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Ganesh GV, Gayathri B, Jayasuriya R, Ramkumar KM. Exosomal miR16 induced by allyl isothiocyanate (AITC) inhibits tumor growth in cervical cancer via modulation of apoptotic and inflammatory pathways. Arch Biochem Biophys 2025; 770:110446. [PMID: 40315946 DOI: 10.1016/j.abb.2025.110446] [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: 02/18/2025] [Revised: 04/14/2025] [Accepted: 04/30/2025] [Indexed: 05/04/2025]
Abstract
The tumor micro-environment is a key determinant for promoting cancer cell growth and development with exosomal miRNAs emerging as key regulators of tumor growth and metastasis. miR16 is one well-established tumor suppressor miRNAs that induces apoptosis, while inhibiting angiogenesis and inflammation across various cancers. Herein, we investigated the role of exosomal miR16 in the cervical cancer microenvironment and its underlying molecular mechanisms. We treated human cervical cancer HeLa cells with Allyl Isothiocyanate (AITC) and observed the impact of miR16-enriched exosomes on human fibrosarcoma HT1080 cells. We found a significant increase of miR16 expression in AITC-treated HeLa cells and purified exosomes. When the exosomes were cultured with fibroblasts, miR16 expression was increased in fibroblast cells. Treatment with AITC-exposed HeLa exosomes induced increased Bax/Bcl2 ratio and downregulated PCNA, HIF-1α, SDF-1α, IL-6, and p22phox expression in fibroblasts. Remarkably, the knockdown of miR16 in fibroblasts inhibited the AITC-induced increase in the Bax/Bcl2 ratio and restored VEGF, PCNA, HIF-1α, SDF-1α, IL-6, and p22phox expression. In sum, our findings demonstrate the potential of AITC-mediated exosomal miR16 enrichment as an effective approach to inhibit cancer growth and development, and reveal a new potential for cancer management and therapy.
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Affiliation(s)
- Goutham V Ganesh
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Balu Gayathri
- SRM-DBT Platform for Advanced Life Science Technologies, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Ravichandran Jayasuriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India.
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Bartoszewska E, Misiąg P, Czapla M, Rakoczy K, Tomecka P, Filipski M, Wawrzyniak-Dzierżek E, Choromańska A. The Role of microRNAs in Lung Cancer: Mechanisms, Diagnostics and Therapeutic Potential. Int J Mol Sci 2025; 26:3736. [PMID: 40332376 PMCID: PMC12027727 DOI: 10.3390/ijms26083736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/03/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
MicroRNAs (miRNAs) are small RNA molecules that do not have coding functions but play essential roles in various biological processes. In lung cancer, miRNAs affect the processes of tumor initiation, progression, metastasis, and resistance to treatment by regulating gene expression. Tumor-suppressive miRNAs inhibit oncogenic pathways, while oncogenic miRNAs, known as oncomiRs, promote malignant transformation and tumor growth. These dual roles position miRNAs as critical players in lung cancer biology. Studies in recent years have shown the significant potential of miRNAs as both prognostic and diagnostic biomarkers. Circulating miRNAs in plasma or sputum demonstrate specificity and sensitivity in detecting early-stage lung cancer. Liquid biopsy-based miRNA panels distinguish malignant from benign lesions, and specific miRNA expression patterns correlate with disease progression, response to treatment, and overall survival. Therapeutically, miRNAs hold promise for targeted interventions. Strategies such as miRNA replacement therapy using mimics for tumor-suppressive miRNAs and inhibition of oncomiRs with antagomiRs or miRNA sponges have shown preclinical success. Key miRNAs, including the let-7 family, miR-34a, and miR-21, are under investigation for their therapeutic potential. It should be emphasized that delivery difficulties, side effects, and limited stability of therapeutic miRNA molecules remain obstacles to their clinical use. This article examines the roles of miRNAs in lung cancer by indicating their mechanisms of action, diagnostic significance, and therapeutic potential. By addressing current limitations, miRNA-based approaches could revolutionize lung cancer management, offering precise, personalized, and minimally invasive solutions for diagnosis and treatment.
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Affiliation(s)
- Elżbieta Bartoszewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Piotr Misiąg
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Melania Czapla
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Paulina Tomecka
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Michał Filipski
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Elżbieta Wawrzyniak-Dzierżek
- Department and Clinic of Bone Marrow Transplantation, Oncology and Pediatric Hematology, Borowska 213, 50-556 Wroclaw, Poland;
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Evin D, Evinová A, Baranovičová E, Šarlinová M, Jurečeková J, Kaplán P, Poláček H, Halašová E, Dušenka R, Briš L, Brožová MK, Sivoňová MK. Integrative Metabolomic Analysis of Serum and Selected Serum Exosomal microRNA in Metastatic Castration-Resistant Prostate Cancer. Int J Mol Sci 2024; 25:2630. [PMID: 38473877 DOI: 10.3390/ijms25052630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease due to the absence of effective therapies. A more comprehensive understanding of molecular events, encompassing the dysregulation of microRNAs (miRs) and metabolic reprogramming, holds the potential to unveil precise mechanisms underlying mCRPC. This study aims to assess the expression of selected serum exosomal miRs (miR-15a, miR-16, miR-19a-3p, miR-21, and miR-141a-3p) alongside serum metabolomic profiling and their correlation in patients with mCRPC and benign prostate hyperplasia (BPH). Blood serum samples from mCRPC patients (n = 51) and BPH patients (n = 48) underwent metabolome analysis through 1H-NMR spectroscopy. The expression levels of serum exosomal miRs in mCRPC and BPH patients were evaluated using a quantitative real-time polymerase chain reaction (qRT-PCR). The 1H-NMR metabolomics analysis revealed significant alterations in lactate, acetate, citrate, 3-hydroxybutyrate, and branched-chain amino acids (BCAAs, including valine, leucine, and isoleucine) in mCRPC patients compared to BPH patients. MiR-15a, miR-16, miR-19a-3p, and miR-21 exhibited a downregulation of more than twofold in the mCRPC group. Significant correlations were predominantly observed between lactate, citrate, acetate, and miR-15a, miR-16, miR-19a-3p, and miR-21. The importance of integrating metabolome analysis of serum with selected serum exosomal miRs in mCRPC patients has been confirmed, suggesting their potential utility for distinguishing of mCRPC from BPH.
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Affiliation(s)
- Daniel Evin
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
- Clinic of Nuclear Medicine, Jessenius Faculty of Medicine in Martin, University Hospital in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Andrea Evinová
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Eva Baranovičová
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Miroslava Šarlinová
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Jana Jurečeková
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Peter Kaplán
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Hubert Poláček
- Clinic of Nuclear Medicine, Jessenius Faculty of Medicine in Martin, University Hospital in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Erika Halašová
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Róbert Dušenka
- Clinic of Urology, Jessenius Faculty of Medicine in Martin, University Hospital in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Lukáš Briš
- Clinic of Urology, Jessenius Faculty of Medicine in Martin, University Hospital in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Martina Knoško Brožová
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Monika Kmeťová Sivoňová
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
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Wang R, Zhong J, Pan X, Su Z, Xu Y, Zhang M, Chen X, Chen N, Yu T, Zhou Q. A novel intronic circular RNA circFGFR1 int2 up-regulates FGFR1 by recruiting transcriptional activators P65/FUS and suppressing miR-4687-5p to promote prostate cancer progression. J Transl Med 2023; 21:840. [PMID: 37993879 PMCID: PMC10664560 DOI: 10.1186/s12967-023-04718-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023] Open
Abstract
Fibroblast growth factor receptor 1 (FGFR1) is a core component of the FGFs/FGFR pathway that activates multiple signalling pathways, including ERK1/2, PI3K/AKT, PLCγ, and NF-κB. Aberrant expression of FGFR1 due to gene amplification, chromosome rearrangement, point mutation, and epigenetic deregulations, have been reported in various cancers. FGFR1 overexpression has also been reported in prostate cancer (PCa), but the underlining mechanisms are not clear. Here we report a novel circular RNA, circFGFR1int2, derived from intron 2 of FGFR1 gene, which is overexpressed in PCa and associated with tumor progression. Importantly, we show that circFGFR1int2 facilitates FGFR1 transcription by recruiting transcription activators P65/FUS and by interacting with FGFR1 promoter. Moreover, we show that circFGFR1int2 suppresses post-transcriptional inhibitory effects of miR-4687-5p on FGFR1 mRNA. These mechanisms synergistically promote PCa cell growth, migration, and invasion. Overexpression of circFGFR1int2 is significantly correlated with higher tumor grade, Gleason score, and PSA level, and is a significant unfavorable prognosticator for CRPC-free survival (CFS) (RR = 3.277, 95% confidence interval: 1.192-9.009; P = 0.021). These findings unravelled novel mechanisms controlling FGFR1 gene expression by intronic circRNA and its potential clinicopathological utility as a diagnostic or therapeutic target.
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Affiliation(s)
- Ruyue Wang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinjing Zhong
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiuyi Pan
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhengzheng Su
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yunyi Xu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mengni Zhang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xueqin Chen
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ni Chen
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ting Yu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qiao Zhou
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Wan L, Thomas-Ahner JM, Pearl DK, Erdman JW, Moran NE, Clinton SK. Orchestration of miRNA Patterns by Testosterone and Dietary Tomato Carotenoids during Early Prostate Carcinogenesis in TRAMP Mice. J Nutr 2023; 153:1877-1888. [PMID: 37187350 PMCID: PMC10375503 DOI: 10.1016/j.tjnut.2023.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/27/2023] [Accepted: 05/11/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND The integrative effects of prostate cancer risk factors, such as diet and endocrine status, on cancer-associated miRNA expression are poorly defined. OBJECTIVES This study aimed to define the influence of androgens and diet (tomato and lycopene) on prostatic miRNA expression during early carcinogenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. METHODS Wild type (WT) and TRAMP mice were fed control, tomato-containing, or lycopene-containing diets from 4 to 10 weeks of age. Mice underwent either sham (intact) or castration surgery at 8 wk, and half of the castrated mice received testosterone (2.5 mg/kg body weight/d) at 9 wk. Mice were killed at 10 wk, and dorsolateral prostate expression of 602 miRNAs was assessed. RESULTS We detected expression of 88 miRNAs (15% of 602), all of which were present in the TRAMP, in comparison with 49 miRNAs being detectable (8%) in WT. Expression of 61 miRNAs differed by TRAMP genotype, with the majority upregulated in TRAMP. Of the 61 miRNAs, 42 were responsive to androgen status. Diet affected 41% of the miRNAs, which differed by genotype (25/61) and 48% of the androgen-sensitive miRNAs (20/42), indicating overlapping genetic and dietary influences on prostate miRNAs. Tomato and lycopene feeding influenced miRNAs previously associated with the regulation of androgen (miR-145 and let-7), MAPK (miR-106a, 204, 145/143, and 200b/c), and p53 signaling (miR-125 and miR-98) pathways. CONCLUSIONS Expression of miRNAs in early prostate carcinogenesis is sensitive to genetic, endocrine, and diet drivers, suggesting novel mechanisms by which tomato and lycopene feeding modulate early prostate carcinogenesis.
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Affiliation(s)
- Lei Wan
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Interdisciplinary Nutrition Program
| | | | - Dennis K Pearl
- Department of Statistics, The Pennsylvania State University, University Park, PA, USA
| | - John W Erdman
- Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA
| | - Nancy E Moran
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
| | - Steven K Clinton
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
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Chakrabortty A, Patton DJ, Smith BF, Agarwal P. miRNAs: Potential as Biomarkers and Therapeutic Targets for Cancer. Genes (Basel) 2023; 14:1375. [PMID: 37510280 PMCID: PMC10378777 DOI: 10.3390/genes14071375] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/25/2023] [Accepted: 06/25/2023] [Indexed: 07/30/2023] Open
Abstract
MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and canine diseases. Most cancers tested to date have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we comprehensively summarized the importance of miRNA in human and canine cancer research. We discussed the current state of development and potential for the miRNA as both a diagnostic marker and a therapeutic target.
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Affiliation(s)
- Atonu Chakrabortty
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Daniel J Patton
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Bruce F Smith
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Payal Agarwal
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
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Shinde SS, Ahmed S, Malik JA, Hani U, Khanam A, Ashraf Bhat F, Ahmad Mir S, Ghazwani M, Wahab S, Haider N, Almehizia AA. Therapeutic Delivery of Tumor Suppressor miRNAs for Breast Cancer Treatment. BIOLOGY 2023; 12:467. [PMID: 36979159 PMCID: PMC10045434 DOI: 10.3390/biology12030467] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023]
Abstract
The death rate from breast cancer (BC) has dropped due to early detection and sophisticated therapeutic options, yet drug resistance and relapse remain barriers to effective, systematic treatment. Multiple mechanisms underlying miRNAs appear crucial in practically every aspect of cancer progression, including carcinogenesis, metastasis, and drug resistance, as evidenced by the elucidation of drug resistance. Non-coding RNAs called microRNAs (miRNAs) attach to complementary messenger RNAs and degrade them to inhibit the expression and translation to proteins. Evidence suggests that miRNAs play a vital role in developing numerous diseases, including cancer. They affect genes critical for cellular differentiation, proliferation, apoptosis, and metabolism. Recently studies have demonstrated that miRNAs serve as valuable biomarkers for BC. The contrast in the expression of miRNAs in normal tissue cells and tumors suggest that miRNAs are involved in breast cancer. The important aspect behind cancer etiology is the deregulation of miRNAs that can specifically influence cellular physiology. The main objective of this review is to emphasize the role and therapeutic capacity of tumor suppressor miRNAs in BC and the advancement in the delivery system that can deliver miRNAs specifically to cancerous cells. Various approaches are used to deliver these miRNAs to the cancer cells with the help of carrier molecules, like nanoparticles, poly D, L-lactic-co-glycolic acid (PLGA) particles, PEI polymers, modified extracellular vesicles, dendrimers, and liposomes. Additionally, we discuss advanced strategies of TS miRNA delivery techniques such as viral delivery, self-assembled RNA-triple-helix hydrogel drug delivery systems, and hyaluronic acid/protamine sulfate inter-polyelectrolyte complexes. Subsequently, we discuss challenges and prospects on TS miRNA therapeutic delivery in BC management so that miRNAs will become a routine technique in developing individualized patient profiles.
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Affiliation(s)
- Sonali S. Shinde
- Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, India
| | - Sakeel Ahmed
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad 382355, India
| | - Jonaid Ahmad Malik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati 781101, India
- Department of Biomedical Engineering, Indian Institute of Technology, Rupnagar 140001, India
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Afreen Khanam
- Department of Pharmacognosy and Phytochemistry, Jamia Hamdard, New Delhi 110062, India
| | | | - Suhail Ahmad Mir
- Department of Pharmaceutical Sciences, University of Kashmir, Jammu and Kashmir, Hazratbal, Srinagar 190006, India
| | - Mohammed Ghazwani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Nazima Haider
- Department of Pathology, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Abdulrahman A. Almehizia
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited. Cancers (Basel) 2023; 15:cancers15020376. [PMID: 36672326 PMCID: PMC9856874 DOI: 10.3390/cancers15020376] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/28/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.
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Fang Z, Meng Q, Xu J, Wang W, Zhang B, Liu J, Liang C, Hua J, Zhao Y, Yu X, Shi S. Signaling pathways in cancer-associated fibroblasts: recent advances and future perspectives. Cancer Commun (Lond) 2023; 43:3-41. [PMID: 36424360 PMCID: PMC9859735 DOI: 10.1002/cac2.12392] [Citation(s) in RCA: 120] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/20/2022] [Accepted: 11/04/2022] [Indexed: 11/26/2022] Open
Abstract
As a critical component of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well-known signaling pathways, including the transforming growth factor-β (TGF-β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa-B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia-inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.
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Affiliation(s)
- Zengli Fang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Qingcai Meng
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Jin Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Wei Wang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Bo Zhang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Jiang Liu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Chen Liang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Jie Hua
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Yingjun Zhao
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Xianjun Yu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Si Shi
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
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10
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Arosh JA, Sivakumar KK, Lee J, Banu SK. Effects of selective inhibition of prostaglandin E2 receptors EP2 and EP4 on the miRNA profile in endometriosis. Mol Cell Endocrinol 2022; 558:111728. [PMID: 35944745 DOI: 10.1016/j.mce.2022.111728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/12/2022] [Accepted: 07/13/2022] [Indexed: 12/15/2022]
Abstract
Endometriosis is an estrogen-dependent, progesterone-resistant, chronic inflammatory gynecological disease of reproductive-age women. Two major clinical symptoms of endometriosis are chronic pelvic pain and infertility, which profoundly affect the quality of life in women. Current hormonal therapies to induce a hypoestrogenic state are unsuccessful because of undesirable side effects, reproductive health concerns, and failure to prevent disease recurrence. Prostaglandin E2 (PGE2) plays an important role in the survival and growth of endometriotic lesions. MicroRNAs (miRNAs) are small, noncoding RNAs that control gene expressions through multiple mechanisms and have important roles in the pathogenesis of endometriosis. The objective of the present study is to determine the effects of pharmacological inhibition of PGE2 receptors, EP2 and EP4, on miRNA profile in endometriosis. The novel results collectively indicate that inhibition of PGE2-EP2/EP4 signaling regulated several miRNA clusters associated with cell adhesion, migration, invasion, survival and growth in cell-specific and the chromosome-specific manner and reverses the epigenetic silencing of proapoptotic miRNAs 15a and 34c in the human endometriotic epithelial and stromal cells and experimental endometriotic lesions. Thus, selective inhibition of EP2/EP4 receptors could emerge as a potential nonsteroidal therapy for endometriosis.
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Affiliation(s)
- Joe A Arosh
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA.
| | - Kirthiram K Sivakumar
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA
| | - JeHoon Lee
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA
| | - Sakhila K Banu
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA
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11
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Wang B, Jiang W, Zheng X, Han Y, Liu R. Research on a Weighted Gene Co-expression Network Analysis method for mining pathogenic genes in thyroid cancer. PLoS One 2022; 17:e0272403. [PMID: 35913967 PMCID: PMC9342754 DOI: 10.1371/journal.pone.0272403] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 07/19/2022] [Indexed: 11/23/2022] Open
Abstract
Thyroid cancer (TC) is one of the most common thyroid malignancies occurring worldwide, and accounts for about 1% of all the malignant tumors. It is one of the fastest growing tumor and can occur at any age, but it is more common in women. It is important to find the pathogenesis and treatment targets of TC. In this pursuit, the present study was envisaged to investigate the effective carcinogenic biological macromolecules, so as to provide a better understanding of the occurrence and development of TC. The clinical and gene expression data were collected from The Cancer Genome Atlas (TCGA). We clustered mRNA and long non-coding RNA (lncRNA) into different modules by Weighted Gene Co-expression Network Analysis (WGCNA), and calculated the correlation coefficient between the genes and clinical phenotypes. Using WGCNA, we identified the module with the highest correlation coefficient. Subsequently, by using the differential genes expression analysis to screen the differential micro-RNA (miRNA), the univariate Cox proportional hazard regression was employed to screen the hub genes related to overall survival (OS), with P < 0.05 as the statistical significance threshold. Finally, we designed a hub competitive endogenous RNA(ceRNA) network of disease-associated lncRNAs, miRNAs, and mRNAs. From the results of enrichment analysis, the association of these genes could be related to the occurrence and development of TC, and these hub RNAs can be valuable prognostic markers and therapeutic targets in TC.
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Affiliation(s)
- Bo Wang
- College of Computer and Control Engineering, Qiqihar University, Qiqihar, People’s Republic of China
- * E-mail:
| | - Wei Jiang
- College of Computer and Control Engineering, Qiqihar University, Qiqihar, People’s Republic of China
| | - Xiaodong Zheng
- College of Computer and Control Engineering, Qiqihar University, Qiqihar, People’s Republic of China
| | - Yu Han
- College of Computer and Control Engineering, Qiqihar University, Qiqihar, People’s Republic of China
| | - Runjie Liu
- College of Computer and Control Engineering, Qiqihar University, Qiqihar, People’s Republic of China
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12
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Kaller M, Hünten S, Siemens H, Hermeking H. Analysis of the p53/microRNA Network in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1385:187-228. [DOI: 10.1007/978-3-031-08356-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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13
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Yildiz MT, Tutar L, Giritlioğlu NI, Bayram B, Tutar Y. MicroRNAs and Heat Shock Proteins in Breast Cancer Biology. Methods Mol Biol 2022; 2257:293-310. [PMID: 34432285 DOI: 10.1007/978-1-0716-1170-8_15] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Breast cancer has five major immune types; luminal A, luminal B, HER2, Basal-like, and normal-like. Cells produce a family of protein called heat shock proteins (Hsps) in response to exposure to thermal and other proteotoxic stresses play essential roles in cancer metabolism and this large family shows a diverse set of Hsp involvement in different breast cancer immune types. Recently, Hsp members categorized according to their immune type roles. Hsp family consists of several subtypes formed by molecular weight; Hsp70, Hsp90, Hsp100, Hsp40, Hsp60, and small molecule Hsps. Cancer cells employ Hsps as survival factors since most of these proteins prevent apoptosis. Several studies monitored Hsp roles in breast cancer cells and reported Hsp27 involvement in drug resistance, Hsp70 in tumor cell transformation-progression, and interaction with p53. Furthermore, the association of Hsp90 with steroid receptors and signaling proteins in patients with breast cancer directed research to focus on Hsp-based treatments. miRNAs are known to play key roles in all types of cancer that are upregulated or downregulated in cancer which respectively referred to as oncogenes (oncomirs) or tumor suppressors. Expression profiles of miRNAs may be used to classify, diagnose, and predict different cancer types. It is clear that miRNAs play regulatory roles in gene expression and this work reveals miRNA correlation to Hsp depending on specific breast cancer immune types. Deregulation of specific Hsp genes in breast cancer subtypes allows for identification of new targets for drug design and cancer treatment. Here, we performed miRNA network analysis by recruiting Hsp genes detected in breast cancer subtypes and reviewed some of the miRNAs related to aforementioned Hsp genes.
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Affiliation(s)
- Mehmet Taha Yildiz
- Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Lütfi Tutar
- Department of Molecular Biology and Genetics, Faculty of Art and Sciences, Kırşehir Ahi Evran University, Kırşehir, Turkey
| | - Nazlı Irmak Giritlioğlu
- Department of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Banu Bayram
- Department of Nutrition and Dietetics, Hamidiye Faculty of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Yusuf Tutar
- Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey.
- Division of Biochemistry, Department of Basic Pharmaceutical Sciences, Hamidiye Faculty of Pharmacy, University of Health Sciences, Istanbul, Turkey.
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14
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Xiao K, Peng G. Long non-coding RNA FAM66C regulates glioma growth via the miRNA/LATS1 signaling pathway. Biol Chem 2021; 403:679-689. [PMID: 34954927 DOI: 10.1515/hsz-2021-0333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 12/07/2021] [Indexed: 12/29/2022]
Abstract
Glioma is one of the most common primary intracranial carcinomas and typically associated with a dismal prognosis and poor quality of life. The identification of novel oncogenes is clinically valuable for early screening and prevention. Recently, the studies have revealed that long non-coding RNAs (lncRNAs) play important roles in the development and progression of cancers including glioma. The expression of lncRNA FAM66C is reduced in glioma cell lines and clinical samples compared to non-tumor samples. Knockdown of FAM66C in U87 and U251 cells significantly promoted cell proliferation and migration, respectively. Furthermore, the correlation between FAM66C and Hippo pathway regulators YAP1 and LATS1, along with the alteration of their protein expression level indicated that FAM66C regulated cell growth through this pathway. Moreover, luciferase assay demonstrated that another two noncoding RNAs, miR15a/miR15b, directly bonded to the 3'UTR of LATS1 to facilitated its transcriptional expression and inhibited cell growth. In addition, the luciferase activity of FAM66C was block by miR15a/miR15b, and the promotion of cell growth effects caused by FAM66C deficiency was attenuated by miR15a/miR15b mimics, further proved that FAM66C functioned as a competing endogenous RNA to regulate glioma growth via the miRNA/LATS1 signaling pathway.
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Affiliation(s)
- Kai Xiao
- Department of Neurosurgery, Xiangya Hospital of Central South University, Xiangya Road, Kaifu District, Changsha 410008, Hunan Province, People's Republic of China
| | - Gang Peng
- Department of Neurosurgery, Xiangya Hospital of Central South University, Xiangya Road, Kaifu District, Changsha 410008, Hunan Province, People's Republic of China
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15
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Otmani K, Lewalle P. Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications. Front Oncol 2021; 11:708765. [PMID: 34722255 PMCID: PMC8554338 DOI: 10.3389/fonc.2021.708765] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 09/27/2021] [Indexed: 01/07/2023] Open
Abstract
MicroRNAs (miRNAs) are noncoding RNAs that have been identified as important posttranscriptional regulators of gene expression. miRNAs production is controlled at multiple levels, including transcriptional and posttranscriptional regulation. Extensive profiling studies have shown that the regulation of mature miRNAs expression plays a causal role in cancer development and progression. miRNAs have been identified to act as tumor suppressors (TS) or as oncogenes based on their modulating effect on the expression of their target genes. Upregulation of oncogenic miRNAs blocks TS genes and leads to tumor formation. In contrast, downregulation of miRNAs with TS function increases the translation of oncogenes. Several miRNAs exhibiting TS properties have been studied. In this review we focus on recent studies on the role of TS miRNAs in cancer cells and the tumor microenvironment (TME). Furthermore, we discuss how TS miRNA impacts the aggressiveness of cancer cells, with focus of the mechanism that regulate its expression. The study of the mechanisms of miRNA regulation in cancer cells and the TME may paved the way to understand its critical role in the development and progression of cancer and is likely to have important clinical implications in a near future. Finally, the potential roles of miRNAs as specific biomarkers for the diagnosis and the prognosis of cancer and the replacement of tumor suppressive miRNAs using miRNA mimics could be promising approaches for cancer therapy.
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Affiliation(s)
- Khalid Otmani
- Experimental Hematology Laboratory, Jules Bordet Institute, Université libre de Bruxelles, Brussels, Belgium
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16
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Zhang M, Xian HC, Dai L, Tang YL, Liang XH. MicroRNAs: emerging driver of cancer perineural invasion. Cell Biosci 2021; 11:117. [PMID: 34187567 PMCID: PMC8243427 DOI: 10.1186/s13578-021-00630-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
The perineural invasion (PNI), which refers to tumor cells encroaching on nerve, is a clinical feature frequently occurred in various malignant tumors, and responsible for postoperative recurrence, metastasis and decreased survival. The pathogenesis of PNI switches from 'low-resistance channel' hypothesis to 'mutual attraction' theory between peripheral nerves and tumor cells in perineural niche. Among various molecules in perineural niche, microRNA (miRNA) as an emerging modulator of PNI through generating RNA-induced silencing complex (RISC) to orchestrate oncogene and anti-oncogene has aroused a wide attention. This article systematically reviewed the role of microRNA in PNI, promising to identify new biomarkers and offer cancer therapeutic targets.
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Affiliation(s)
- Mei Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Hong-Chun Xian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Li Dai
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China.
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China.
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17
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Signore M, Alfonsi R, Federici G, Nanni S, Addario A, Bertuccini L, Aiello A, Di Pace AL, Sperduti I, Muto G, Giacobbe A, Collura D, Brunetto L, Simone G, Costantini M, Crinò L, Rossi S, Tabolacci C, Diociaiuti M, Merlino T, Gallucci M, Sentinelli S, Papalia R, De Maria R, Bonci D. Diagnostic and prognostic potential of the proteomic profiling of serum-derived extracellular vesicles in prostate cancer. Cell Death Dis 2021; 12:636. [PMID: 34155195 PMCID: PMC8215487 DOI: 10.1038/s41419-021-03909-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 05/31/2021] [Accepted: 06/07/2021] [Indexed: 12/16/2022]
Abstract
Extracellular vesicles (EVs) and their cargo represent an intriguing source of cancer biomarkers for developing robust and sensitive molecular tests by liquid biopsy. Prostate cancer (PCa) is still one of the most frequent and deadly tumor in men and analysis of EVs from biological fluids of PCa patients has proven the feasibility and the unprecedented potential of such an approach. Here, we exploited an antibody-based proteomic technology, i.e. the Reverse-Phase Protein microArrays (RPPA), to measure key antigens and activated signaling in EVs isolated from sera of PCa patients. Notably, we found tumor-specific protein profiles associated with clinical settings as well as candidate markers for EV-based tumor diagnosis. Among others, PD-L1, ERG, Integrin-β5, Survivin, TGF-β, phosphorylated-TSC2 as well as partners of the MAP-kinase and mTOR pathways emerged as differentially expressed endpoints in tumor-derived EVs. In addition, the retrospective analysis of EVs from a 15-year follow-up cohort generated a protein signature with prognostic significance. Our results confirm that serum-derived EV cargo may be exploited to improve the current diagnostic procedures while providing potential prognostic and predictive information. The approach proposed here has been already applied to tumor entities other than PCa, thus proving its value in translational medicine and paving the way to innovative, clinically meaningful tools.
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Affiliation(s)
- Michele Signore
- RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | - Romina Alfonsi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | | | - Simona Nanni
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore Largo F. Vito 1, 00168, Rome, Italy.,Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Antonio Addario
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Lucia Bertuccini
- RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | - Aurora Aiello
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore Largo F. Vito 1, 00168, Rome, Italy
| | - Anna Laura Di Pace
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | | | - Giovanni Muto
- Department of Urology, Humanitas University, Turin, Italy.,Department of Urology, S. Giovanni Bosco Hospital, Turin, Italy
| | - Alessandro Giacobbe
- Department of Urology, Humanitas University, Turin, Italy.,Department of Urology, S. Giovanni Bosco Hospital, Turin, Italy
| | - Devis Collura
- Department of Urology, Humanitas University, Turin, Italy.,Department of Urology, S. Giovanni Bosco Hospital, Turin, Italy
| | - Lidia Brunetto
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giuseppe Simone
- Department of Urology-IRCCS Regina Elena National Cancer Institute of Rome, Rome, Italy
| | - Manuela Costantini
- Department of Urology-IRCCS Regina Elena National Cancer Institute of Rome, Rome, Italy
| | - Lucio Crinò
- Department of Oncology, IRST-Meldola, Meldola, Italy
| | - Stefania Rossi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Claudio Tabolacci
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Marco Diociaiuti
- Department of Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Tania Merlino
- IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Michele Gallucci
- Department of Urology-IRCCS Regina Elena National Cancer Institute of Rome, Rome, Italy.,Department of Urology, Sapienza University of Rome, Rome, Italy
| | | | | | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore Largo F. Vito 1, 00168, Rome, Italy.,Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Désirée Bonci
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. .,IRCCS, Regina Elena National Cancer Institute, Rome, Italy.
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18
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Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q, Deng S, Zhou H. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther 2021; 6:218. [PMID: 34108441 PMCID: PMC8190181 DOI: 10.1038/s41392-021-00641-0] [Citation(s) in RCA: 384] [Impact Index Per Article: 96.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/20/2021] [Accepted: 05/06/2021] [Indexed: 02/05/2023] Open
Abstract
To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial-mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.
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Affiliation(s)
- Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jin Yang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Junjiang Liu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ye Wang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jingtian Mu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qingxiang Zeng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shuzhi Deng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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19
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Natua S, Dhamdhere SG, Mutnuru SA, Shukla S. Interplay within tumor microenvironment orchestrates neoplastic RNA metabolism and transcriptome diversity. WILEY INTERDISCIPLINARY REVIEWS-RNA 2021; 13:e1676. [PMID: 34109748 DOI: 10.1002/wrna.1676] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/03/2021] [Accepted: 05/25/2021] [Indexed: 12/11/2022]
Abstract
The heterogeneous population of cancer cells within a tumor mass interacts intricately with the multifaceted aspects of the surrounding microenvironment. The reciprocal crosstalk between cancer cells and the tumor microenvironment (TME) shapes the cancer pathophysiome in a way that renders it uniquely suited for immune tolerance, angiogenesis, metastasis, and therapy resistance. This dynamic interaction involves a dramatic reconstruction of the transcriptomic landscape of tumors by altering the synthesis, modifications, stability, and processing of gene readouts. In this review, we categorically evaluate the influence of TME components, encompassing a myriad of resident and infiltrating cells, signaling molecules, extracellular vesicles, extracellular matrix, and blood vessels, in orchestrating the cancer-specific metabolism and diversity of both mRNA and noncoding RNA, including micro RNA, long noncoding RNA, circular RNA among others. We also highlight the transcriptomic adaptations in response to the physicochemical idiosyncrasies of TME, which include tumor hypoxia, extracellular acidosis, and osmotic stress. Finally, we provide a nuanced analysis of existing and prospective therapeutics targeting TME to ameliorate cancer-associated RNA metabolism, consequently thwarting the cancer progression. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Subhashis Natua
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, Madhya Pradesh, 462066, India
| | - Shruti Ganesh Dhamdhere
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, Madhya Pradesh, 462066, India
| | - Srinivas Abhishek Mutnuru
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, Madhya Pradesh, 462066, India
| | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, Madhya Pradesh, 462066, India
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20
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Dzobo K, Dandara C. Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 24:314-339. [PMID: 32496970 DOI: 10.1089/omi.2020.0023] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The tumor stroma, a key component of the tumor microenvironment (TME), is a key determinant of response and resistance to cancer treatment. The stromal cells, extracellular matrix (ECM), and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and therapeutic outcomes. Of the stromal cells present in the TME, much attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and important in cancer initiation, progression, and therapy resistance. Besides releasing several factors, CAFs also synthesize the ECM, a key component of the tumor stroma. In this expert review, we examine the role of CAFs in the regulation of tumor cell behavior and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. Importantly, CAFs display both phenotypic and functional heterogeneity, with significant ramifications on CAF-directed therapies. Principal anti-cancer therapies targeting CAFs take the form of: (1) CAFs' ablation through use of immunotherapies, (2) re-education of CAFs to normalize the cells, (3) cellular therapies involving CAFs delivering drugs such as oncolytic adenoviruses, and (4) stromal depletion via targeting the ECM and its related signaling. The CAFs' heterogeneity could be a result of different cellular origins and the cancer-specific tumor microenvironmental effects, underscoring the need for further multiomics and biochemical studies on CAFs and the subsets. Lastly, we present recent advances in therapeutic targeting of CAFs and the success of such endeavors or their lack thereof. We recommend that to advance global public health and personalized medicine, treatments in the oncology clinic should be combinatorial in nature, strategically targeting both cancer cells and stromal cells, and their interactions.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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21
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Manifar S, Koopaie M, Lahiji SS. Assessment of MicroRNA-15a and MicroRNA-16-1 Salivary Level in Oral Squamous Cell Carcinoma Patients. Microrna 2021; 10:74-79. [PMID: 33970852 DOI: 10.2174/2211536610666210506125036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/26/2020] [Accepted: 12/09/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Squamous Cell Carcinoma (SCC) includes more than 90% of malignancies of the oral cavity. Early diagnosis could effectively improve patients' quality of life and treatment outcomes of oral cancers. MicroRNAs as non-encoding genes have great potential to initiate or suppress cancer progression. Recent studies have shown that disruption of micro-RNA regulation is a common occurrence in cancers. OBJECTIVE This study set out to evaluate the expression of microRNA-15a (miR-15a) and microRNA-16-1 (miR-16-1) in the saliva of Oral Squamous Cell Carcinoma (OSCC) patients in comparison with a healthy control group. METHODS This case-control study was performed on fifteen patients with OSCC and fifteen healthy volunteers as the control group. A 5 ml of non-stimulating whole saliva was collected by spitting method from patients and controls and stored at -70oC. The expression of miR-15a and miR-16-1 was investigated using quantitative Reverse-Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS MiR-15a and miR-16-1 were downregulated in OSCC patients compared with the control group (p<0.001). The sensitivity of miR-15a and miR-16-1 in differentiating OSCC patients from healthy individuals was 93.3% and 86.67%, respectively, and their specificity was 86.67% and 92.33%, respectively. The diagnostic accuracy of miR-15a was 90%, and miR-16-1 was 93.3%. CONCLUSION The present study showed a decrease in the relative expression of miR-15a and miR-16-1 in OSCC patients compared with healthy individuals. It is probable to introduce salivary values of miR-15a and miR-16-1 as a non-invasive tool for early detection of OSCC. Decreased expression of miR-15a and miR-16-1 in OSCC indicates the possible effective role of these genes in OSCC etiopathogenesis.
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Affiliation(s)
- Soheila Manifar
- Department of Oral Medicine, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Koopaie
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahab Shokouhi Lahiji
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
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22
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Khoei SG, Sadeghi H, Samadi P, Najafi R, Saidijam M. Relationship between Sphk1/S1P and microRNAs in human cancers. Biotechnol Appl Biochem 2021; 68:279-287. [PMID: 32275078 DOI: 10.1002/bab.1922] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 04/04/2020] [Indexed: 12/12/2022]
Abstract
Sphingosine kinases type 1 (SphK1) is a key enzyme in the phosphorylation of sphingosine to sphingosine 1-phosphate (S1P). Different abnormalities in SphK1 functions may correspond with poor prognosis in various cancers. Additionally, upregulated SphK1/S1P could promote cancer cell proliferation, angiogenesis, mobility, invasion, and metastasis. MicroRNAs as conserved small noncoding RNAs play major roles in cancer initiation, progression, metastasis, etc. Their posttranscriptionally mechanisms could affect the development of cancer growth or tumorigenesis suppression. The growing number of studies has described that various microRNAs can be regulated by SphK1, and its expression level can also be regulated by microRNAs. In this review, the relationship of SphK1 and microRNA functions and their interaction in human malignancies have been discussed. Based on them novel treatment strategies can be introduced.
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Affiliation(s)
- Saeideh Gholamzadeh Khoei
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Sadeghi
- Department of Microbiology and Virology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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23
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Rae C, Amato F, Braconi C. Patient-Derived Organoids as a Model for Cancer Drug Discovery. Int J Mol Sci 2021; 22:ijms22073483. [PMID: 33801782 PMCID: PMC8038043 DOI: 10.3390/ijms22073483] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/12/2022] Open
Abstract
In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell–cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue–tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models.
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Affiliation(s)
- Colin Rae
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (C.R.); (F.A.)
| | - Francesco Amato
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (C.R.); (F.A.)
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (C.R.); (F.A.)
- Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
- Correspondence:
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24
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Konoshenko MY, Laktionov PP. MiRNAs and radical prostatectomy: Current data, bioinformatic analysis and utility as predictors of tumour relapse. Andrology 2021; 9:1092-1107. [PMID: 33638886 DOI: 10.1111/andr.12994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/20/2021] [Accepted: 02/25/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Studies of microRNAs (miRNAs) and genes have particular interest for cancer biology and medicine due to the discovery of new therapeutic targets and markers. These studies are extensively influenced by anticancer therapy, as miRNAs interfere with the therapy's efficacy in prostate cancer (PCa). OBJECTIVES In this article, we summarise the available data on the influence of radical prostatectomy (RP) and biochemical recurrence on miRNA expression. MATERIALS AND METHODS Molecular targets of these miRNAs, as well as the reciprocal relations between different miRNAs and their targets, were studied using the DIANA, STRING and TransmiR databases. Special attention was dedicated to the mechanisms of PCa development, miRNA, and associated genes as tumour development mediators. RESULTS AND DISCUSSION Combined analysis of the databases and available literature indicates that expression of four miRNAs that are associated with prostate cancer relapse and alter their expression after RP, combined with genes that closely interact with selected miRNAs, has high potential for the prediction of PCa relapse after RP. PCa tissues and biofluids, both immediately after RP for diagnostics/prognostics and in long-term (relapse) monitoring, may be used as sources of these miRNAs. CONCLUSION An overview of the usefulness of published data and bioinformatics resources looking for diagnostic markers and molecular targets is presented in this article. The selected miRNA and gene panels have good potential as prognostic and PCa relapse markers after RP and likely could also serve as markers for therapeutic efficiency on a broader scale.
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Affiliation(s)
- Maria Yu Konoshenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia
| | - Pavel P Laktionov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia
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25
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Le P, Romano G, Nana-Sinkam P, Acunzo M. Non-Coding RNAs in Cancer Diagnosis and Therapy: Focus on Lung Cancer. Cancers (Basel) 2021; 13:cancers13061372. [PMID: 33803619 PMCID: PMC8003033 DOI: 10.3390/cancers13061372] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/03/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Over the last several decades, clinical evaluation and treatment of lung cancers have largely improved with the classification of genetic drivers of the disease, such as EGFR, ALK, and ROS1. There are numerous regulatory factors that exert cellular control over key oncogenic pathways involved in lung cancers. In particular, non-coding RNAs (ncRNAs) have a diversity of regulatory roles in lung cancers such that they have been shown to be involved in inducing proliferation, suppressing apoptotic pathways, increasing metastatic potential of cancer cells, and acquiring drug resistance. The dysregulation of various ncRNAs in human cancers has prompted preclinical studies examining the therapeutic potential of restoring and/or inhibiting these ncRNAs. Furthermore, ncRNAs demonstrate tissue-specific expression in addition to high stability within biological fluids. This makes them excellent candidates as cancer biomarkers. This review aims to discuss the relevance of ncRNAs in cancer pathology, diagnosis, and therapy, with a focus on lung cancer.
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26
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Arrighetti N, Beretta GL. miRNAs as Therapeutic Tools and Biomarkers for Prostate Cancer. Pharmaceutics 2021; 13:380. [PMID: 33805590 PMCID: PMC7999286 DOI: 10.3390/pharmaceutics13030380] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/14/2022] Open
Abstract
Prostate cancer (PCa) is the fifth cause of tumor-related deaths in man worldwide. Despite the considerable improvement in the clinical management of PCa, several limitations emerged both in the screening for early diagnosis and in the medical treatment. The use of prostate-specific antigen (PSA)-based screening resulted in patients' overtreatment and the standard therapy of patients suffering from locally advanced/metastatic tumors (e.g., radical prostatectomy, radiotherapy, and androgen deprivation therapy) showed time-limited efficacy with patients undergoing progression toward the lethal metastatic castration-resistant PCa (mCRPC). Although valuable alternative therapeutic options have been recently proposed (e.g., docetaxel, cabazitaxel, abiraterone, enzalutamide, and sipuleucel-T), mCRPC remains incurable. Based on this background, there is an urgent need to identify new and more accurate prostate-specific biomarkers for PCa diagnosis and prognosis and to develop innovative medical approaches to counteract mCRPC. In this context, microRNA (miRNAs) emerged as potential biomarkers in prostate tissues and biological fluids and appeared to be promising therapeutic targets/tools for cancer therapy. Here we overview the recent literature and summarize the achievements of using miRNAs as biomarkers and therapeutic targets/tools for fighting PCa.
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Affiliation(s)
| | - Giovanni Luca Beretta
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy;
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27
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Xiong B, Nie Y, Yu Y, Wang S, Zuo X. Reduced miR-16 levels are associated with VEGF upregulation in high-risk myelodysplastic syndromes. J Cancer 2021; 12:1967-1977. [PMID: 33753995 PMCID: PMC7974534 DOI: 10.7150/jca.52455] [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: 08/26/2020] [Accepted: 12/26/2020] [Indexed: 11/05/2022] Open
Abstract
Objective: Overexpression of vascular endothelial growth factor (VEGF), a major angiogenic factor, was found in myelodysplastic syndromes (MDS) and showed different expression statuses in different risk groups of MDS. We aimed to investigate the possible role of microRNA (miR)-15a and miR-16 on the regulation of VEGF expression and their effect on angiogenesis in lower- and higher-risk MDS. Methods: We studied peripheral blood and bone marrow samples of MDS patients or several leukaemia and MDS cell lines by enzyme-linked immunosorbent assay, immunohistochemical staining, immunofluorescence and quantitative PCR for expression levels of VEGF, miR-15a and miR-16. MiRNA transfection and Luciferase reporter assays were conducted to investigate whether VEGF is a target of miR-16. Migration and tube formation assays were performed in cells exposed to medium from cells with overexpressed or knockdown miR-16. Results: It showed a significantly lower level of miR-16 in higher-risk MDS patients, while the VEGF levels were upregulated. Inverse correlation between VEGF and miR-16 were determined in cells lines including SKM-1, THP-1, and K562 cells. Overexpression of miR-16 in SKM-1 cells resulted in reduced VEGF secretion and cell protein levels. Direct binding of miR-16 to the 3' untranslated region (3'-UTR) of VEGF was confirmed by luciferase reporter assays. The migration and tube formation of human umbilical vein endothelial cells decreased in the presence of medium from SKM-1 cells with overexpressed miR-16. Conclusion: These data suggest that miR-16 may play a role in angiogenesis in higher-risk MDS by targeting VEGF and therefore modulating MDS progression. MiR-16 might be a novel therapeutic target in higher-risk MDS.
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Affiliation(s)
- Bei Xiong
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | | | - Yalan Yu
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shixuan Wang
- Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xuelan Zuo
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
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28
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Zhu Z, Tang G, Yan J. MicroRNA-122 regulates docetaxel resistance of prostate cancer cells by regulating PKM2. Exp Ther Med 2020; 20:247. [PMID: 33178345 PMCID: PMC7651870 DOI: 10.3892/etm.2020.9377] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 02/25/2020] [Indexed: 02/06/2023] Open
Abstract
Prostate cancer (PCa), an epithelial malignancy that occurs in the prostate, is the second leading cause of cancer death worldwide. MicroRNAs (miRs/miRNAs) are reported to have important applications in the field of cancer diagnosis and treatment. The present study aimed to investigate the function of miRNA-122 in the chemoresistance of PCa cells and the underlying mechanism. Significantly decreased miR-122 and increased pyruvate kinase (PKM2) levels were observed in docetaxel-resistant PCa cells, and PKM2 was negatively correlated with miR-122. MiR-122 mimic transfection in docetaxel-resistant LNCaP cells significantly inhibited cell proliferation, promoted apoptosis and decreased glucose uptake and lactate production, which was counteracted by PKM2 overexpression. Inhibition of miR-122 in LNCaP cells had an opposite effect to miR-122 mimic transfection. In addition, miR-122 mimic transfection significantly increased the sensitivity of docetaxel-resistant LNCaP cells to docetaxel, while inhibition of miR-122 significantly decreased the sensitivity of LNCaP cells to docetaxel. Luciferase reporter assays showed that miR-122 regulated PKM2 expression by binding to the 3'-untranslated region of PKM2. The results suggest that upregulation of miR-122 could enhance docetaxel sensitivity, inhibit cell proliferation and promote apoptosis in PCa cells,possibly through the downregulation of its target protein PKM2.
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Affiliation(s)
- Zhirong Zhu
- Department of Urology, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, P.R. China
| | - Guiliang Tang
- Department of Urology, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, P.R. China
| | - Jiajun Yan
- Department of Urology, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, P.R. China
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Fang Z, Xu J, Zhang B, Wang W, Liu J, Liang C, Hua J, Meng Q, Yu X, Shi S. The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives. J Hematol Oncol 2020; 13:154. [PMID: 33213510 PMCID: PMC7678062 DOI: 10.1186/s13045-020-00988-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.
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Affiliation(s)
- Zengli Fang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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Cupido-Sánchez MG, Herrera-González NE, Mendoza CCB, Hernández MLM, Ramón-Gallegos E. In silico analysis of the association of hsa-miR-16 expression and cell survival in MDA-MB-231 breast cancer cells subjected to photodynamic therapy. Photodiagnosis Photodyn Ther 2020; 33:102106. [PMID: 33217568 DOI: 10.1016/j.pdpdt.2020.102106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 10/28/2020] [Accepted: 11/09/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND Breast cancer is the most common malignancy effecting women, and the triple-negative breast cancer (TNBC) subtype is particularly aggressive. This study aimed to evaluate the differential expression pattern of microRNAs (miRNAs) between untreated MDA-MB-231 cells (TNBC cell model) and those that survived photodynamic therapy (PDT) to gain insights into cell survival mechanisms. METHODS Two PDT cycles were applied to MDA-MB-231 cells, using δ-aminolevulinic acid (ALA) followed by laser light at 635 nm. RNA was obtained from cells surviving PDT and untreated cells. The miRNAs expression profile was analyzed to detect the differences between the two groups. The potential target network of hsa-miR-16 was examined in silico with the integrative database Ingenuity® Pathway Analysis software. RESULTS After the first and second PDT cycles, 17.8% and 49.6% of the MDA-MB-231 cells were viable. Microarray profiling of miRNAs showed decreased hsa-miR-16 expression (p < 0.05) in MDA-MB-231 cells surviving PDT when compared to the control cells. The predicted downstream targets of hsa-miR-16 were: 1) tumor suppressor protein 53; 2) molecules related to the cell cycle, such as cyclin D1, D3, and E1, and checkpoint kinase 1; 3) cell proliferation molecules, including fibroblast growth factor 1, 2 and 7 and fibroblast growth factor receptor 1; and 4) apoptosis-related molecules, consisting of BCL-2, B-cell leukemia/lymphoma 2, caspase 3, and cytochrome c. CONCLUSIONS The differential expression of hsa-miR-16 between untreated MDA-MB-231 cells and those surviving PDT has not been previously reported. There was a lower expression of hsa-miR-16 in treated cells, which probably altered its downstream target network. In silico analysis predicted, a network related to the cell cycle, proliferation and apoptosis. These results are congruent with previous descriptions of hsa-miR-16 as a tumor suppressor and suggest that the treated population has increased their capacity to survive.
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Affiliation(s)
- María Guadalupe Cupido-Sánchez
- Molecular Oncology Lab, Escuela Superior de Medicina, Instituto Politécnico Nacional. Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomás, 11340, Ciudad de México, Mexico.
| | - Norma Estela Herrera-González
- Molecular Oncology Lab, Escuela Superior de Medicina, Instituto Politécnico Nacional. Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomás, 11340, Ciudad de México, Mexico.
| | - Columba Citlalli Barrera Mendoza
- Environmental Cytopathology Lab, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Wilfrido Massieu, Esq. Cda. Manuel Stampa Zacatenco, Gustavo A. Madero, 07736, Ciudad de México, Mexico.
| | - María Luisa Morales Hernández
- Environmental Cytopathology Lab, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Wilfrido Massieu, Esq. Cda. Manuel Stampa Zacatenco, Gustavo A. Madero, 07736, Ciudad de México, Mexico.
| | - Eva Ramón-Gallegos
- Environmental Cytopathology Lab, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Wilfrido Massieu, Esq. Cda. Manuel Stampa Zacatenco, Gustavo A. Madero, 07736, Ciudad de México, Mexico.
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Louault K, Li RR, DeClerck YA. Cancer-Associated Fibroblasts: Understanding Their Heterogeneity. Cancers (Basel) 2020; 12:E3108. [PMID: 33114328 PMCID: PMC7690906 DOI: 10.3390/cancers12113108] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 10/12/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023] Open
Abstract
The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming and therapeutic resistance. Nevertheless, their role is not fully understood, and is sometimes controversial due to their heterogeneity. CAFs are heterogeneous in their origin, phenotype, function and presence within tumors. As a result, strategies to target CAFs in cancer therapy have been hampered by the difficulties in better defining the various populations of CAFs and by the lack of clear recognition of their specific function in cancer progression. This review discusses how a greater understanding of the heterogeneous nature of CAFs could lead to better approaches aimed at their use or at their targeting in the treatment of cancer.
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Affiliation(s)
- Kévin Louault
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Rong-Rong Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA;
| | - Yves A. DeClerck
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
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32
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Bordignon P, Bottoni G, Xu X, Popescu AS, Truan Z, Guenova E, Kofler L, Jafari P, Ostano P, Röcken M, Neel V, Dotto GP. Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant. Cell Rep 2020; 28:2358-2372.e6. [PMID: 31461652 PMCID: PMC6718812 DOI: 10.1016/j.celrep.2019.07.092] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 06/17/2019] [Accepted: 07/24/2019] [Indexed: 12/14/2022] Open
Abstract
Heterogeneity of cancer-associated fibroblasts (CAFs) can result from activation of distinct signaling pathways. We show that in primary human dermal fibroblasts (HDFs), fibroblast growth factor (FGF) and transforming growth factor β (TGF-β) signaling oppositely modulate multiple CAF effector genes. Genetic abrogation or pharmacological inhibition of either pathway results in induction of genes responsive to the other, with the ETV1 transcription factor mediating the FGF effects. Duality of FGF/TGF-β signaling and differential ETV1 expression occur in multiple CAF strains and fibroblasts of desmoplastic versus non-desmoplastic skin squamous cell carcinomas (SCCs). Functionally, HDFs with opposite TGF-β versus FGF modulation converge on promoting cancer cell proliferation. However, HDFs with increased TGF-β signaling enhance invasive properties and epithelial-mesenchymal transition (EMT) of SCC cells, whereas HDFs with increased FGF signaling promote macrophage infiltration. The findings point to a duality of FGF versus TGF-β signaling in distinct CAF populations that promote cancer development through modulation of different processes.
FGF and TGF-β signaling exert opposite control over multiple CAF effector genes ETV1 transcription factor mediates FGF effects and suppresses those of TGF-β Modulation of either pathway leads to different tumor-promoting CAF populations TGF-β-activated CAFs promote EMT, but FGF-activated CAFs increase inflammation
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Affiliation(s)
- Pino Bordignon
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland
| | - Giulia Bottoni
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Xiaoying Xu
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland
| | - Alma S Popescu
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland
| | - Zinnia Truan
- Department of Otolaryngology-Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne 1011, Switzerland
| | - Emmanuella Guenova
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland
| | - Lukas Kofler
- Department of Dermatology, Eberhard Karls University, Tübingen 72076, Germany
| | - Paris Jafari
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA; International Cancer Prevention Institute, Epalinges 1066, Switzerland
| | - Paola Ostano
- Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella 13900, Italy
| | - Martin Röcken
- Department of Dermatology, Eberhard Karls University, Tübingen 72076, Germany
| | - Victor Neel
- Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - G Paolo Dotto
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA; International Cancer Prevention Institute, Epalinges 1066, Switzerland.
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33
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Chen QH, Li B, Liu DG, Zhang B, Yang X, Tu YL. LncRNA KCNQ1OT1 sponges miR-15a to promote immune evasion and malignant progression of prostate cancer via up-regulating PD-L1. Cancer Cell Int 2020; 20:394. [PMID: 32821247 PMCID: PMC7429893 DOI: 10.1186/s12935-020-01481-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 08/04/2020] [Indexed: 12/19/2022] Open
Abstract
Background We focused on the KCNQ1OT1/miR-15a/PD-L1 axis and explored its significance in regulating immune evasion and malignant behaviors of prostate cancer (PC) cells. Methods The expression levels of KCNQ1OT1, miR-15a, PD-L1, and CD8 in cells or tissues were examined by RT-qPCR, western blot or immunohistochemistry (IHC) assays. The direct regulations between KCNQ1OT1, miR-15a and PD-L1 were validated by luciferase reporter assay. PC cells were co-cultured with CD8+ T cells to study the immune evasion. Proliferation, apoptosis, migration and invasion abilities were detected by MTT, flow cytometry, wound healing and Transwell assays, respectively. The cytotoxicity of CD8+ T cells was determined by LDH cytotoxicity Kit. Epithelial–mesenchymal transition (EMT) and Ras/ERK signaling markers were evaluated by western blot. Results KCNQ1OT1, PD-L1 and CD8 were increased, while miR-15a was decreased in PC tissues. MiR-15a directly bound to the 3′-UTR of PD-L1 and inhibited the expression of PD-L1. Overexpressing miR-15a in PC cells was sufficient to promote cytotoxicity and proliferation, while inhibit apoptosis of CD8+ T cells, and also suppressed viability, migration, invasion and EMT while promoted apoptosis of PC cells. The above anti-tumor effects of miR-15a were reversed by overexpressing PD-L1. KCNQ1OT1 sponged miR-15a and released its inhibition on PD-L1. Functionally, KCNQ1OT1 in PC cells was essential for suppressing the cytotoxicity of CD8+ T cells and maintaining multiple malignant phenotypes of PC cells. The Ras/ERK signaling was suppressed after overexpressing miR-15a or knocking down KCNQ1OT1. Conclusions LncRNA KCNQ1OT1 sponges miR-15a to promote immune evasion and malignant progression of PC via up-regulating PD-L1.
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Affiliation(s)
- Qi-Hua Chen
- Department of Andrology, The First Hospital, Hunan University of Chinese Medicine, No.95, Shaoshan Middle Road, Yuhua District, Changsha, 410007 Hunan People's Republic of China
| | - Bo Li
- Department of Andrology, The First Hospital, Hunan University of Chinese Medicine, No.95, Shaoshan Middle Road, Yuhua District, Changsha, 410007 Hunan People's Republic of China
| | - De-Guo Liu
- Graduate School, Hunan University of Chinese Medicine, Changsha, 410208 People's Republic of China
| | - Biao Zhang
- Graduate School, Hunan University of Chinese Medicine, Changsha, 410208 People's Republic of China
| | - Xian Yang
- Department of Dermatology, The First Hospital, Hunan University of Chinese Medicine, Changsha, 410007 People's Republic of China
| | - Ya-Ling Tu
- Graduate School, Hunan University of Chinese Medicine, Changsha, 410208 People's Republic of China
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34
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Rzeszutek I, Singh A. Small RNAs, Big Diseases. Int J Mol Sci 2020; 21:E5699. [PMID: 32784829 PMCID: PMC7460979 DOI: 10.3390/ijms21165699] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/06/2020] [Accepted: 08/08/2020] [Indexed: 02/06/2023] Open
Abstract
The past two decades have seen extensive research done to pinpoint the role of microRNAs (miRNAs) that have led to discovering thousands of miRNAs in humans. It is not, therefore, surprising to see many of them implicated in a number of common as well as rare human diseases. In this review article, we summarize the progress in our understanding of miRNA-related research in conjunction with different types of cancers and neurodegenerative diseases, as well as their potential in generating more reliable diagnostic and therapeutic approaches.
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Affiliation(s)
- Iwona Rzeszutek
- Institute of Biology and Biotechnology, Department of Biotechnology, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, Poland
| | - Aditi Singh
- Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, 72076 Tübingen, Germany
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35
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Giacomini A, Grillo E, Rezzola S, Ribatti D, Rusnati M, Ronca R, Presta M. The FGF/FGFR system in the physiopathology of the prostate gland. Physiol Rev 2020; 101:569-610. [PMID: 32730114 DOI: 10.1152/physrev.00005.2020] [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] [Indexed: 02/06/2023] Open
Abstract
Fibroblast growth factors (FGFs) are a family of proteins possessing paracrine, autocrine, or endocrine functions in a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis, wound repair, and cancer. Canonical FGFs bind and activate tyrosine kinase FGF receptors (FGFRs), triggering intracellular signaling cascades that mediate their biological activity. Experimental evidence indicates that FGFs play a complex role in the physiopathology of the prostate gland that ranges from essential functions during embryonic development to modulation of neoplastic transformation. The use of ligand- and receptor-deleted mouse models has highlighted the requirement for FGF signaling in the normal development of the prostate gland. In adult prostate, the maintenance of a functional FGF/FGFR signaling axis is critical for organ homeostasis and function, as its disruption leads to prostate hyperplasia and may contribute to cancer progression and metastatic dissemination. Dissection of the molecular landscape modulated by the FGF family will facilitate ongoing translational efforts directed toward prostate cancer therapy.
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Affiliation(s)
- Arianna Giacomini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; and Italian Consortium for Biotechnology, Unit of Brescia, Brescia, Italy
| | - Elisabetta Grillo
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; and Italian Consortium for Biotechnology, Unit of Brescia, Brescia, Italy
| | - Sara Rezzola
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; and Italian Consortium for Biotechnology, Unit of Brescia, Brescia, Italy
| | - Domenico Ribatti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; and Italian Consortium for Biotechnology, Unit of Brescia, Brescia, Italy
| | - Marco Rusnati
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; and Italian Consortium for Biotechnology, Unit of Brescia, Brescia, Italy
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; and Italian Consortium for Biotechnology, Unit of Brescia, Brescia, Italy
| | - Marco Presta
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; and Italian Consortium for Biotechnology, Unit of Brescia, Brescia, Italy
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36
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Emerging Therapeutic RNAs for the Targeting of Cancer Associated Fibroblasts. Cancers (Basel) 2020; 12:cancers12061365. [PMID: 32466591 PMCID: PMC7352655 DOI: 10.3390/cancers12061365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/23/2020] [Accepted: 05/24/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor mass consists of a complex ensemble of malignant cancer cells and a wide variety of resident and infiltrating cells, secreted factors, and extracellular matrix proteins that are referred as tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) are key TME components that support tumor growth, generating a physical barrier against drugs and immune infiltration, and contributing to regulate malignant progression. Thus, it is largely accepted that therapeutic approaches aimed at hampering the interactions between tumor cells and CAFs can enhance the effectiveness of anti-cancer treatments. In this view, nucleic acid therapeutics have emerged as promising molecules. Here, we summarize recent knowledge about their role in the regulation of CAF transformation and tumor-promoting functions, highlighting their therapeutic utility and challenges.
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37
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Liu Q, Li Q, Zhu S, Yi Y, Cao Q. B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer. Asian J Androl 2020; 21:224-232. [PMID: 29862993 PMCID: PMC6498728 DOI: 10.4103/aja.aja_38_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
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Affiliation(s)
- Qipeng Liu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Xiangya School of Medicine, Central South University, Changsha 410008, China
| | - Qiaqia Li
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Xiangya School of Medicine, Central South University, Changsha 410008, China
| | - Sen Zhu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Yang Yi
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China.,Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qi Cao
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA.,Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA
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38
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Jin W, Fei X, Wang X, Song Y, Chen F. Detection and Prognosis of Prostate Cancer Using Blood-Based Biomarkers. Mediators Inflamm 2020; 2020:8730608. [PMID: 32454797 PMCID: PMC7218965 DOI: 10.1155/2020/8730608] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/24/2020] [Accepted: 04/27/2020] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PCa) is second only to lung cancer as a cause of death. Clinical assessment of patients and treatment efficiency therefore depend on the disease being diagnosed as early as possible. However, due to issues regarding the use of prostate-specific antigen (PSA) for screening purposes, PCa management is among the most contentious of healthcare matters. PSA screening is problematic primarily because of diagnosis difficulties and the high rate of false-positive biopsies. Novel PCa biomarkers, such as the Prostate Health Index (PHI) and the 4Kscore, have been proposed in recent times to improve PSA prediction accuracy and have shown higher performance by preventing redundant biopsies. The 4Kscore also shows high precision in determining the risk of developing high-grade PCa, whereas elevated PHI levels suggest that the tumor is aggressive. Some evidence also supports the effectiveness of miRNAs as biomarkers for distinguishing PCa from benign prostatic hyperplasia and for assessing the aggressiveness of the disease. A number of miRNAs that possibly act as tumor inhibitors or oncogenes are impaired in PCa. These new biomarkers are comprehensively reviewed in the present study in terms of their potential use in diagnosing and treating PCa.
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Affiliation(s)
- Wei Jin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiang Fei
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yan Song
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fangjie Chen
- Department of Medical Genetics, School of Life Sciences, China Medical University, Shenyang, Liaoning, China
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39
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Hoseinbeyki M, Taha MF, Javeri A. miR-16 enhances miR-302/367-induced reprogramming and tumor suppression in breast cancer cells. IUBMB Life 2020; 72:1075-1086. [PMID: 32057163 DOI: 10.1002/iub.2249] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 01/31/2020] [Indexed: 12/24/2022]
Abstract
Overexpression of either miR-302 or miR-302/367 cluster induces reprogramming of cancer cells and exerts tumor-suppressive effects by induction of mesenchymal-to-epithelial transition, apoptosis and a less proliferative capacity. Several reports have described miR-16 as a tumor suppressor microRNA (miRNA). Here, we studied the impact of exogenous induction of miR-16 in MDA-MB-231 and SK-BR-3 breast cancer cells following overexpression of miR-302/367 cluster and investigated whether transfection of these cells by a mature miR-16 mimic could affect the reprogramming state of the cells and their tumorigenicity. miR-16 enhanced the expression levels of OCT4A, SOX2, and NANOG, generally known as transcription or pluripotency factors, and suppressed proliferation and invasiveness of these cells. Meanwhile, inhibition of miR-16 counteracted both the reprogramming effect and the antitumor function of miR-302/367 in the breast cancer cells. Current results indicate that miR-16 can work as an adjuvant to improve both cancer cell reprogramming and tumor-suppressive function of miR-302/367 cluster in MDA-MB-231 and SK-BR-3 cells, while its inhibition counteracts all of these effects. Combined application of miRNAs that share some common targets in cancer cell signaling pathways may provide new approaches for repression of multiple hallmarks of cancer.
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Affiliation(s)
- Moslem Hoseinbeyki
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Masoumeh F Taha
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Arash Javeri
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
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40
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Pan Z, Tian Y, Niu G, Cao C. Role of microRNAs in remodeling the tumor microenvironment (Review). Int J Oncol 2020; 56:407-416. [PMID: 31894326 PMCID: PMC6959460 DOI: 10.3892/ijo.2019.4952] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 12/17/2019] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are short non‑coding RNAs that are known to regulate gene expression at the post‑transcriptional level. miRNA expression is often deregulated in several human cancers, affecting the communication between tumor stroma and tumor cells, among other functions. Understanding the role of miRNAs in the tumor microenvironment is crucial for fully elucidating the molecular mechanisms underlying tumor progression and exploring novel diagnostic biomarkers and therapeutic targets. The present review focused on the role of miRNAs in remodeling the tumor microenvironment, with an emphasis on their impact on tumor growth, metastasis and resistance to treatment, as well as their potential clinical applications.
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Affiliation(s)
- Zhaoji Pan
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221000
| | - Yiqing Tian
- Xinyi People’s Hospital, Xuzhou, Jiangsu 221400, P.R. China
| | - Guoping Niu
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221000
| | - Chengsong Cao
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221000
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41
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High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network. Int J Mol Sci 2020; 21:ijms21030717. [PMID: 31979076 PMCID: PMC7038092 DOI: 10.3390/ijms21030717] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 12/11/2022] Open
Abstract
High mobility group A (HMGA) proteins are oncofoetal chromatin architectural factors that are widely involved in regulating gene expression. These proteins are unique, because they are highly expressed in embryonic and cancer cells, where they play a relevant role in cell proliferation, stemness, and the acquisition of aggressive tumour traits, i.e., motility, invasiveness, and metastatic properties. The HMGA protein expression levels and activities are controlled by a connected set of events at the transcriptional, post-transcriptional, and post-translational levels. In fact, microRNA (miRNA)-mediated RNA stability is the most-studied mechanism of HMGA protein expression modulation. In this review, we contribute to a comprehensive overview of HMGA-targeting miRNAs; we provide detailed information regarding HMGA gene structural organization and a comprehensive evaluation and description of HMGA-targeting miRNAs, while focusing on those that are widely involved in HMGA regulation; and, we aim to offer insights into HMGA-miRNA mutual cross-talk from a functional and cancer-related perspective, highlighting possible clinical implications.
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42
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Sylvestre M, Tarte K, Roulois D. Epigenetic mechanisms driving tumor supportive microenvironment differentiation and function: a role in cancer therapy? Epigenomics 2019; 12:157-169. [PMID: 31849241 DOI: 10.2217/epi-2019-0165] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The tumor microenvironment (TME) plays a central role in tumor development and drug resistance. Within TME, the stromal cell subset, called cancer-associated fibroblasts, is a heterogeneous population originating from poorly characterized precursors. Since cancer-associated fibroblasts do not acquire somatic mutations, other mechanisms like epigenetic regulation, could be involved in the development of these cells and in the acquisition of tumor supportive phenotypes. Moreover, such epigenetic modulations have been correlated to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. These findings underline the need to deepen our knowledge on epigenetic mechanisms driving TME development and function, and to understand the impact of epigenetic drugs that could be used in future to target both tumor cells and their TME.
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Affiliation(s)
- Marvin Sylvestre
- UMR _S 1236, Université de Rennes 1, INSERM, Établissement français du sang (EFS) Bretagne, Rennes, France
| | - Karin Tarte
- UMR _S 1236, Université de Rennes 1, INSERM, Établissement français du sang (EFS) Bretagne, Rennes, France.,Laboratoire Suivi Immunologique des Thérapeutiques Innovantes (SITI), Centre Hospitalier Universitaires de Rennes, Rennes, France
| | - David Roulois
- UMR _S 1236, Université de Rennes 1, INSERM, Établissement français du sang (EFS) Bretagne, Rennes, France.,Niches & Epigenetics of Tumors from Cancéropole Grand Ouest, France
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43
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Guo S, Li M, Li J, Lv Y. Inhibition mechanism of lung cancer cell metastasis through targeted regulation of Smad3 by miR-15a. Oncol Lett 2019; 19:1516-1522. [PMID: 31966076 PMCID: PMC6956405 DOI: 10.3892/ol.2019.11194] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023] Open
Abstract
Effect of targeted regulation of mothers against decapentaplegic homolog 3 (Smad3) by microRNA-15a (miR-15a) on the proliferation, invasion and metastasis of non-small cell lung cancer (NSCLC) cells and its related mechanisms were investigated. Fifty pairs of NSCLC and para-cancerous tissues were collected to identify the expression level of miR-15a in NSCLC, para-cancerous tissue, and cell lines A549, H1299, H1975 and BEAS-2B by real-time fluorescence quantitative PCR (RT-PCR); A549 cells were transfected with miR-15a mimic; the MTT assay was performed to detect the role of miR-15a transfection in proliferation of A549 cells, the wound healing assay was carried out to identify the role of miR-15a in migration of A549 cells; Transwell invasion assay was conducted to analyze the role of miR-15a in invasion of A549 cells; western blotting was carried out to find the effect of miR-15a on Smad3 expression, and Spearman's rank correlation was used to analyze the correlation between miR-15a and Smad3 expression. NSCLC tissues and cells showed significantly lower miR-15a expression, compared with para-cancerous tissues and normal cell lines (P=0.023). miR-15a was significantly more expressed in A549 cells transfected with miR-15a mimic (P=0.043). Overexpression of miR-15a can significantly inhibit A549 cell proliferation (P=0.038), migration (P=0.033) and invasion (P=0.025), and significantly reduced the expression level of Smad3 (P=0.031) in A549 cells. Spearman's rank correlation showed negative correlation of miR-15a expression with Smad3, which may indicate negative regulation (r=−0.34, P<0.0001). Inhibition of proliferation, migration and invasion of NSCLC cells can be achieved with targeted regulation of Smad3 by miR-15a.
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Affiliation(s)
- Shuai Guo
- Department of Medical Oncology, Shandong Provincial Chest Hospital, Jinan, Shandong 250013, P.R. China
| | - Ming Li
- Department of Thoracic Surgery, Shandong Provincial Chest Hospital, Jinan, Shandong 250013, P.R. China
| | - Juan Li
- Department of Pathology, The Forth Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Yan Lv
- Department of Internal Medicine Ward IV, Shandong Provincial Chest Hospital, Jinan, Shandong 250013, P.R. China
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44
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Pan Z, Tian Y, Niu G, Cao C. The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity. Stem Cells Int 2019; 2019:8071842. [PMID: 31885627 PMCID: PMC6914970 DOI: 10.1155/2019/8071842] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/15/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.
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Affiliation(s)
- Zhaoji Pan
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, China
| | - Yiqing Tian
- Xinyi People's Hospital, Xinyi, Xuzhou, Jiangsu, China
| | - Guoping Niu
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, China
| | - Chengsong Cao
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, China
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45
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Savardashtaki A, Shabaninejad Z, Movahedpour A, Sahebnasagh R, Mirzaei H, Hamblin MR. miRNAs derived from cancer-associated fibroblasts in colorectal cancer. Epigenomics 2019; 11:1627-1645. [PMID: 31702390 PMCID: PMC7132634 DOI: 10.2217/epi-2019-0110] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023] Open
Abstract
Currently, the incidence of colorectal cancer (CRC) is increasing across the world. The cancer stroma exerts an impact on the spread, invasion and chemoresistance of CRC. The tumor microenvironment involves a complex interaction between cancer cells and stromal cells, for example, cancer-associated fibroblasts (CAFs). CAFs can promote neoplastic angiogenesis and tumor development in CRC. Mounting evidence suggests that many miRNAs are overexpressed (miR-21, miR-329, miR-181a, miR-199a, miR-382 and miR-215) in CRC CAFs, and these miRNAs can influence the spread, invasiveness and chemoresistance in neighboring tumor cells via paracrine signaling. Herein, we summarize the pathogenic roles of miRNAs and CAFs in CRC. Moreover, for first time, we highlight the miRNAs derived from CRC-associated CAFs and their roles in CRC pathogenesis.
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Affiliation(s)
- Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences … Technologies, Shiraz University of Medical Sciences Shiraz, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Shabaninejad
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ahmad Movahedpour
- Department of Medical Biotechnology, School of Advanced Medical Sciences … Technologies, Shiraz University of Medical Sciences Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA 02114, USA
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46
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The stromal loss of miR-4516 promotes the FOSL1-dependent proliferation and malignancy of triple negative breast cancer. Cancer Lett 2019; 469:256-265. [PMID: 31672492 DOI: 10.1016/j.canlet.2019.10.039] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/24/2019] [Accepted: 10/09/2019] [Indexed: 12/24/2022]
Abstract
Stroma-derived exosomal microRNA (exomiR) contributes to tumor progression, however, which remains poorly understood. In our study, we analyzed exomiRs from the cancer-associated fibroblast (CAF) and normal fibroblast (NF) isolated from an invasive ductal carcinoma (IDC) patient and found that the level of microRNA (miR)-4516 was approximately 5-fold lower in CAF-derived exosomes than NF-derived ones. In gene annotation analysis, miR-4516 target genes were mainly associated with the regulation of proliferation. miR-4516 overexpression or mimic treatment suppressed the proliferation of breast cancer cells, especially triple negative breast cancer (TNBC) cells. Among miR-4516 targets, FOSL1 was overexpressed in TNBC cells compared to non-TNBC cells and promoted tumor proliferation. The expression of miR-4516 and FOSL1 was reversely correlated in breast cancer patient tissues. Particularly, TNBC patients with high FOSL1 expression showed a significant poorer survival than those with low FOSL1 expression. Our results show that the loss of miR-4516 from CAF-derived exosomes is associated with FOSL1-dependent TNBC progression and suggest that miR-4516 can be used as an anti-cancer drug for TNBC.
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47
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Rahmatizadeh F, Gholizadeh-Ghaleh Aziz S, Khodadadi K, Lale Ataei M, Ebrahimie E, Soleimani Rad J, Pashaiasl M. Bidirectional and Opposite Effects of Naïve Mesenchymal Stem Cells on Tumor Growth and Progression. Adv Pharm Bull 2019; 9:539-558. [PMID: 31857958 PMCID: PMC6912184 DOI: 10.15171/apb.2019.063] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/31/2019] [Accepted: 08/13/2019] [Indexed: 12/16/2022] Open
Abstract
Cancer has long been considered as a heterogeneous population of uncontrolled proliferation of
different transformed cell types. The recent findings concerning tumorigeneses have highlighted
the fact that tumors can progress through tight relationships among tumor cells, cellular, and
non-cellular components which are present within tumor tissues. In recent years, studies have
shown that mesenchymal stem cells (MSCs) are essential components of non-tumor cells within
the tumor tissues that can strongly affect tumor development. Several forms of MSCs have been
identified within tumor stroma. Naïve (innate) mesenchymal stem cells (N-MSCs) derived from
different sources are mostly recruited into the tumor stroma. N-MSCs exert dual and divergent
effects on tumor growth through different conditions and factors such as toll-like receptor
priming (TLR-priming), which is the primary underlying causes of opposite effects. Moreover,
MSCs also have the contrary effects by various molecular mechanisms relying on direct cellto-
cell connections and indirect communications through the autocrine, paracrine routes, and
tumor microenvironment (TME).
Overall, cell-based therapies will hold great promise to provide novel anticancer treatments.
However, the application of intact MSCs in cancer treatment can theoretically cause adverse
clinical outcomes. It is essential that to extensively analysis the effective factors and conditions
in which underlying mechanisms are adopted by MSCs when encounter with cancer.
The aim is to review the cellular and molecular mechanisms underlying the dual effects of
MSCs followed by the importance of polarization of MSCs through priming of TLRs.
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Affiliation(s)
- Faramarz Rahmatizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Khodadad Khodadadi
- Murdoch Children's Research Institute, Royal Children's Hospital, The University of Melbourne, Melbourne, Australia
| | - Maryam Lale Ataei
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Esmaeil Ebrahimie
- Adelaide Medical School, University of Adelaide, Adelaide, Australia.,School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, Australia
| | - Jafar Soleimani Rad
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran
| | - Maryam Pashaiasl
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran.,Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Razdan A, de Souza P, Roberts TL. Role of MicroRNAs in Treatment Response in Prostate Cancer. Curr Cancer Drug Targets 2019; 18:929-944. [PMID: 29644941 PMCID: PMC6463399 DOI: 10.2174/1568009618666180315160125] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/14/2017] [Accepted: 06/15/2017] [Indexed: 12/16/2022]
Abstract
Prostate cancer (PCa) is the most common non-skin cancer in men worldwide, resulting in significant mortality and morbidity. Depending on the grade and stage of the cancer, patients may be given radiation therapy, hormonal therapy, or chemotherapy. However, more than half of these patients develop resistance to treatment, leading to disease progression and metastases, often with lethal consequences. MicroRNAs (miRNAs) are short, non-coding RNAs, which regulate numerous physiological as well as pathological processes, including cancer. miRNAs mediate their regulatory effect predominately by binding to the 3'-untranslated region (UTR) of their target mRNAs. In this review, we will describe the mechanisms by which miRNAs mediate resistance to radiation and drug therapy (i.e. hormone therapy and chemotherapy) in PCa, including control of apoptosis, cell growth and proliferation, autophagy, epithelial-to-mesenchymal transition (EMT), invasion and metastasis, and cancer stem cells (CSCs). Furthermore, we will discuss the utility of circulating miRNAs isolated from different body fluids of prostate cancer patients as non-invasive biomarkers of cancer detection, disease progression, and therapy response. Finally, we will shortlist the candidate miRNAs, which may have a role in drug and radioresistance, that could potentially be used as predictive biomarkers of treatment response.
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Affiliation(s)
- Anshuli Razdan
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia
| | - Paul de Souza
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.,School of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.,Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Tara Laurine Roberts
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.,School of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.,The University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia
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49
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Liu M, Song W, Huang L. Drug delivery systems targeting tumor-associated fibroblasts for cancer immunotherapy. Cancer Lett 2019; 448:31-39. [PMID: 30731107 PMCID: PMC10859225 DOI: 10.1016/j.canlet.2019.01.032] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/27/2018] [Accepted: 01/24/2019] [Indexed: 01/12/2023]
Abstract
Solid tumors especially desmoplastic tumors are complex organ-like structures. Tumor-associated fibroblasts (TAFs), one type of the stromal cells, support the initiation, progression, and metastasis of carcinomas. TAFs also contribute to immunosuppressive tumor microenvironment (TME) and hinder T lymphocytes in killing tumors. Here, the role of TAFs in TME is discussed. In specific, TAFs form barriers for the penetration of T lymphocytes. TAFs also act as negative regulators for T lymphocytes. These findings suggest that targeting TAFs is a promising strategy for improving cancer immunotherapy. Our previous studies have indicated the ability of therapeutic nanoparticles to distribute into, and deplete or inactivate TAFs. This approach is discussed in the context of developing specific and effective immunotherapies for cancer.
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Affiliation(s)
- Mengrui Liu
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27559, USA; Department of Pharmaceutics, Collage of Pharmacy, Shandong University, Jinan, 250012, PR China
| | - Wantong Song
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China
| | - Leaf Huang
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27559, USA.
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Prognostic Value of MicroRNA-15a in Human Cancers: A Meta-Analysis and Bioinformatics. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2063823. [PMID: 31061821 PMCID: PMC6466945 DOI: 10.1155/2019/2063823] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
Abstract
Background Although several studies have proved the relationship between the prognostic value of miRNA-15a and different types of cancer, the result remains controversial. Thus, a meta-analysis was conducted to clarify the prognostic value of miRNA-15a expression level in human cancers. Methods We enrolled appropriate literature by searching the databases of PubMed, Embase, and Web of Science. Subsequently, we extracted HRs and their 95% CIs and calculated pooled results of miRNA-15a for overall survival (OS) and disease-free survival (DFS). Besides, subgroup analysis, sensitivity analysis, and publication bias were also revealed in this study. We also further validated this meta-analysis using the Kaplan-Meier plotter database. Result 10 studies, including 1616 patients, were embraced in our meta-analysis. The result showed the lower expression of miRNA-15a significantly predicted adverse OS (HR=2.17, 95% CI: 1.41-3.34), but there is no significant association between the expressing level and DFS in cancer patient (HR=2.04, 95% CI: 0.60-6.88). Based on Kaplan-Meier plotter database, we found the same results in bladder Carcinoma, head-neck squamous cell carcinoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, pancreatic ductal adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma, but opposite results were found in cervical squamous cell carcinoma and esophageal carcinoma. Conclusion Low expressing levels of miRNA-15a indicated poor OS, while miRNA-15a can be used as a prediction biomarker in different cancer types.
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