regulate several target genes and mediate PDAC chemotherapy/radiotherapy resistance. The detection of novel microRNAs would not only reveal the molecular mechanisms of PDAC and resistance to chemotherapy/radiotherapy but also provide new approaches to PDAC therapy. MicroRNAs are thus potential therapeutic targets for PDAC and might be essential in uncovering new mechanisms of the disease.
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29
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Histone Modifications in Stem Cell Development and Their Clinical Implications. Stem Cell Reports 2021; 15:1196-1205. [PMID: 33296672 PMCID: PMC7724464 DOI: 10.1016/j.stemcr.2020.11.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/03/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
Human stem cells bear a great potential for multiple therapeutic applications but at the same time constitute a major threat to human health in the form of cancer stem cells. The molecular processes that govern stem cell maintenance or differentiation have been extensively studied in model organisms or cell culture, but it has been difficult to extrapolate these insights to therapeutic applications. Recent advances in the field suggest that local and global changes in histone modifications that affect chromatin structure could influence the capability of cells to either maintain their stem cell identity or differentiate into specialized cell types. The enzymes that regulate these modifications are therefore among the prime targets for potential drugs that can influence and potentially improve the therapeutic application of stem cells. In this review, we discuss recent findings on the role of histone modifications in stem cell regulation and their potential implications for clinical applications.
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30
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Pajares MJ, Alemany-Cosme E, Goñi S, Bandres E, Palanca-Ballester C, Sandoval J. Epigenetic Regulation of microRNAs in Cancer: Shortening the Distance from Bench to Bedside. Int J Mol Sci 2021; 22:ijms22147350. [PMID: 34298969 PMCID: PMC8306710 DOI: 10.3390/ijms22147350] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer is a complex disease involving alterations of multiple processes, with both genetic and epigenetic features contributing as core factors to the disease. In recent years, it has become evident that non-coding RNAs (ncRNAs), an epigenetic factor, play a key role in the initiation and progression of cancer. MicroRNAs, the most studied non-coding RNAs subtype, are key controllers in a myriad of cellular processes, including proliferation, differentiation, and apoptosis. Furthermore, the expression of miRNAs is controlled, concomitantly, by other epigenetic factors, such as DNA methylation and histone modifications, resulting in aberrant patterns of expression upon the occurrence of cancer. In this sense, aberrant miRNA landscape evaluation has emerged as a promising strategy for cancer management. In this review, we have focused on the regulation (biogenesis, processing, and dysregulation) of miRNAs and their role as modulators of the epigenetic machinery. We have also highlighted their potential clinical value, such as validated diagnostic and prognostic biomarkers, and their relevant role as chromatin modifiers in cancer therapy.
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Affiliation(s)
- María J. Pajares
- Biochemistry Area, Department of Health Sciences, Public University of Navarre, 31008 Pamplona, Spain; (M.J.P.); (S.G.)
- IDISNA Navarra’s Health Research Institute, 31008 Pamplona, Spain;
| | - Ester Alemany-Cosme
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 460026 Valencia, Spain; (E.A.-C.); (C.P.-B.)
| | - Saioa Goñi
- Biochemistry Area, Department of Health Sciences, Public University of Navarre, 31008 Pamplona, Spain; (M.J.P.); (S.G.)
| | - Eva Bandres
- IDISNA Navarra’s Health Research Institute, 31008 Pamplona, Spain;
- Immunology Unit, Department of Hematology, Complejo Hospitalario de Navarra, 31008 Pamplona, Spain
| | - Cora Palanca-Ballester
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 460026 Valencia, Spain; (E.A.-C.); (C.P.-B.)
| | - Juan Sandoval
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 460026 Valencia, Spain; (E.A.-C.); (C.P.-B.)
- Epigenomics Core Facility, Health Research Institute la Fe, 46026 Valencia, Spain
- Correspondence: ; Tel.: +34-961246709
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31
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Yap ZH, Kong WY, Azeez AR, Fang CM, Ngai SC. Anti-cancer Effects of Epigenetics Drugs Scriptaid and Zebularine in Human Breast Adenocarcinoma Cells. Anticancer Agents Med Chem 2021; 22:1582-1591. [PMID: 34102995 DOI: 10.2174/1871520621666210608103251] [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: 12/14/2020] [Revised: 04/09/2021] [Accepted: 04/19/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND High relapse and metastasis progression in breast cancer patients have prompted the need to explore alternative treatments. Epigenetic therapy has emerged as an attractive therapeutic strategy due to the reversibility of epigenome structures. OBJECTIVE This study investigated the anti-cancer effects of epigenetic drugs scriptaid and zebularine in human breast adenocarcinoma MDA-MB-231 and MCF-7 cells. METHODS First, the half maximal inhibitory concentration (IC50) of scriptaid, zebularine and the combination of both drugs on human breast adenocarcinoma MDA-MB-231 cells was determined. Next, MDA-MB-231 and MCF-7 cells were treated with scriptaid, zebularine and the combination of both. After treatments, the anti-cancer effects were evaluated via cell migration assay, cell cycle analysis and apoptotic studies, which included histochemical staining and reverse-transcriptase polymerase chain reaction (RT-PCR) of the apoptotic genes. RESULTS Both epigenetic drugs inhibited cell viability in a dose-dependent manner with 2 nM scriptaid, 8 µM zebularine and combination of 2 nM scriptaid and 2 µM zebularine. Both MDA-MB-231 and MCF-7 cells exhibited a reduction in cell migration after the treatments. In particular, MDA-MB-231 cells exhibited a significant reduction in cell migration (p < 0.05) after the treatments of zebularine and the combination of scriptaid and zebularine. Besides, cell cycle analysis demonstrated that scriptaid and the combination of both drugs could induce cell cycle arrest at the G0/G1 phase in both MDA-MB-231 and MCF-7 cells. Furthermore, histochemical staining allowed the observation of apoptotic features, such as nuclear chromatin condensation, cell shrinkage, membrane blebbing, nuclear chromatin fragmentation and cytoplasmic extension, in both MDA-MB-231 and MCF-7 cells after the treatments. Further apoptotic studies revealed that the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 and elevation of Bax/Bcl-2 ratio were found in MDA-MB-231 cells treated with zebularine and MCF-7 cells treated with all drug regimens. CONCLUSION Collectively, these findings suggest that scriptaid and zebularine are potential anti-cancer drugs, either single or in combination, for the therapy of breast cancer. Further investigations of the gene regulatory pathways directed by scriptaid and zebularine are definitely warranted in the future.
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Affiliation(s)
- Zhi Hung Yap
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor. Malaysia
| | - Wei Yang Kong
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor. Malaysia
| | - Abdur Rahmaan Azeez
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor. Malaysia
| | - Chee-Mun Fang
- Division of Biomedical Sciences, School of Pharmacy, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor. Malaysia
| | - Siew Ching Ngai
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor. Malaysia
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32
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Xu C, Cao X, Cao X, Liu L, Qiu Y, Li X, Zhou L, Ning Y, Ren K, Cao J. Isovitexin Inhibits Stemness and Induces Apoptosis in Hepatocellular Carcinoma SK-Hep-1 Spheroids by Upregulating miR-34a Expression. Anticancer Agents Med Chem 2021; 20:1654-1663. [PMID: 32329692 DOI: 10.2174/1871520620666200424123139] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 02/26/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND We previously demonstrated that isovitexin (apigenin-6-C-glucoside, ISOV) suppressed the stemness of human Hepatocellular Carcinoma (HCC) cells. However, the mechanism of its action remains to be deciphered. OBJECTIVE The current study was to examine whether ISOV regulates the miR-34a expression and hence suppresses the stemness of HCC SK-Hep-1 cells. METHODS After identification of the stemness, apoptosis resistance and decreased miR-34a expression of spheres from SK-Hep-1 cells (SK-SC), we utilized transfection of a miR-34a mimic or inhibitor to investigate the effects of ISOV on miR-34a, Bcl-2, Bax and Mcl-1 expression in order to understand the mechanism underlying ISOV-mediated repression of stemness and promotion of apoptosis. RESULTS Our results demonstrated that SK-SC displayed higher stemness and resistance to apoptosis, as well as reduced miR-34a levels compared to SK-Hep-1 cells. ISOV suppressed sphere and colony formation, and decreased CD44+ cell populations. In addition, ABCG2, ALDH1, and NANOG mRNA levels were decreased, while there was a concomitant increase in miR-34a levels. With regards to apoptosis-related proteins, ISOV increased Bax protein levels, and reduced Bcl-2 and Mcl-1 protein levels in SK-SC. Importantly, there was a cooperative effect when miR-34a was overexpressed in the presence of ISOV in SK-SC, and down-regulation of miR-34a attenuated the effects of ISOV in SK-Hep-1 cells. CONCLUSION We suggest that ISOV-mediated miR-34a upregulation induces apoptosis and suppresses the stemness of SK-SC. Our data indicate that ISOV exhibits therapeutic potential for the treatment of HCC.
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Affiliation(s)
- Chang Xu
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha,
Hunan 410013, China
| | - Xiaocheng Cao
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha,
Hunan 410013, China
| | - XiaoZheng Cao
- Department of Pharmacy, the Second Clinical Medical School of Jinan University, Shenzhen People’s
Hospital, Shenzhen 518020, China,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis,
Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Lihua Liu
- Department of Pharmacy, the Second Clinical Medical School of Jinan University, Shenzhen People’s
Hospital, Shenzhen 518020, China,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis,
Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Yebei Qiu
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha,
Hunan 410013, China
| | - Xiang Li
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha,
Hunan 410013, China
| | - Lingli Zhou
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha,
Hunan 410013, China
| | - Yingxia Ning
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Kaiqun Ren
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha,
Hunan 410013, China
| | - Jianguo Cao
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha,
Hunan 410013, China
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Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines. BIOLOGY 2021; 10:biology10060467. [PMID: 34073238 PMCID: PMC8228543 DOI: 10.3390/biology10060467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 12/25/2022]
Abstract
Simple Summary Glioblastoma multiforme (GBM) is the most common as well as the most aggressive malignant brain tumor, with an overall survival of almost 15 months. Histone deacetylase 6 (HDAC6), an enzyme related to the deacetylation of α-tubulin, is overexpressed in GBM. The aim of our research was to study the effects of HDAC6 silencing in GBM cells. We first confirmed the overexpression of HDAC6 in GBM tissue (n = 40) against control brain (n = 10). Treatment with siHDAC6 diminished viability, clonogenic potential, and migration ability in GBM-derived cell lines. HDAC6 inhibition also reverted the mesenchymal phenotype, inhibited the Sonic Hedgehog pathway, restored primary cilium structure, and decreased autophagy. Thus, we confirm that HDAC6 is a good therapeutic target for GBM treatment. Abstract Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor. We treated glioblastoma cell lines with siHDAC6. HDAC6 silencing inhibited proliferation, migration, and clonogenicity of glioblastoma cell lines. They also reversed the mesenchymal phenotype, decreased autophagy, inhibited Shh pathway, and recovered the expression of primary cilia in glioblastoma cell lines. These results demonstrate that HDAC6 might be a good target for glioblastoma treatment.
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Ramaiah MJ, Tangutur AD, Manyam RR. Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy. Life Sci 2021; 277:119504. [PMID: 33872660 DOI: 10.1016/j.lfs.2021.119504] [Citation(s) in RCA: 179] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/20/2021] [Accepted: 04/09/2021] [Indexed: 12/15/2022]
Abstract
The role of genetic and epigenetic factors in tumor initiation and progression is well documented. Histone deacetylases (HDACs), histone methyl transferases (HMTs), and DNA methyl transferases. (DNMTs) are the main proteins that are involved in regulating the chromatin conformation. Among these, histone deacetylases (HDAC) deacetylate the histone and induce gene repression thereby leading to cancer. In contrast, histone acetyl transferases (HATs) that include GCN5, p300/CBP, PCAF, Tip 60 acetylate the histones. HDAC inhibitors are potent drug molecules that can induce acetylation of histones at lysine residues and induce open chromatin conformation at tumor suppressor gene loci and thus resulting in tumor suppression. The key processes regulated by HDAC inhibitors include cell-cycle arrest, chemo-sensitization, apoptosis induction, upregulation of tumor suppressors. Even though FDA approved drugs are confined mainly to haematological malignancies, the research on HDAC inhibitors in glioblastoma multiforme and triple negative breast cancer (TNBC) are providing positive results. Thus, several combinations of HDAC inhibitors along with DNA methyl transferase inhibitors and histone methyl transferase inhibitors are in clinical trials. This review focuses on how HDAC inhibitors regulate the expression of coding and non-coding genes with specific emphasis on their anti-cancer potential.
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Affiliation(s)
- M Janaki Ramaiah
- Laboratory of Functional genomics and Disease Biology, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India.
| | - Anjana Devi Tangutur
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500 007, Telangana, India
| | - Rajasekhar Reddy Manyam
- Department of Computer Science and Engineering, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Andhra Pradesh, India
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Salek Farrokhi A, Mohammadlou M, Abdollahi M, Eslami M, Yousefi B. Histone Deacetylase Modifications by Probiotics in Colorectal Cancer. J Gastrointest Cancer 2021; 51:754-764. [PMID: 31808058 DOI: 10.1007/s12029-019-00338-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
It has been demonstrated that epigenetic modifications of histone (acetylation/deacetylation) participate in a critical role in cancer progression by the regulation of gene expression. Several processes could be regulated by deacetylation of histone and non-histone proteins such as apoptosis, proliferation, cell metabolism, differentiation, and DNA repair. Hence, histone deacetylase inhibitors (HDACis) are employed as a hopeful group of anti-cancer drugs that could inhibit tumor cell proliferation or apoptosis. The elimination of the acetylation marks that take place as an essential epigenetic change in cancer cells is associated to HDAC expression and activity. In this regard, it has been reported that class I HDACs have a vital role in the regulation of tumor cell proliferation. OBJECTIVES: In this review, we discuss whether gut origin microorganisms could promote cancer or tumor resistance and explain mechanisms of these processes. CONCLUSIONS: According to the enormous capacity of the metabolism of the intestine microbiota, bacteria are likely to convert nutrients and digestive compounds into metabolites that regulate epigenetic in cancer. The effect of the food is of interest on epigenetic changes in the intestinal mucosa and colonocytes, as misleading nucleotide methylation may be a prognostic marker for colorectal cancer (CRC). Since epigenetic changes are potentially reversible, they can serve as therapeutic targets for preventing CRC. However, various mechanisms have been identified in the field of prevention, treatment, and progression of cancer by probiotics, which include intestinal microbiota modulation, increased intestinal barrier function, degradation of potential carcinogens, protective effect on intestinal epithelial damage, and increased immune function.
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Affiliation(s)
- Amir Salek Farrokhi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Maryam Mohammadlou
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Maryam Abdollahi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.
| | - Bahman Yousefi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
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Chhabra R, Rockfield S, Guergues J, Nadeau OW, Hill R, Stevens SM, Nanjundan M. Global miRNA/proteomic analyses identify miRNAs at 14q32 and 3p21, which contribute to features of chronic iron-exposed fallopian tube epithelial cells. Sci Rep 2021; 11:6270. [PMID: 33737539 PMCID: PMC7973504 DOI: 10.1038/s41598-021-85342-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
Malignant transformation of fallopian tube secretory epithelial cells (FTSECs) is a key contributing event to the development of high-grade serous ovarian carcinoma (HGSOC). Our recent findings implicate oncogenic transformative events in chronic iron-exposed FTSECs, including increased expression of oncogenic mediators, increased telomerase transcripts, and increased growth/migratory potential. Herein, we extend these studies by implementing an integrated transcriptomic and mass spectrometry-based proteomics approach to identify global miRNA and protein alterations, for which we also investigate a subset of these targets to iron-induced functional alterations. Proteomic analysis identified > 4500 proteins, of which 243 targets were differentially expressed. Sixty-five differentially expressed miRNAs were identified, of which 35 were associated with the “top” proteomic molecules (> fourfold change) identified by Ingenuity Pathway Analysis. Twenty of these 35 miRNAs are at the 14q32 locus (encoding a cluster of 54 miRNAs) with potential to be regulated by DNA methylation and histone deacetylation. At 14q32, miR-432-5p and miR-127-3p were ~ 100-fold downregulated whereas miR-138-5p was 16-fold downregulated at 3p21 in chronic iron-exposed FTSECs. Combinatorial treatment with methyltransferase and deacetylation inhibitors reversed expression of these miRNAs, suggesting chronic iron exposure alters miRNA expression via epigenetic alterations. In addition, PAX8, an important target in HGSOC and a potential miRNA target (from IPA) was epigenetically deregulated in iron-exposed FTSECs. However, both PAX8 and ALDH1A2 (another IPA-predicted target) were experimentally identified to be independently regulated by these miRNAs although TERT RNA was partially regulated by miR-138-5p. Interestingly, overexpression of miR-432-5p diminished cell numbers induced by long-term iron exposure in FTSECs. Collectively, our global profiling approaches uncovered patterns of miRNA and proteomic alterations that may be regulated by genome-wide epigenetic alterations and contribute to functional alterations induced by chronic iron exposure in FTSECs. This study may provide a platform to identify future biomarkers for early ovarian cancer detection and new targets for therapy.
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Affiliation(s)
- Ravneet Chhabra
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA
| | - Stephanie Rockfield
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA.,Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jennifer Guergues
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA.,Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 261 Mountain View Drive, Colchester, VT, 05446, USA
| | - Owen W Nadeau
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 261 Mountain View Drive, Colchester, VT, 05446, USA
| | - Robert Hill
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA
| | - Stanley M Stevens
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA.,Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 261 Mountain View Drive, Colchester, VT, 05446, USA
| | - Meera Nanjundan
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA.
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Zając A, Król SK, Rutkowski P, Czarnecka AM. Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype. Cancers (Basel) 2021; 13:1317. [PMID: 33804155 PMCID: PMC8001927 DOI: 10.3390/cancers13061317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
Chondrosarcoma (ChS) is a primary malignant bone tumor. Due to its heterogeneity in clinical outcomes and resistance to chemo- and radiotherapies, there is a need to develop new potential therapies and molecular targets of drugs. Many genes and pathways are involved in in ChS progression. The most frequently mutated genes are isocitrate dehydrogenase ½ (IDH1/2), collagen type II alpha 1 chain (COL2A1), and TP53. Besides the point mutations in ChS, chromosomal aberrations, such as 12q13 (MDM2) amplification, the loss of 9p21 (CDKN21/p16/INK4A and INK4A-p14ARF), and several gene fusions, commonly occurring in sarcomas, have been found. ChS involves the hypermethylation of histone H3 and the decreased methylation of some transcription factors. In ChS progression, changes in the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-AKT-mTOR) and hedgehog pathways are known to play a role in tumor growth and chondrocyte proliferation. Due to recent discoveries regarding the potential of immunotherapy in many cancers, in this review we summarize the current state of knowledge concerning cellular markers of ChS and tumor-associated immune cells. This review compares the latest discoveries in ChS biology from gene alterations to specific cellular markers, including advanced molecular pathways and tumor microenvironment, which can help in discovering new potential checkpoints in inhibitory therapy.
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Affiliation(s)
- Agnieszka Zając
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (A.Z.); (P.R.)
| | - Sylwia K. Król
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (A.Z.); (P.R.)
| | - Anna M. Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (A.Z.); (P.R.)
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-176 Warsaw, Poland
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Deng S, Wang J, Zhang L, Li J, Jin Y. LncRNA HOTAIR Promotes Cancer Stem-Like Cells Properties by Sponging miR-34a to Activate the JAK2/STAT3 Pathway in Pancreatic Ductal Adenocarcinoma. Onco Targets Ther 2021; 14:1883-1893. [PMID: 33737813 PMCID: PMC7966354 DOI: 10.2147/ott.s286666] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Introduction Pancreatic Ductal Adenocarcinoma (PDAC) stem cells (CSCs) play a vital role in the occurrence, development and recurrence of PDAC. Previous studies have shown that long non-coding RNAs (lncRNA) are closely associated with occurrence and development of malignant tumors. Among them, a LncRNA called homeobox transcription antisense RNA (HOTAIR) plays a key role in cancer progression in a variety of malignant tumors, including PDAC. Numerous studies have associated HOTAIR with poor prognosis of malignant tumor treatment, owing to its role in regulating downstream microRNAs (miRNAs). However, its underlying mechanism of action on CSCs-like properties of PDAC remain unclear. Methods We enriched CSCs of PDAC with a serum-free medium (SFM), and analyzed the expression levels of HOTAIR and miR-34a after enrichment. In addition, we evaluated the regulatory effects of HOTAIR and miR-34a on CSCs-like properties, invasion and migration of PDAC. Finally, we elucidated the role of HOTAIR in pancreatic tumor xenotransplantation. Results HOTAIR was upregulated in CSCs following PDAC enrichment of PDAC. Conversely, miR-34a was downregulated and appeared to be a direct target of HOTAIR. Moreover, knocking down HOTAIR or overexpressing miR-34a significantly inhibited CSCs-like properties, invasion and migration of PDAC cells. Furthermore, HOTAIR activated the JAK2/STAT3 pathway through miR-34a, thereby promoting CSCs-like properties, invasion and migration of PDAC cells. In vivo experiments indicated that knocking down HOTAIR could inhibit the tumorigenicity of CFPAC-1 cells. Conclusion This is the first report of HOTAIR-mediated activation of the JAK2/STAT3 pathway via miR-34a inhibition. This activation promotes CSCs-like properties, invasion and migration of PDAC.
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Affiliation(s)
- Shikang Deng
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan, 650500, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650032, People's Republic of China
| | - Junfeng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650032, People's Republic of China
| | - Li Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650032, People's Republic of China
| | - Jiao Li
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650032, People's Republic of China
| | - Yan Jin
- Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650032, People's Republic of China
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.
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Crosstalk between miRNAs and signaling pathways involved in pancreatic cancer and pancreatic ductal adenocarcinoma. Eur J Pharmacol 2021; 901:174006. [PMID: 33711308 DOI: 10.1016/j.ejphar.2021.174006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/19/2021] [Accepted: 03/02/2021] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide with 5-year survival rates below 8%. Most patients with PC and pancreatic ductal adenocarcinoma (PDAC) die after relapse and cancer progression as well as resistance to treatment. Pancreatic tumors contain a high desmoplastic stroma that forms a rigid mass and has a potential role in tumor growth and metastasis. PC initiates from intraepithelial neoplasia lesions leading to invasive cancer through various pathways. These lesions harbor particular changes in signaling pathways involved in the tumorigenesis process. These events affect both the epithelial cells, including the tumor and the surrounding stroma, and eventually lead to the formation of complex signaling networks. Genetic studies of PC have revealed common molecular features such as the presence of mutations in KRAS gene in more than 90% of patients, as well as the inactivation or deletion mutations of some tumor suppressor genes including TP53, CDKN2A, and SMAD4. In recent years, studies have also identified different roles of microRNAs in PC pathogenesis as well as their importance in PC diagnosis and treatment, and their involvement in various signaling pathways. In this study, we discussed the most common pathways involved in PC and PDAC as well as their role in tumorigenesis and progression. Furthermore, the miRNAs participating in the regulation of these signaling pathways in PC progression are summarized in this study. Therefore, understanding more about pathways involved in PC can help with the development of new and effective therapies in the future.
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Li WJ, Wang Y, Liu R, Kasinski AL, Shen H, Slack FJ, Tang DG. MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic. Front Cell Dev Biol 2021; 9:640587. [PMID: 33763422 PMCID: PMC7982597 DOI: 10.3389/fcell.2021.640587] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/03/2021] [Indexed: 12/17/2022] Open
Abstract
Overwhelming evidence indicates that virtually all treatment-naive tumors contain a subpopulation of cancer cells that possess some stem cell traits and properties and are operationally defined as cancer cell stem cells (CSCs). CSCs manifest inherent heterogeneity in that they may exist in an epithelial and proliferative state or a mesenchymal non-proliferative and invasive state. Spontaneous tumor progression, therapeutic treatments, and (epi)genetic mutations may also induce plasticity in non-CSCs and reprogram them into stem-like cancer cells. Intrinsic cancer cell heterogeneity and induced cancer cell plasticity, constantly and dynamically, generate a pool of CSC subpopulations with varying levels of epigenomic stability and stemness. Despite the dynamic and transient nature of CSCs, they play fundamental roles in mediating therapy resistance and tumor relapse. It is now clear that the stemness of CSCs is coordinately regulated by genetic factors and epigenetic mechanisms. Here, in this perspective, we first provide a brief updated overview of CSCs. We then focus on microRNA-34a (miR-34a), a tumor-suppressive microRNA (miRNA) devoid in many CSCs and advanced tumors. Being a member of the miR-34 family, miR-34a was identified as a p53 target in 2007. It is a bona fide tumor suppressor, and its expression is dysregulated and downregulated in various human cancers. By targeting stemness factors such as NOTCH, MYC, BCL-2, and CD44, miR-34a epigenetically and negatively regulates the functional properties of CSCs. We shall briefly discuss potential reasons behind the failure of the first-in-class clinical trial of MRX34, a liposomal miR-34a mimic. Finally, we offer several clinical settings where miR-34a can potentially be deployed to therapeutically target CSCs and advanced, therapy-resistant, and p53-mutant tumors in order to overcome therapy resistance and curb tumor relapse.
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Affiliation(s)
- Wen Jess Li
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Experimental Therapeutics Graduate Program, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Yunfei Wang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Department of Gynecology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Ruifang Liu
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Andrea L Kasinski
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Haifa Shen
- Department of Nanomedicine, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Frank J Slack
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Experimental Therapeutics Graduate Program, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
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Wang J, Yang S, Min L, Zhu S, Guo S, Zhang S. ECT2 Increases the stability of EGFR and Tumorigenicity by Inhibiting Grb2 Ubiquitination in Pancreatic Cancer. Front Oncol 2021; 10:589241. [PMID: 33634019 PMCID: PMC7901901 DOI: 10.3389/fonc.2020.589241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 12/17/2020] [Indexed: 11/13/2022] Open
Abstract
The poor prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is associated with the invasion and metastasis of tumor cells. Epithelial cell transforming 2 (ECT2) is a guanine nucleotide exchange factor (GEF) of the Rho family of GTPases. It has also been reported that upregulation of ECT2 in pancreatic cancer, but the role and mechanism of ECT2 have not been previously determined. We found that ECT2 was significantly elevated in PDAC tissues and cells, correlated with more advanced AJCC stage, distant metastases, and overall survival of patients with PDAC. Inhibition and overexpression tests showed that ECT2 promoted proliferation, migration and invasion in vitro, and promoted tumor growth and metastasis in vivo. We determined that ECT2 was involved in the post-translational regulation of Grb2. ECT2 inhibited the degradation of Grb2 through deubiquitination. Furthermore, knockdown of ECT2 downregulated EGFR levels by accelerating EGFR degradation. EGF stimulation facilitated the formation of ECT2-Grb2 complex. Overall, our findings indicated that ECT2 could be used as a promising new therapeutic candidate for PDAC.
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Affiliation(s)
- Junxiong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China.,National Clinical Research Centre for Digestive Diseases, Beijing, China
| | - Shuo Yang
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China.,National Clinical Research Centre for Digestive Diseases, Beijing, China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China.,National Clinical Research Centre for Digestive Diseases, Beijing, China
| | - Shuilong Guo
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China.,National Clinical Research Centre for Digestive Diseases, Beijing, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China.,National Clinical Research Centre for Digestive Diseases, Beijing, China
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Chen YL, Liu XL, Li L. Prognostic value of low microRNA-34a expression in human gastrointestinal cancer: a systematic review and meta-analysis. BMC Cancer 2021; 21:63. [PMID: 33446130 PMCID: PMC7807881 DOI: 10.1186/s12885-020-07751-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/18/2020] [Indexed: 11/10/2022] Open
Abstract
Background Mounting evidence shows that microRNA-34a (miR-34a) is involved in cancer prognosis. Therefore, we summarize the predictive role of miR-34a for survival in patients with gastrointestinal cancers (GICs). Methods All eligible studies were found by searching PubMed, Web of Science and EMBASE, and survival results were extracted. Then, the hazard ratio (HR) with the corresponding 95% confidence interval (CI) was calculated to evaluate the prognostic role of miR-34a in GICs. The association between miR-34a expression and clinicopathological characteristics was estimated by odds ratios (ORs) and 95% CIs. Results A total of 20 studies were included in this meta-analysis. For overall survival (OS), lower miR-34a expression could probably predict poorer outcome in GICs, with a pooled HR of 1.86 (95% CI: 1.52–2.28, P < 0.01). For disease-free survival (DFS), progression-free survival (PFS), and recurrence-free survival (RFS), lower miR-34a expression was related to worse DFS/PFS/RFS with a pooled HR of 1.86 (95% CI: 1.31–2.63, P < 0.01). A significant relation of differentiation/TNM stage/lymphatic metastasis and the expression level of miR-34a was identified. Conclusion This meta-analysis revealed that lower miR-34a expression is significantly connected with worse OS and DFS/PFS/RFS in GIC patients. In addition, the miR-34a expression level is relatively lower in patients with lymph node metastasis than in patients without lymph node metastasis, and decreased miR-34a expression levels are linked to poor tumour differentiation and late TNM stage. MiR-34a may become a new factor for the prognosis prediction and progression of GICs. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07751-y.
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Affiliation(s)
- Yan-Ling Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 899 Ping Hai Road, Suzhou, 215006, Jiangsu, China
| | - Xiao-Lin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 899 Ping Hai Road, Suzhou, 215006, Jiangsu, China.
| | - Ling Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 899 Ping Hai Road, Suzhou, 215006, Jiangsu, China.
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Tu MJ, Duan Z, Liu Z, Zhang C, Bold RJ, Gonzalez FJ, Kim EJ, Yu AM. MicroRNA-1291-5p Sensitizes Pancreatic Carcinoma Cells to Arginine Deprivation and Chemotherapy through the Regulation of Arginolysis and Glycolysis. Mol Pharmacol 2020; 98:686-694. [PMID: 33051382 PMCID: PMC7673485 DOI: 10.1124/molpharm.120.000130] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer cells are dysregulated and addicted to continuous supply and metabolism of nutritional glucose and amino acids (e.g., arginine) to drive the synthesis of critical macromolecules for uncontrolled growth. Recent studies have revealed that genome-derived microRNA (miRNA or miR)-1291-5p (miR-1291-5p or miR-1291) may modulate the expression of argininosuccinate synthase (ASS1) and glucose transporter protein type 1 (GLUT1). We also developed a novel approach to produce recombinant miR-1291 agents for research, which are distinguished from conventional chemo-engineered miRNA mimics. Herein, we firstly demonstrated that bioengineered miR-1291 agent was selectively processed to high levels of target miR-1291-5p in human pancreatic cancer (PC) cells. After the suppression of ASS1 protein levels, miR-1291 perturbed arginine homeostasis and preferably sensitized ASS1-abundant L3.3 cells to arginine deprivation therapy. In addition, miR-1291 treatment reduced the protein levels of GLUT1 in both AsPC-1 and PANC-1 cells, leading to a lower glucose uptake (deceased > 40%) and glycolysis capacity (reduced approximately 50%). As a result, miR-1291 largely improved cisplatin efficacy in the inhibition of PC cell viability. Our results demonstrated that miR-1291 was effective to sensitize PC cells to arginine deprivation treatment and chemotherapy through targeting ASS1- and GLUT1-mediated arginolysis and glycolysis, respectively, which may provide insights into understanding miRNA signaling underlying cancer cell metabolism and development of new strategies for the treatment of lethal PC. SIGNIFICANCE STATEMENT: Many anticancer drugs in clinical use and under investigation exert pharmacological effects or improve efficacy of coadministered medications by targeting cancer cell metabolism. Using new recombinant miR-1291 agent, we revealed that miR-1291 acts as a metabolism modulator in pancreatic carcinoma cells through the regulation of argininosuccinate synthase- and glucose transporter protein type 1-mediated arginolysis and glycolysis. Consequently, miR-1291 effectively enhanced the efficacy of arginine deprivation (pegylated arginine deiminase) and chemotherapy (cisplatin), offering new insights into development of rational combination therapies.
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Affiliation(s)
- Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Zhijian Duan
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Zhenzhen Liu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Chao Zhang
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Richard J Bold
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Frank J Gonzalez
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Edward J Kim
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
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Pisano S, Wang X, Garcia-Parra J, Gazze A, Edwards K, Feltracco V, Hu Y, He L, Gonzalez D, Francis LW, Conlan RS, Li C. Nanomicelles potentiate histone deacetylase inhibitor efficacy in vitro. Cancer Nanotechnol 2020. [DOI: 10.1186/s12645-020-00070-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Abstract
Background
Amphiphilic block copolymers used as nanomicelle drug carriers can effectively overcome poor drug solubility and specificity issues. Hence, these platforms have a broad applicability in cancer treatment. In this study, Pluronic F127 was used to fabricate nanomicelles containing the histone deacetylase inhibitor SAHA, which has an epigenetic-driven anti-cancer effect in several tumor types. SAHA-loaded nanomicelles were prepared using a thin-film drying method and characterized for size, surface charge, drug content, and drug release properties. Loaded particles were tested for in vitro activity and their effect on cell cycle and markers of cancer progression.
Results
Following detailed particle characterization, cell proliferation experiments demonstrated that SAHA-loaded nanomicelles more effectively inhibited the growth of HeLa and MCF-7 cell lines compared with free drug formulations. The 30 nm SAHA containing nanoparticles were able to release up to 100% of the encapsulated drug over a 72 h time window. Moreover, gene and protein expression analyses suggested that their cytoreductive effect was achieved through the regulation of p21 and p53 expression. SAHA was also shown to up-regulate E-cadherin expression, potentially influencing tumor migration.
Conclusions
This study highlights the opportunity to exploit pluronic-based nanomicelles for the delivery of compounds that regulate epigenetic processes, thus inhibiting cancer development and progression.
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Irani S, Paknejad M, Soleimani M, Soleimani A. Evaluation of miR-34a Effect on CCND1 mRNA Level and Sensitization of Breast Cancer Cell Lines to Paclitaxel. IRANIAN BIOMEDICAL JOURNAL 2020; 24:361-9. [PMID: 32660221 PMCID: PMC7601542 DOI: 10.29252/ibj.24.6.356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 01/18/2020] [Indexed: 01/08/2023]
Abstract
Background A growing body of literature has revealed the effective role of miR-34a, as a tumor suppressor and regulator of expression of multiple targets in tumorigenesis and cancer progression. This study aimed at evaluating the potential effects of miR-34a alone or in combination with paclitaxel on breast cancer cells. Methods After miR-34a transduction by lentiviral vectors in two MCF-7 and MDA-MB-231 cell lines of breast cancer, effects of the elevated expression of miR-34a in the cell viability and the cell proliferation were determined using MTT assay in treated and untreated cells with paclitaxel. The mRNA level of the CCND1 (Cyclin D1)gene was then measured in the two cell lines using the qRT-PCR assay. Finally, the influence of miR-34a and paclitaxel on apoptosis and cell cycle progression were examined by flow cytometry. Results The CCND1 mRNA expression levels were significantly down-regulated by overexpressed lentiviral miR-34a in MCF-7 and MDA-MB-231 cells. Combined treatment by miR-34a and paclitaxel reduced the cell viability and proliferation compared to single-drug treatment. In addition, the cell cycle arrest appeared at two phases by the combination of miR-34a and paclitaxel in MDA-MB-231 cells. Conclusion Our results suggest that miR34a, in combination with paclitaxel, has a potential for decreasing the cell viability and proliferation. Moreover, it can reduce the expression of CCND1 mRNA independent of the paclitaxel effect.
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Affiliation(s)
- Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mahsa Paknejad
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Azam Soleimani
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
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Role of Nrf2 and mitochondria in cancer stem cells; in carcinogenesis, tumor progression, and chemoresistance. Biochimie 2020; 179:32-45. [PMID: 32946993 DOI: 10.1016/j.biochi.2020.09.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 08/05/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) are rare sub-population in tumor mass with self-renewal and differentiation abilities; CSCs are considered as the main cells which are responsible for tumor metastasis, cancer recurrence, and chemo/radio-resistance. CSCs are believed to contain low mitochondria in quantity, high concentration of nuclear factor erythroid 2-related factor 2 (Nrf2), and low reactive oxygen species (ROS) levels. Mitochondria regulate certain cellular functions, including controlling of cellular energetics, calcium signaling, cell growth and cell differentiation, cell cycle regulation, and cell death. Also, mitochondria are the main sources of intrinsic ROS production. Dysfunction of CSCs mitochondria due to oxidative phosphorylation is reported in several pathological conditions, including metabolic disorders, age-related diseases, and various types of cancers. ROS levels play a significant role in cellular signal transduction and CSCs' identity and differentiation capability. Nrf2 is a master transcription factor that plays critical functions in maintaining cellular redox hemostasis by regulating several antioxidant and detoxification pathways. Recently, the critical function of Nrf2 in CSCs has been revealed by several studies. Nrf2 is an essential molecule in the maintenance of CSCs' stemness and self-renewal in response to different oxidative stresses such as chemotherapy-induced elevation of ROS. Nrf2 enables these cells to recover from chemotherapy damages, and promotes establishment of invasion and dissemination. In this study, we have summarized the role of Nrf2 and mitochondria function CSCs, which promote cancer development. The significant role of Nrf2 in the regulation of mitochondrial function and ROS levels suggests this molecule as a potential target to eradicate CSCs.
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Zhang B, Yang L, Zheng W, Lin T. MicroRNA-34 expression in gingival crevicular fluid correlated with orthodontic tooth movement. Angle Orthod 2020; 90:702-706. [PMID: 33378474 PMCID: PMC8032257 DOI: 10.2319/090219-574.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 01/01/2020] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES To explore the expression of miR-34a and its effect on expression of matrix metalloproteinases (MMPs) during orthodontic tooth movement (OTM). MATERIALS AND METHODS Twenty patients, age 12-18 years old, who underwent orthodontic treatment were enrolled. The expression of miR-34a and MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-14) were detected in gingival crevicular fluid by enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction at different time points. The miR-34a mimics or inhibitors were transfected into human periodontal ligament (hPDL) cells, and the MMP expression was measured by ELISA. RESULTS The miR-34 expression in GCF on both the tension and pressure sides after orthodontic treatment were significantly downregulated, while the levels of MMPs were significantly upregulated compared with baseline level. The levels of miR-34 and MMPs returned to baseline level 3 months after orthodontic treatment. The expression of miR-34 was negatively correlated with the expression of MMP-2, MMP-9, and MMP-14. After transfection with miR-34, the MMP-2, MMP-9, and MMP-14 expression by hPDL cells were significantly downregulated compared with miR-control and miR-34 inhibitor. CONCLUSIONS Downregulated miR-34 expression was positively correlated with MMP-2, MMP-9, and MMP-14 expression. The miR-34a transfection into hPDL cells inhibited expression of MMPs. The results suggest that miR-34a is involved in expression of MMPs during OTM.
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Vares G, Ahire V, Sunada S, Ho Kim E, Sai S, Chevalier F, Romeo PH, Yamamoto T, Nakajima T, Saintigny Y. A multimodal treatment of carbon ions irradiation, miRNA-34 and mTOR inhibitor specifically control high-grade chondrosarcoma cancer stem cells. Radiother Oncol 2020; 150:253-261. [PMID: 32717360 DOI: 10.1016/j.radonc.2020.07.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND PURPOSE High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed. MATERIAL AND METHODS Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated. RESULTS We show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. CONCLUSION Our results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.
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Affiliation(s)
- Guillaume Vares
- Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Japan.
| | - Vidhula Ahire
- Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France
| | - Shigeaki Sunada
- Department of Radiation Effects Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan; Department of Molecular Genetics, Tokyo Medical and Dental University (TMDU), Japan
| | - Eun Ho Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea
| | - Sei Sai
- Department of Charged Particle Therapy Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - François Chevalier
- Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France
| | - Paul-Henri Romeo
- Research Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS), François Jacob Institute of Biology, CEA/DRF/IBFJ/IRCM, Fontenay-aux-Roses, France
| | - Tadashi Yamamoto
- Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Japan
| | - Tetsuo Nakajima
- Department of Radiation Effects Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - Yannick Saintigny
- Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France.
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Could Protons and Carbon Ions Be the Silver Bullets Against Pancreatic Cancer? Int J Mol Sci 2020; 21:ijms21134767. [PMID: 32635552 PMCID: PMC7369903 DOI: 10.3390/ijms21134767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a very aggressive cancer type associated with one of the poorest prognostics. Despite several clinical trials to combine different types of therapies, none of them resulted in significant improvements for patient survival. Pancreatic cancers demonstrate a very broad panel of resistance mechanisms due to their biological properties but also their ability to remodel the tumour microenvironment. Radiotherapy is one of the most widely used treatments against cancer but, up to now, its impact remains limited in the context of pancreatic cancer. The modern era of radiotherapy proposes new approaches with increasing conformation but also more efficient effects on tumours in the case of charged particles. In this review, we highlight the interest in using charged particles in the context of pancreatic cancer therapy and the impact of this alternative to counteract resistance mechanisms.
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