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Zhang D, Zuo M, Zhou J, Ouyang S, Liu S, Yuan J, Ou C, Chen Q, Yu D, Cheng D, Wang J. A facile combined therapy of chemotherapeutic agent and microRNA for hepatocellular carcinoma using non-cationic nanogel. J Mater Chem B 2025. [PMID: 39868422 DOI: 10.1039/d4tb02256d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
High drug resistance remains a challenge for chemotherapy against hepatocellular carcinoma (HCC). Combining chemotherapeutic agents with microRNA (miRNA), which simultaneously regulates multiple pathways, offers a promising approach to improve therapeutic efficacy against HCC. Although cationic amphiphilic copolymers have been used to co-deliver these agents, their effectiveness is often limited by low co-encapsulation efficiency and inherent cationic toxicity. In this study, we developed a facile approach to co-deliver doxorubicin (DOX) and miRNA-26a (miR-26a) using a non-cationic nanogel. The incorporation of an amphiphilic monomer and a lysosomal enzyme-sensitive crosslinker endows the nanomedicine with several advantages, including high co-encapsulation efficiency, lysosomal escape, and minimal toxicity. miR-26a significantly increased the sensitivity of HCC to DOX by 3.35-fold through targeting multiple pathways, and promoted DOX penetration within tumor tissue through reducing type I collagen content, thereby showing significant synergistic anticancer effects. This study provides a facile and biosafe nanoplatform for the efficient co-delivery of DOX and miRNA with synergistic drug effect.
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Affiliation(s)
- Dingyue Zhang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
| | - Mingxiang Zuo
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Jinhui Zhou
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
| | - Siyu Ouyang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
| | - Shuang Liu
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Jianming Yuan
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Chiyi Ou
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Qinghua Chen
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Dongsheng Yu
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Du Cheng
- PCFM Lab of Ministry of Education, School of Material Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
| | - Jin Wang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, P. R. China.
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2
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Fakeri M, Shakoul F, Yaghoubi SM, Koulaeizadeh S, Haghi M. Comprehensive insights into circular RNAs, miRNAs, and lncRNAs as biomarkers in retinoblastoma. Ophthalmic Genet 2025:1-11. [PMID: 39849678 DOI: 10.1080/13816810.2025.2456607] [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: 05/03/2024] [Revised: 12/21/2024] [Accepted: 01/16/2025] [Indexed: 01/25/2025]
Abstract
Retinoblastoma (RB) is a common and potentially lethal cancer that primarily affects young children worldwide, with survival rates significantly varying between high- and low-income countries. This review aims to identify essential diagnostic markers for early diagnosis by investigating the molecular pathways associated with RB. The prevalence of RB cases is notably concentrated in Asia and Africa, contributing to a global survival rate estimate of less than 30%. Current management strategies involve complex, individualized treatment plans that consider cultural nuances, genetic abnormalities, staging, and the availability of medical resources. Recent studies suggest that circular RNAs (circRNAs) may serve as predictive and diagnostic biomarkers in the etiology of RB. This review examines the roles of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circRNAs in RB, with the goal of improving survival rates, particularly in low- and middle-income countries. A deeper understanding of the molecular pathways of RB may facilitate the development of personalized treatment plans and targeted therapies. Elevated expression of circRNAs has been observed in most patient cases, and studies indicate that reducing specific circRNA production can inhibit tumor cell development and progression. Investigating the roles and mechanisms of circular RNAs in RB holds promise for future treatment approaches.
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Affiliation(s)
- Mahsa Fakeri
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Fatemeh Shakoul
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Shabnam Koulaeizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mehdi Haghi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
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3
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Zhang B, Ma X, Zhou Y, Zhu B, Yu J, Liu H, Ma Y, Luan Y, Chen M. Diagnostic Value of Circulating microRNAs for Hepatocellular Carcinoma: Results of a Meta-analysis and Validation. Biochem Genet 2025:10.1007/s10528-024-11001-2. [PMID: 39751721 DOI: 10.1007/s10528-024-11001-2] [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: 09/24/2024] [Accepted: 12/09/2024] [Indexed: 01/04/2025]
Abstract
Mounting evidence suggests that circulating microRNAs (miRNAs) hold diagnostic value in various malignancies. To identify circulating miRNAs for the early diagnosis of hepatocellular carcinoma (HCC), we conducted a meta-analysis to evaluate the diagnostic utility of miRNAs in HCC and further validated the results of the meta-analysis. English articles published prior to December 2023 were retrieved from databases including PubMed, Embase, and Web of Science. A random-effects or fixed-effects model was applied depending on the heterogeneity among studies. The pooled sensitivity, specificity, and the area under the summary receiver operating characteristic curve (AUC) were calculated to assess diagnostic accuracy. Additionally, RT-qPCR and receiver operating characteristic (ROC) analyses were employed to further validate the findings. A total of 36 studies were included, involving 3362 patients with HCC and 2150 patients with chronic hepatitis. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.79 (95% CI 0.75-0.82), 0.79 (95% CI 0.73-0.84), and 14 (95% CI 9-22), respectively; the positive and negative likelihood ratios were 4.0 and 0.27, respectively; the area under the curve (AUC) in the summary receiver operating characteristic (ROC) was 0.85 (95% CI 0.82-0.88). Validation indicated a significant upregulation of miR-1246, miR-21, and miR-221 in HCC patients compared to those with chronic hepatitis (P < 0.01), while miR-122 and miR-26a were significantly downregulated (P < 0.01). Moreover, the validation results also demonstrated that serum levels of miR-21, miR-26a, miR-122, miR-221, and miR-1246 exhibit high sensitivity and specificity in the diagnosis of HCC. Circulating miRNAs may be promising biomarkers for HCC diagnosis.
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Affiliation(s)
- Bingqiang Zhang
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Xiaoyan Ma
- Department of Oncology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266111, Shandong, People's Republic of China
| | - Yang Zhou
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Boyang Zhu
- School of Clinical and Basic Medical Sciences, Shandong First Medical, University& Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Junmei Yu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - He Liu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Yongchao Ma
- College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266111, Shandong, People's Republic of China
| | - Yansong Luan
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China.
| | - Mengmeng Chen
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China.
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4
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Zhang D, Hao W, Zhu R, Wang L, Wu X, Tian M, Liu D, Yang X. MiR-26a Inhibits Porcine Adipogenesis by Regulating ACADM and ACSL1 Genes and Cell Cycle Progression. Animals (Basel) 2024; 14:3491. [PMID: 39682455 DOI: 10.3390/ani14233491] [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: 11/04/2024] [Revised: 11/29/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
MicroRNAs play essential roles in biological processes by regulating gene expression at the post-transcriptional level. Our previous studies suggested the role of miR-26a in porcine fat accumulation. Here, through gain- and loss-of-function analyses, we first showed that miR-26a increased the proliferation of porcine preadipocytes by promoting cell division and that miR-26a inhibited the preadipocyte differentiation. Next, acyl-CoA dehydrogenase, medium chain (ACADM) was revealed to promote the proliferation and differentiation of preadipocytes for the first time. Then, it was revealed that miR-26a regulates adipogenesis by directly binding to the 3' untranslated region of ACADM and the long-chain acyl-Co A synthetase 1 (ACSL1) gene, a previously known regulator of adipogenesis. Finally, RNA-sequencing, performed on preadipocytes overexpressing miR-26a, identified 337 differentially expressed genes in the early stage of adipogenesis; among them, nine genes were characterized as potential targets of miR-26a. The 337 genes were mainly involved in Gene Ontology terms related to cell division, indicating that cell cycle progression was also a major event regulated by miR-26a during adipogenesis. We provide novel data for understanding the molecular mechanisms underlying adipogenesis, which will contribute to controlling fat accumulation in animals.
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Affiliation(s)
- Dongjie Zhang
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150086, China
| | - Wanjun Hao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Rongru Zhu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Liang Wang
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150086, China
| | - Xiaoxu Wu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Ming Tian
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150086, China
| | - Di Liu
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150086, China
| | - Xiuqin Yang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
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5
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Pathak S, Singh V, Kumar G N, Jayandharan GR. AAV-mediated combination gene therapy of inducible Caspase 9 and miR-199a-5p is therapeutic in hepatocellular carcinoma. Cancer Gene Ther 2024; 31:1796-1803. [PMID: 39385010 DOI: 10.1038/s41417-024-00844-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/11/2024]
Abstract
Advanced-stage hepatocellular carcinoma (HCC) remains an untreatable disease with an overall survival of less than one year. One of the critical molecular mediators contributing to increased resistance to therapy and relapse, is increased hypoxia-inducible factor 1α (HIF-1α) levels, leading to metastasis of tumor cells. Several microRNAs are known to be dysregulated and impact HIF-1α expression in HCC. An in silico analysis demonstrated that hsa-miR-199a-5p is downregulated at various stages of HCC and is known to repress HIF-1α expression. Based on this analysis, we developed a combinatorial suicide gene therapy by employing hepatotropic Adeno-associated virus-based vectors encoding an inducible caspase 9 (iCasp9) and miR-199a. The overexpression of miR-199a-5p alone significantly decreased ( ~ 2-fold vs. Mock treated cells, p < 0.05) HIF-1α mRNA levels, with a concomitant increase in cancer cell cytotoxicity in Huh7 cells in vitro and in xenograft models in vivo. To further enhance the efficacy of gene therapy, we evaluated the synergistic therapeutic effect of AAV8-miR-199a and AAV6-iCasp9 in a xenograft model of HCC. Our data revealed that mice receiving combination suicide gene therapy exhibited reduced expression of HIF-1α ( ~ 4-fold vs. Mock, p < 0.001), with a significant reduction in tumor growth when compared to mock-treated animals. These findings underscore the therapeutic potential of downregulating HIF-1α during suicide gene therapy for HCC.
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Affiliation(s)
- Subhajit Pathak
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India
| | - Vijayata Singh
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India
| | - Narendra Kumar G
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India
| | - Giridhara R Jayandharan
- Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Uttar Pradesh, Kanpur, 208016, India.
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6
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Kaneko Y, Ohzawa H, Kimura Y, Takahashi R, Matsumiya M, Tamura K, Futoh Y, Miyato H, Saito S, Yamaguchi H, Hosoya Y, Watano R, Mizukami H, Sata N, Kitayama J. Intraperitoneal administration of adeno-associated virus encoding microRNA-29b for the treatment of peritoneal metastasis. Cancer Gene Ther 2024; 31:1818-1830. [PMID: 39390194 DOI: 10.1038/s41417-024-00837-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/07/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024]
Abstract
This study explores a novel therapeutic approach for peritoneal metastasis (PM) using AAV-mediated delivery of tumor suppressor microRNA-29b (miR-29b) to peritoneal mesothelial cells (PMC). AAV serotypes 2 and DJ demonstrate high transduction efficiency for human and murine PMC, respectively. In vitro analysis indicates that AAV vectors encoding miR-29b precursor successfully elevate miR-29b expression in PMC and their secreted small extracellular vesicle (sEV), thereby inhibiting mesothelial mesenchymal transition and reducing subsequent attachment of tumor cells. A single intraperitoneal (IP) administration of AAV-DJ-miR-29b demonstrates robust and sustained transgene expression, suppressing peritoneal fibrosis and inhibiting the development of PM from gastric and pancreatic cancers. Additionally, AAV-DJ-miR-29b enhances the efficacy of IP chemotherapy using paclitaxel, restraining the growth of established PM. While conventional gene therapy for cancer encounters challenges targeting tumor cells directly but delivering miRNA to the tumor stroma offers a straightforward and efficient means of altering the microenvironment, leading to substantial inhibition of tumor growth. AAV-mediated miR-29b delivery to peritoneum via IP route presents a simple, minimally invasive, and promising therapeutic strategy for refractory PM.
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Affiliation(s)
- Yuki Kaneko
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyuki Ohzawa
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan
| | - Yuki Kimura
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Rei Takahashi
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Misaki Matsumiya
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Kohei Tamura
- Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Japan
| | - Yurie Futoh
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyo Miyato
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Shin Saito
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hironori Yamaguchi
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan
| | - Yoshinori Hosoya
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Ryota Watano
- Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Hiroaki Mizukami
- Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Joji Kitayama
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan.
- Center for Clinical Research, Jichi Medical University Hospital, Shimotsuke, Japan.
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7
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Sumaira S, Vijayarathna S, Hemagirri M, Adnan M, Hassan MI, Patel M, Gupta R, Shanmugapriya, Chen Y, Gopinath SC, Kanwar JR, Sasidharan S. Plant bioactive compounds driven microRNAs (miRNAs): A potential source and novel strategy targeting gene and cancer therapeutics. Noncoding RNA Res 2024; 9:1140-1158. [PMID: 39022680 PMCID: PMC11250886 DOI: 10.1016/j.ncrna.2024.06.003] [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: 04/10/2023] [Revised: 05/21/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
Irrespective of medical technology improvements, cancer ranks among the leading causes of mortality worldwide. Although numerous cures and treatments exist, creating alternative cancer therapies with fewer adverse side effects is vital. Since ancient times, plant bioactive compounds have already been used as a remedy to heal cancer. These plant bioactive compounds and their anticancer activity can also deregulate the microRNAs (miRNAs) in the cancerous cells. Therefore, the deregulation of miRNAs in cancer cells by plant bioactive compounds and the usage of the related miRNA could be a promising approach for cancer cure, mainly to prevent cancer and overcome chemotherapeutic side effect problems. Hence, this review highlights the function of plant bioactive compounds as an anticancer agent through the underlying mechanism that alters the miRNA expression in cancer cells, ultimately leading to apoptosis. Moreover, this review provides insight into using plant bioactive compounds -driven miRNAs as an anticancer agent to develop miRNA-based cancer gene therapy. They can be the potential resource for gene therapy and novel strategies targeting cancer therapeutics.
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Affiliation(s)
- Sahreen Sumaira
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Soundararajan Vijayarathna
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Manisekaran Hemagirri
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, P.O. Box 2440, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Mitesh Patel
- Research and Development Cell and Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Vadodara, 391760, Gujarat, India
| | - Reena Gupta
- Institute of Pharmaceutical Research, Department. Pharmaceutical Research, GLA University, Mathura, India
| | - Shanmugapriya
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Yeng Chen
- Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Subash C.B. Gopinath
- Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis, Perlis, Malaysia
| | - Jagat R. Kanwar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), 174001, Bilaspur, Himachal Pradesh, India
| | - Sreenivasan Sasidharan
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
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8
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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
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Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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9
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Prasad M, Sekar R, Priya MDL, Varma SR, Karobari MI. A new perspective on diagnostic strategies concerning the potential of saliva-based miRNA signatures in oral cancer. Diagn Pathol 2024; 19:147. [PMID: 39548527 PMCID: PMC11568613 DOI: 10.1186/s13000-024-01575-1] [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: 08/23/2024] [Accepted: 11/06/2024] [Indexed: 11/18/2024] Open
Abstract
Oral cancer, the most prevalent cancer worldwide, is far more likely to occur after the age of forty-five, according to the World Health Organization. Although many biomarkers have been discovered over the years using non-invasive saliva samples, biopsies, and human blood, these biomarkers have not been incorporated into standard clinical practice. Investigating the function of microRNAs (miRNAs) in the diagnosis, aetiology, prognosis, and treatment of oral cancer has drawn more attention in recent years. Though salivary microRNA can act as a window into the molecular environment of the tumour, there are challenges due to the heterogeneity of oral squamous cell carcinoma (OSCC), diversity in sample collection, processing techniques, and storage conditions. The up and downregulation of miRNAs has been found to have a profound role in OSCC as it regulates tumour stages by targeting many genes. As a result, the regulatory functions of miRNAs in OSCC underscore their significance in the field of cancer biology. Salivary miRNAs are useful diagnostic and prognostic indicators because their abnormal expression profiles shed light on tumour behaviour and patient prognosis. In addition to their diagnostic and prognostic value, miRNAs hold promise as therapeutic targets for oral cancer intervention. The current review sheds light on the challenges and potentials of microRNA studies that could lead to a better understanding of oral cancer prognosis, diagnosis, and therapeutic intervention. Furthermore, the clinical translation of OSCC biomarkers requires cooperation between investigators, physicians, regulatory bodies, and business partners. There is much potential for improving early identification, tracking therapy response, and forecasting outcomes in OSCC patients by including saliva-based miRNAs as biomarkers.
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Affiliation(s)
- Monisha Prasad
- Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospitals, Saveetha University, Chennai, Tamil Nadu, 602105, India
| | - Ramya Sekar
- Department of Oral and Maxillofacial Pathology & Oral Microbiology, Meenakshi Ammal Dental College and Hospital, MAHER, Alapakkam Main Road, Maduravoyal, Chennai, Tamil Nadu, 600095, India
| | | | - Sudhir Rama Varma
- Department of Clinical Sciences, College of Dentistry, Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman University, Ajman - 346, Ajman, UAE
| | - Mohmed Isaqali Karobari
- Department of Conservative Dentistry and Endodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, 600077, India.
- Department of Restorative Dentistry & Endodontics, Faculty of Dentistry, University of Puthisastra, Phnom Penh, 12211, Cambodia.
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10
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Mo C, Wei N, Li T, Ahmed Bhat M, Mohammadi M, Kuang C. CDK9 inhibitors for the treatment of solid tumors. Biochem Pharmacol 2024; 229:116470. [PMID: 39127153 DOI: 10.1016/j.bcp.2024.116470] [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: 05/14/2024] [Revised: 08/04/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Cyclin-dependent kinase 9 (CDK9) regulates mRNA transcription by promoting RNA Pol II elongation. CDK9 is now emerging as a potential therapeutic target for cancer, since its overexpression has been found to correlate with cancer development and worse clinical outcomes. While much work on CDK9 inhibition has focused on hematologic malignancies, the role of this cancer driver in solid tumors is starting to come into focus. Many solid cancers also overexpress CDK9 and depend on its activity to promote downstream oncogenic signaling pathways. In this review, we summarize the latest knowledge of CDK9 biology in solid tumors and the studies of small molecule CDK9 inhibitors. We discuss the results of the latest clinical trials of CDK9 inhibitors in solid tumors, with a focus on key issues to consider for improving the therapeutic impact of this drug class.
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Affiliation(s)
- Christiana Mo
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA
| | - Ning Wei
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Terence Li
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Muzaffer Ahmed Bhat
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Mahshid Mohammadi
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Chaoyuan Kuang
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA.
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11
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Zhang Z. Diagnosis of liver diseases based on artificial intelligence. Biotechnol Genet Eng Rev 2024; 40:1193-1201. [PMID: 36966433 DOI: 10.1080/02648725.2023.2193057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/14/2023] [Indexed: 03/27/2023]
Abstract
Due to a series of problems in the diagnosis of liver disease, the mortality rate of liver disease patients is very high. Therefore, it is necessary for doctors and researchers to find a more effective non-invasive diagnostic method to meet clinical needs. We analyzed data from 416 patients with liver disease and 167 patients without liver disease from northeastern Andhra Pradesh, India. On the basis of considering age, gender and other basic data of patients, this paper uses total bilirubin and other clinical data as parameters to build a diagnostic model. In this paper, the accuracy of artificial intelligence method Random Forest (RF) and Support Vector Machine (SVM) model in the diagnosis of liver patients was compared. The results show that the support vector machine model based on Gaussian kernel function is more excellent in diagnostic accuracy, that is, SVM method is more suitable for the diagnosis of liver diseases.
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Affiliation(s)
- Zhe Zhang
- Faculty of Science, Hong Kong Baptist University, Hongkong, China
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12
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Cardus DF, Smith MT, Vernaza A, Smith JL, Del Buono B, Parajuli A, Lewis EG, Mesa-Diaz N, Du L. Systematic Analysis of miR-506-3p Target Genes Identified Key Mediators of Its Differentiation-Inducing Function. Genes (Basel) 2024; 15:1268. [PMID: 39457392 PMCID: PMC11507652 DOI: 10.3390/genes15101268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: miR-506-3p has been demonstrated to be a strong inducer of neuroblastoma cell differentiation, highlighting the potential of applying miR-506-3p mimics to neuroblastoma differentiation therapy. However, the target genes of miR-506-3p that mediate its differentiation-inducing function have not been fully defined. This study aims to comprehensively investigate the targetome of miR-506-3p regarding its role in regulating neuroblastoma cell differentiation. Methods: We combined gene expression profiling and functional high-content screening (HCS) to identify miR-506-3p target genes that have differentiation-modulating functions. For evaluating the potential clinical relevance of the identified genes, we analyzed the correlations of gene expressions with neuroblastoma patient survival. Results: We identified a group of 19 target genes with their knockdown significantly inducing cell differentiation, suggesting that these genes play a key role in mediating the differentiation-inducing activity of miR-506-3p. We observed significant correlations of higher mRNA levels with lower patient survival with 13 of the 19 genes, suggesting that overexpression of these 13 genes plays important roles in promoting neuroblastoma development by disrupting the cell differentiation pathways. Conclusions: Through this study, we identified novel target genes of miR-506-3p that function as strong modulators of neuroblastoma cell differentiation. Our findings represent a significant advancement in understanding the mechanisms by which miR-506-3p induces neuroblastoma cell differentiation. Future investigations of the identified 13 genes are needed to fully define their functions and mechanisms in controlling neuroblastoma cell differentiation, the understanding of which may reveal additional targets for developing novel differentiation therapeutic agents.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Liqin Du
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA (M.T.S.); (A.V.); (J.L.S.); (B.D.B.); (A.P.); (E.G.L.)
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13
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Dume B, Licarete E, Banciu M. Advancing cancer treatments: The role of oligonucleotide-based therapies in driving progress. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102256. [PMID: 39045515 PMCID: PMC11264197 DOI: 10.1016/j.omtn.2024.102256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/25/2024]
Abstract
Although recent advancements in cancer immunology have resulted in the approval of numerous immunotherapies, minimal progress has been observed in addressing hard-to-treat cancers. In this context, therapeutic oligonucleotides, including interfering RNAs, antisense oligonucleotides, aptamers, and DNAzymes, have gained a central role in cancer therapeutic approaches due to their capacity to regulate gene expression and protein function with reduced toxicity compared with conventional chemotherapeutics. Nevertheless, systemic administration of naked oligonucleotides faces many extra- and intracellular challenges that can be overcome by using effective delivery systems. Thus, viral and non-viral carriers can improve oligonucleotide stability and intracellular uptake, enhance tumor accumulation, and increase the probability of endosomal escape while minimizing other adverse effects. Therefore, gaining more insight into fundamental mechanisms of actions of various oligonucleotides and the challenges posed by naked oligonucleotide administration, this article provides a comprehensive review of the recent progress on oligonucleotide delivery systems and an overview of completed and ongoing cancer clinical trials that can shape future oncological treatments.
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Affiliation(s)
- Bogdan Dume
- Doctoral School in Integrative Biology, Faculty of Biology and Geology, Babes-Bolyai University, 400006 Cluj-Napoca, Romania
| | - Emilia Licarete
- Department of Molecular Biology and Biotechnology, Centre of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai University, 400006 Cluj-Napoca, Romania
| | - Manuela Banciu
- Department of Molecular Biology and Biotechnology, Centre of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai University, 400006 Cluj-Napoca, Romania
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14
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Mahboobnia K, Beveridge DJ, Yeoh GC, Kabir TD, Leedman PJ. MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities. Int J Mol Sci 2024; 25:9393. [PMID: 39273339 PMCID: PMC11395074 DOI: 10.3390/ijms25179393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.
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Affiliation(s)
- Khadijeh Mahboobnia
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - George C Yeoh
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Tasnuva D Kabir
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
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15
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Alimohammadi M, Rahimzadeh P, Khorrami R, Bonyadi M, Daneshi S, Nabavi N, Raesi R, Farani MR, Dehkhoda F, Taheriazam A, Hashemi M. A comprehensive review of the PTEN/PI3K/Akt axis in multiple myeloma: From molecular interactions to potential therapeutic targets. Pathol Res Pract 2024; 260:155401. [PMID: 38936094 DOI: 10.1016/j.prp.2024.155401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/02/2024] [Accepted: 06/09/2024] [Indexed: 06/29/2024]
Abstract
Phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) signaling pathways contribute to the development of several cancers, including multiple myeloma (MM). PTEN is a tumor suppressor that influences the PI3K/Akt/mTOR pathway, which in turn impacts vital cellular processes like growth, survival, and treatment resistance. The current study aims to present the role of PTEN and PI3K/Akt/mTOR signaling in the development of MM and its response to treatment. In addition, the molecular interactions in MM that underpin the PI3K/Akt/mTOR pathway and address potential implications for the development of successful treatment plans are also discussed in detail. We investigate their relationship to both upstream and downstream regulators, highlighting new developments in combined therapies that target the PTEN/PI3K/Akt axis to overcome drug resistance, including the use of PI3K and mitogen-activated protein kinase (MAPK) inhibitors. We also emphasize that PTEN/PI3K/Akt pathway elements may be used in MM diagnosis, prognosis, and therapeutic targets.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Islamic Republic of Iran
| | - Mojtaba Bonyadi
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Islamic Republic of Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Islamic Republic of Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Rasoul Raesi
- Department of Health Services Management, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran; Department of Nursing, Torbat Jam Faculty of Medical Sciences, Torbat Jam, Iran
| | - Marzieh Ramezani Farani
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, 100 Inha-ro, Incheon 22212, Republic of Korea
| | - Farshid Dehkhoda
- Department of Orthopedics, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Islamic Republic of Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Islamic Republic of Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Islamic Republic of Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Islamic Republic of Iran.
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16
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Chen Y, Hu Y, Zhou H, Jiang N, Wang Y, Zhang J, Shen Y, Yu G, Cao J. Induction of hepatic fibrosis in mice with schistosomiasis by extracellular microRNA-30 derived from Schistosoma japonicum eggs. Front Immunol 2024; 15:1425384. [PMID: 39139565 PMCID: PMC11319242 DOI: 10.3389/fimmu.2024.1425384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/24/2024] [Indexed: 08/15/2024] Open
Abstract
Background Schistosomiasis is a zoonotic parasitic disorder induced by the infestation of schistosomes, a genus of trematodes. MicroRNAs (miRNAs) in egg-derived exosomes are crucial for modulating the host's immune responses and orchestrating the pathophysiological mechanisms. Although the exosomes secreted by S. japonicum contain abundant miRNAs, the specific roles of these miRNAs in the pathogenesis of schistosomiasis-induced hepatic fibrosis are yet to be comprehensively elucidated. The egg exosomes of S. japonicum secrete miRNA-30, a novel miRNA. Methods In vitro, the effect of miRNA-30 was evaluated by transfecting HSCs with miRNA mimics. The target gene biosignature for miRNA-30 was predicted using the miRDB software. The effect of miRNA-30 in hepatic fibrosis was evaluated by either elevating its expression in healthy mice or by inhibiting its activity in infected mice by administration of recombinant adeno-associated virus serotype eight vectors expressing miRNA-30 or miRNA sponges. Results This novel miRNA can activate hepatic stellate cells (HSCs), the prinary effector cells of hepatic fibrosis, in vitro, i.e., it significantly increases the fibrogenic factors Col1(α1), Col3(α1), and α-SMA at both mRNA and protein levels. In addition, miRNA-30 may activate HSCs by targeting the host RORA gene. In addition, in vivo experiments were conducted by administering a recombinant adeno-associated viral vector to modulate the expression levels of miRNA-30. The overexpression of miRNA-30 in healthy mice significantly elevated the expression of Col1(α1), Col3(α1), and α-SMA at both the transcriptomic and proteomic scales. This overexpression was coupled with a pronounced augmentation in the hepatic hydroxyproline content. Conversely, the in vivo silencing of miRNA-30 in infected mice induced a considerable reduction in the size of hepatic granulomas and areas of collagen deposition. Hence, in vivo, modulation of miRNA-30 expression may play a pivotal role in ameliorating the severity of hepatic fibrosis in mice afflicted with S. japonica. Conclusions The study results suggest that miRNA-30 may augment schistosomiasis-induced hepatic fibrosis through a probable interaction with the host RORA. Our study may improve the current theoretical framework regarding cross-species regulation by miRNAs of hepatic fibrosis in schistosomiasis.
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Affiliation(s)
- Yang Chen
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Pingyuan Laboratory, Henan Normal University, Xinxiang, China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Yuan Hu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Hao Zhou
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Pingyuan Laboratory, Henan Normal University, Xinxiang, China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Nan Jiang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Yiluo Wang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Jing Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Yujuan Shen
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Guoying Yu
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Pingyuan Laboratory, Henan Normal University, Xinxiang, China
| | - Jianping Cao
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
- The School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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17
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Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
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Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
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18
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El Hayek T, Alnaser-Almusa OA, Alsalameh SM, Alhalabi MT, Sabbah AN, Alshehri EA, Mir TA, Mani NK, Al-Kattan K, Chinnappan R, Yaqinuddin A. Emerging role of exosomal microRNA in liver cancer in the era of precision medicine; potential and challenges. Front Mol Biosci 2024; 11:1381789. [PMID: 38993840 PMCID: PMC11236732 DOI: 10.3389/fmolb.2024.1381789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 06/05/2024] [Indexed: 07/13/2024] Open
Abstract
Exosomal microRNAs (miRNAs) have great potential in the fight against hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related death worldwide. In this study, we explored the various applications of these small molecules while analyzing their complex roles in tumor development, metastasis, and changes in the tumor microenvironment. We also discussed the complex interactions that exist between exosomal miRNAs and other non-coding RNAs such as circular RNAs, and show how these interactions coordinate important biochemical pathways that propel the development of HCC. The possibility of targeting exosomal miRNAs for therapeutic intervention is paramount, even beyond their mechanistic significance. We also highlighted their growing potential as cutting-edge biomarkers that could lead to tailored treatment plans by enabling early identification, precise prognosis, and real-time treatment response monitoring. This thorough analysis revealed an intricate network of exosomal miRNAs lead to HCC progression. Finally, strategies for purification and isolation of exosomes and advanced biosensing techniques for detection of exosomal miRNAs are also discussed. Overall, this comprehensive review sheds light on the complex web of exosomal miRNAs in HCC, offering valuable insights for future advancements in diagnosis, prognosis, and ultimately, improved outcomes for patients battling this deadly disease.
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Affiliation(s)
- Tarek El Hayek
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | | | | | | | | | - Eman Abdullah Alshehri
- Tissue/Organ Bioengineering and BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Tanveer Ahmad Mir
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Tissue/Organ Bioengineering and BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Naresh Kumar Mani
- Centre for Microfluidics, Biomarkers, Photoceutics and Sensors (μBioPS), Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India
| | - Khaled Al-Kattan
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Lung Health Center Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Raja Chinnappan
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Tissue/Organ Bioengineering and BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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19
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Murshed A, Alnoud MAH, Ahmad S, Khan SU, Alissa M, Alsuwat MA, Ahmed AE, Khan MU. Genetic Alchemy unveiled: MicroRNA-mediated gene therapy as the Artisan craft in the battlefront against hepatocellular carcinoma-a comprehensive chronicle of strategies and innovations. Front Genet 2024; 15:1356972. [PMID: 38915826 PMCID: PMC11194743 DOI: 10.3389/fgene.2024.1356972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 05/03/2024] [Indexed: 06/26/2024] Open
Abstract
Investigating therapeutic miRNAs is a rewarding endeavour for pharmaceutical companies. Since its discovery in 1993, our understanding of miRNA biology has advanced significantly. Numerous studies have emphasised the disruption of miRNA expression in various diseases, making them appealing candidates for innovative therapeutic approaches. Hepatocellular carcinoma (HCC) is a significant malignancy that poses a severe threat to human health, accounting for approximately 70%-85% of all malignant tumours. Currently, the efficacy of several HCC therapies is limited. Alterations in various biomacromolecules during HCC progression and their underlying mechanisms provide a basis for the investigation of novel and effective therapeutic approaches. MicroRNAs, also known as miRNAs, have been identified in the last 20 years and significantly impact gene expression and protein translation. This atypical expression pattern is strongly associated with the onset and progression of various malignancies. Gene therapy, a novel form of biological therapy, is a prominent research area. Therefore, miRNAs have been used in the investigation of tumour gene therapy. This review examines the mechanisms of action of miRNAs, explores the correlation between miRNAs and HCC, and investigates the use of miRNAs in HCC gene therapy.
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Affiliation(s)
- Abduh Murshed
- Department of Intensive Care Unit, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Mohammed A. H. Alnoud
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Saleem Ahmad
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Safir Ullah Khan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Meshari A. Alsuwat
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ahmed Ezzat Ahmed
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Prince Sultan Bin Abdelaziz for Environmental Research and Natural Resources Sustainability Center, King Khalid University, Abha, Saudi Arabia
| | - Munir Ullah Khan
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for XPolymers, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
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20
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Lee HJ, Choi HJ, Jeong YJ, Na YH, Hong JT, Han JM, Hoe HS, Lim KH. Developing theragnostics for Alzheimer's disease: Insights from cancer treatment. Int J Biol Macromol 2024; 269:131925. [PMID: 38685540 DOI: 10.1016/j.ijbiomac.2024.131925] [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: 01/01/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/02/2024]
Abstract
The prevalence of Alzheimer's disease (AD) and its associated economic and societal burdens are on the rise, but there are no curative treatments for AD. Interestingly, this neurodegenerative disease shares several biological and pathophysiological features with cancer, including cell-cycle dysregulation, angiogenesis, mitochondrial dysfunction, protein misfolding, and DNA damage. However, the genetic factors contributing to the overlap in biological processes between cancer and AD have not been actively studied. In this review, we discuss the shared biological features of cancer and AD, the molecular targets of anticancer drugs, and therapeutic approaches. First, we outline the common biological features of cancer and AD. Second, we describe several anticancer drugs, their molecular targets, and their effects on AD pathology. Finally, we discuss how protein-protein interactions (PPIs), receptor inhibition, immunotherapy, and gene therapy can be exploited for the cure and management of both cancer and AD. Collectively, this review provides insights for the development of AD theragnostics based on cancer drugs and molecular targets.
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Affiliation(s)
- Hyun-Ju Lee
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
| | - Hee-Jeong Choi
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
| | - Yoo Joo Jeong
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 333, Techno jungang-daero, Hyeonpung-eup, Dalseong-gun, Daegu 42988, Republic of Korea
| | - Yoon-Hee Na
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea
| | - Ji Min Han
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea.
| | - Hyang-Sook Hoe
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 333, Techno jungang-daero, Hyeonpung-eup, Dalseong-gun, Daegu 42988, Republic of Korea.
| | - Key-Hwan Lim
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea.
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21
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Zhu J, Wang L. The Role of lncRNA-miR-26a-mRNA Network in Cancer Progression and Treatment. Biochem Genet 2024; 62:1443-1461. [PMID: 37730965 DOI: 10.1007/s10528-023-10475-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/24/2023] [Indexed: 09/22/2023]
Abstract
The role of non-coding RNAs in regulating biological processes associated with cancer progression, such as proliferation, migration, and apoptosis, has been extensively studied. Long non-coding RNAs (lncRNAs) play a role in regulating these processes through various mechanisms, including transcriptional and post-transcriptional modifications. In post-transcriptional regulation, lncRNAs can bind to specific miRNAs and affect their function, which can either promote or inhibit cancer development. The interaction between lncRNAs, miRNAs, and mRNAs forms a network known as competitive endogenous RNA (ceRNA), which is involved in cancer progression or inhibition. One specific miRNA called miR-26a-5p has been identified as having tumor-suppressive properties. However, when lncRNAs bind to and inhibit miR-26a-5p, it can lead to cancer progression. Therefore, targeting this ceRNA network could be a promising strategy for preventing cancer development. This review will first discuss the anticancer effects of miR-26a-5p and then explore the involvement of the lncRNA-miR26a-5p-mRNA axis in cancer progression and potential targeted therapies.
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Affiliation(s)
- Jun Zhu
- Department of Oncology, Daye People's Hospital, Daye, Hubei, 435100, China.
| | - Liya Wang
- Department of Obstetrics and Gynecology, Pengren Hospital, Daye, Hubei, 435100, China
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22
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Jiang MJ, Lin CJ, Liu FR, Mei Z, Gu DN, Tian L. Pancreatic cancer cells hijack tumor suppressive microRNA-26a to promote radioresistance and potentiate tumor repopulation. Heliyon 2024; 10:e31346. [PMID: 38807872 PMCID: PMC11130661 DOI: 10.1016/j.heliyon.2024.e31346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/30/2024] Open
Abstract
Pancreatic cancer is one of the most lethal cancers with significant radioresistance and tumor repopulation after radiotherapy. As a type of short non-coding RNA that regulate various biological and pathological processes, miRNAs might play vital role in radioresistance. We found by miRNA sequencing that microRNA-26a (miR-26a) was upregulated in pancreatic cancer cells after radiation, and returned to normal state after a certain time. miR-26a was defined as a tumor suppressive miRNA by conventional tumor biology experiments. However, transient upregulation of miR-26a after radiation significantly promoted radioresistance, while stable overexpression inhibited radioresistance, highlighting the importance of molecular dynamic changes after treatment. Mechanically, transient upregulation of miR-26a promoted cell cycle arrest and DNA damage repair to promote radioresistance. Further experiments confirmed HMGA2 as the direct functional target, which is an oncogene but enhances radiosensitivity. Moreover, PTGS2 was also the target of miR-26a, which might potentiate tumor repopulation via delaying the synthesis of PGE2. Overall, this study revealed that transient upregulation of miR-26a after radiation promoted radioresistance and potentiated tumor repopulation, highlighting the importance of dynamic changes of molecules upon radiotherapy.
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Affiliation(s)
- Ming-jie Jiang
- Department of Head and Neck Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Chen-jing Lin
- Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Fu-rao Liu
- Department of Oncology, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200032, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Zhu Mei
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Dian-na Gu
- Department of Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Ling Tian
- Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
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23
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Tian Y, Zhang M, Liu LX, Wang ZC, Liu B, Huang Y, Wang X, Ling YZ, Wang F, Feng X, Tu Y. Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis. Front Immunol 2024; 15:1400744. [PMID: 38799446 PMCID: PMC11116607 DOI: 10.3389/fimmu.2024.1400744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.
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Affiliation(s)
- Yu Tian
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
- School of Public Health, Benedictine University, Lisle, IL, United States
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Li-xia Liu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Zi-chao Wang
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Youcai Huang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoling Wang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Yun-zhi Ling
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Furong Wang
- Department of Pathology, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People’s Hospital, Gaozhou, Guangdong, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
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24
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Wu L, Zhang Y, Ren J. Targeting non-coding RNAs and N 6-methyladenosine modification in hepatocellular carcinoma. Biochem Pharmacol 2024; 223:116153. [PMID: 38513741 DOI: 10.1016/j.bcp.2024.116153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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25
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Hosseinpour-Soleimani F, Salmasi Z, Ghasemi Y, Tajbakhsh A, Savardashtaki A. MicroRNAs and proteolytic cleavage of receptors in cancers: A comprehensive review of regulatory interactions and therapeutic implications. Heliyon 2024; 10:e28167. [PMID: 38560206 PMCID: PMC10979173 DOI: 10.1016/j.heliyon.2024.e28167] [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: 12/09/2023] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 04/04/2024] Open
Abstract
Cancer remains a challenging disease worldwide, necessitating innovative approaches to better comprehend its underlying molecular mechanisms and devise effective therapeutic strategies. Over the past decade, microRNAs (miRNAs) have emerged as crucial players in cancer progression due to their regulatory roles in various cellular processes. Moreover, the involvement of unwanted soluble receptors has gained increasing attention because they contribute to tumorigenesis or drug resistance by disrupting normal signaling pathways and neutralizing ligands. This comprehensive review explores the intricate interplay between miRNAs and unwanted-soluble receptors in the context of cancer biology. This study provides an analysis of the regulatory interactions between miRNAs and these receptors, elucidating how miRNAs can either suppress or enhance their expression. MiRNAs can directly target receptor transcripts, thereby regulating soluble receptor levels. They also modulate the proteolytic cleavage of membrane-bound receptors into soluble forms by targeting sheddases, such as ADAMs and MMPs. Furthermore, the review delves into the therapeutic potential of manipulating miRNAs to modulate unwanted soluble receptors. Various strategies, including synthetic miRNA mimics or anti-miRNAs, hold promise for restoring or inhibiting miRNA function to counteract aberrant receptor activity. Moreover, exploring miRNA-based delivery systems may provide targeted and precise therapies that minimizing off-target effects. In conclusion, this review sheds light on the intricate regulatory networks involving miRNAs and unwanted soluble receptors in cancer biology thereby uncovering novel therapeutic targets, and paving the way for developing innovative anti-cancer therapies.
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Affiliation(s)
- Fatemeh Hosseinpour-Soleimani
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Applied Cell Sciences and Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Salmasi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Younes Ghasemi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Medical Biotechnology, School of Advanced Medical Sciences And, Technologies, Shiraz University Of, Medical Sciences, Shiraz, 71362 81407, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences And, Technologies, Shiraz University Of, Medical Sciences, Shiraz, 71362 81407, Iran
- Infertility Research Center, Shiraz University Med Ical Sciences, Shiraz, Iran
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26
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Jigari Asl F, Khordadmehr M, Baradaran B, Baghbani E, Noorolyai S, Rahmani S, Saberivand A. Restoration of miR-451a-5p/miR-34a-5p could suppress the proliferation and migration of human breast cancer cells through Wnt/β- catenin and ERK/P-ERK signaling pathways. ARCHIVES OF RAZI INSTITUTE 2024; 79:367-377. [PMID: 39463723 PMCID: PMC11512187 DOI: 10.32592/ari.2024.79.2.367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2024]
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs with a length of 21-25 nucleotides and play an essential role in the regulation of cancer initiation, development and progression. Breast cancer (BC) is the most commonly detected malignancy in women and one of the leading causes of death worldwide. In this study, the effects of transfection of microRNA-451a-5p and miR-34a-5p (tumor suppressors), individually and in combination on apoptosis, proliferation and migration of breast cancer cells in vitro were investigated. For this study, malignant breast cancer cells (MDA-MB-231) were transfected with the miR-451a-5p and miR-34a-5p mimics. Subsequently cytotoxicity, apoptosis, proliferation, migration protein and gene expression of caspase-3, caspase-8, MMP9, ROCK, vimentin and c-Myc of the cancer cells were analyzed by MTT, flow cytometry, q-RT-PCR (expression level of caspase-3, caspase-8, MMP9, ROCK, vimentin and c-Myc genes), wound healing and Western blot assays. The results showed that miR-34a-5p and miR-451a-5p could additionally induce apoptosis and cell cycle arrest in the sub-G1phase, suppress proliferation and migration in breast cancer cells, and also decrease the expression of β- catenin and ERK/P-ERK proteins . The present data document that restoration of the tumor suppressor miR-451/miR-34 strongly induces programmed cell death in vitro and apparently inhibits cell proliferation and migration in human breast cancer cells. In summary, miR-451a and miR-34a play an important role in breast cancer cell proliferation and migration via the Wnt/β-catenin and ERK/P-ERK signaling pathways. Therefore, the simultaneous restoration of the presented tumor suppressor miRNAs can be proposed as a valuable and potential therapeutic strategy in the treatment of breast cancer. However, further studies should be useful.
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Affiliation(s)
- F Jigari Asl
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - M Khordadmehr
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - B Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - E Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - S Noorolyai
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - S Rahmani
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - A Saberivand
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
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27
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Kaurani L. Clinical Insights into MicroRNAs in Depression: Bridging Molecular Discoveries and Therapeutic Potential. Int J Mol Sci 2024; 25:2866. [PMID: 38474112 PMCID: PMC10931847 DOI: 10.3390/ijms25052866] [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: 01/31/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Depression is a major contributor to the overall global burden of disease. The discovery of biomarkers for diagnosis or prediction of treatment responses and as therapeutic agents is a current priority. Previous studies have demonstrated the importance of short RNA molecules in the etiology of depression. The most extensively researched of these are microRNAs, a major component of cellular gene regulation and function. MicroRNAs function in a temporal and tissue-specific manner to regulate and modify the post-transcriptional expression of target mRNAs. They can also be shuttled as cargo of extracellular vesicles between the brain and the blood, thus informing about relevant mechanisms in the CNS through the periphery. In fact, studies have already shown that microRNAs identified peripherally are dysregulated in the pathological phenotypes seen in depression. Our article aims to review the existing evidence on microRNA dysregulation in depression and to summarize and evaluate the growing body of evidence for the use of microRNAs as a target for diagnostics and RNA-based therapies.
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Affiliation(s)
- Lalit Kaurani
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany
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28
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Bestepe F, Ghanem GF, Fritsche CM, Weston J, Sahay S, Mauro AK, Sahu P, Tas SM, Ruemmele B, Persing S, Good ME, Chatterjee A, Huggins GS, Salehi P, Icli B. MicroRNA-409-3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice. FASEB J 2024; 38:e23459. [PMID: 38329343 DOI: 10.1096/fj.202302124rr] [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: 10/27/2023] [Revised: 01/09/2024] [Accepted: 01/18/2024] [Indexed: 02/09/2024]
Abstract
Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type-2 diabetes (T2D). Expression of miR-409-3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non-wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR-409-3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA-Seq transcriptomic profiling revealed BTG2 as a target of miR-409-3p, where overexpression of miR-409-3p significantly decreased BTG2 mRNA and protein expression. A 3' untranslated region (3'-UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR-409-3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR-409-3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG-anti-proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial-specific and tamoxifen-inducible miR-409-3p knockout mice (MiR-409IndECKO ) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR-409-3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.
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Affiliation(s)
- Furkan Bestepe
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - George F Ghanem
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Colette M Fritsche
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - James Weston
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Sumedha Sahay
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Amanda K Mauro
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Parul Sahu
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Sude M Tas
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Brooke Ruemmele
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA
| | - Sarah Persing
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA
| | - Miranda E Good
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Abhishek Chatterjee
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA
| | - Gordon S Huggins
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Payam Salehi
- Division of Vascular Surgery, Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts, USA
| | - Basak Icli
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
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29
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Xu W, Huang Y, Lei Z, Zhou J. miR-939-3p induces sarcoma proliferation and poor prognosis via suppressing BATF2. Front Oncol 2024; 14:1346531. [PMID: 38420020 PMCID: PMC10899471 DOI: 10.3389/fonc.2024.1346531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/31/2024] [Indexed: 03/02/2024] Open
Abstract
Background Sarcoma is a rare and aggressive malignancy with poor prognosis, in which oncogene activation and tumor suppressor inactivation are involved. Accumulated studies suggested basic leucine zipper transcription factor ATF-like 2 (BATF2) as a candidate tumor suppressor, but its specific role and mechanism in sarcoma remain unclear. Methods The expression levels of BATF2 and miR-939-3p were evaluated by using human sarcoma samples, cell lines and xenograft mouse models. Bioinformatics analysis, qPCR, Western blot, cell proliferation assay, overexpression plasmid construction, point mutation and dual luciferase reporter assay were utilized to investigate the role and mechanism of miR-939-3p in sarcoma. Results In this study, we demonstrated that the expression of BATF2 was downregulated in human sarcoma tissues and cell lines. The downregulation of BATF2 was negatively associated with the prognosis of sarcoma patients. Subsequent bioinformatic prediction and experimental validations showed that BATF2 expression was reduced by microRNA (miR)-939-3p mimic and increased by miR-939-3p inhibitor. Additionally, miR-939-3p was upregulated in sarcoma tissues and cells, correlating with a poor prognosis of sarcoma patients. Moreover, miR-939-3p overexpression suppressed sarcoma cell proliferation, which was significantly attenuated by the restoration of BATF2, while siRNA-mediated knockdown of BATF2 aggravated the miR-939-3p-induced promotion of sarcoma cell proliferation. Further computational algorithms and dual-luciferase reporter assays demonstrated that miR-939-3p repressed BATF2 expression via directly binding to its 3' untranslated region (3' UTR). Conclusion Collectively, these findings identified miR-939-3p as a novel regulator of BATF2, as well as a prognostic biomarker in sarcoma, and revealed that suppressing miR-939-3p or inducing BATF2 expression may serve as a promising therapeutic strategy against sarcoma.
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Affiliation(s)
- Wanwen Xu
- Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, Hubei, China
| | - Yinghui Huang
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Zengjie Lei
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jie Zhou
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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30
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Vianello C, Monti E, Leoni I, Galvani G, Giovannini C, Piscaglia F, Stefanelli C, Gramantieri L, Fornari F. Noncoding RNAs in Hepatocellular Carcinoma: Potential Applications in Combined Therapeutic Strategies and Promising Candidates of Treatment Response. Cancers (Basel) 2024; 16:766. [PMID: 38398157 PMCID: PMC10886468 DOI: 10.3390/cancers16040766] [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: 12/22/2023] [Revised: 02/03/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing, and 40% of patients are diagnosed at advanced stages. Over the past 5 years, the number of clinically available treatments has dramatically increased for HCC, making patient management particularly complex. Immune checkpoint inhibitors (ICIs) have improved the overall survival of patients, showing a durable treatment benefit over time and a different response pattern with respect to tyrosine kinase inhibitors (TKIs). Although there is improved survival in responder cases, a sizeable group of patients are primary progressors or are ineligible for immunotherapy. Indeed, patients with nonviral etiologies, such as nonalcoholic steatohepatitis (NASH), and alterations in specific driver genes might be less responsive to immunotherapy. Therefore, improving the comprehension of mechanisms of drug resistance and identifying biomarkers that are informative of the best treatment approach are required actions to improve patient survival. Abundant evidence indicates that noncoding RNAs (ncRNAs) are pivotal players in cancer. Molecular mechanisms through which ncRNAs exert their effects in cancer progression and drug resistance have been widely investigated. Nevertheless, there are no studies summarizing the synergistic effect between ncRNA-based strategies and TKIs or ICIs in the preclinical setting. This review aims to provide up-to-date information regarding the possible use of ncRNAs as therapeutic targets in association with molecular-targeted agents and immunotherapies and as predictive tools for the selection of optimized treatment options in advanced HCCs.
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Affiliation(s)
- Clara Vianello
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy; (C.V.); (E.M.); (I.L.); (G.G.)
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;
| | - Elisa Monti
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy; (C.V.); (E.M.); (I.L.); (G.G.)
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;
| | - Ilaria Leoni
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy; (C.V.); (E.M.); (I.L.); (G.G.)
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;
| | - Giuseppe Galvani
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy; (C.V.); (E.M.); (I.L.); (G.G.)
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;
| | - Catia Giovannini
- Department of Medical and Surgical Sciences, University of Bologna, 40128 Bologna, Italy; (C.G.); (F.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, 40128 Bologna, Italy; (C.G.); (F.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Claudio Stefanelli
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Francesca Fornari
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy; (C.V.); (E.M.); (I.L.); (G.G.)
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;
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AMJAD ELHAM, PEZZANI RAFFAELE, SOKOUTI BABAK. A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma. Oncol Res 2024; 32:439-461. [PMID: 38361756 PMCID: PMC10865741 DOI: 10.32604/or.2023.044473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/24/2023] [Indexed: 02/17/2024] Open
Abstract
Noncoding RNAs instruct the Cas9 nuclease to site-specifically cleave DNA in the CRISPR/Cas9 system. Despite the high incidence of hepatocellular carcinoma (HCC), the patient's outcome is poor. As a result of the emergence of therapeutic resistance in HCC patients, clinicians have faced difficulties in treating such tumor. In addition, CRISPR/Cas9 screens were used to identify genes that improve the clinical response of HCC patients. It is the objective of this article to summarize the current understanding of the use of the CRISPR/Cas9 system for the treatment of cancer, with a particular emphasis on HCC as part of the current state of knowledge. Thus, in order to locate recent developments in oncology research, we examined both the Scopus database and the PubMed database. The ability to selectively interfere with gene expression in combinatorial CRISPR/Cas9 screening can lead to the discovery of new effective HCC treatment regimens by combining clinically approved drugs. Drug resistance can be overcome with the help of the CRISPR/Cas9 system. HCC signature genes and resistance to treatment have been uncovered by genome-scale CRISPR activation screening, although this method is not without limitations. It has been extensively examined whether CRISPR can be used as a tool for disease research and gene therapy. CRISPR and its applications to tumor research, particularly in HCC, are examined in this study through a review of the literature.
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Affiliation(s)
- ELHAM AMJAD
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, 5165665813, Iran
| | - RAFFAELE PEZZANI
- Phytotherapy Lab, Endocrinology Unit, Dipartimento di Medicina (DIMED), University of Padova, Via Ospedale 105, Padova, 35128, Italy
- Associazione Italiana Per La Ricerca Oncologica Di Base, Associazione Italiana Per La Ricerca Oncologica Di Base, Padova, 35128, Italy
| | - BABAK SOKOUTI
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, 5165665813, Iran
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Guan X, Pei Y, Song J. DNA-Based Nonviral Gene Therapy─Challenging but Promising. Mol Pharm 2024; 21:427-453. [PMID: 38198640 DOI: 10.1021/acs.molpharmaceut.3c00907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Over the past decades, significant progress has been made in utilizing nucleic acids, including DNA and RNA molecules, for therapeutic purposes. For DNA molecules, although various DNA delivery systems have been established, viral vector systems are the go-to choice for large-scale commercial applications. However, viral systems have certain disadvantages such as immune response, limited payload capacity, insertional mutagenesis and pre-existing immunity. In contrast, nonviral systems are less immunogenic, not size limited, safer, and easier for manufacturing compared with viral systems. What's more, nonviral DNA vectors have demonstrated their capacity to mediate specific protein expression in vivo for diverse therapeutic objectives containing a wide range of diseases such as cancer, rare diseases, neurodegenerative diseases, and infectious diseases, yielding promising therapeutic outcomes. However, exogenous plasmid DNA is prone to degrade and has poor immunogenicity in vivo. Thus, various strategies have been developed: (i) designing novel plasmids with special structures, (ii) optimizing plasmid sequences for higher expression, and (iii) developing more efficient nonviral DNA delivery systems. Based on these strategies, many interesting clinical results have been reported. This Review discusses the development of DNA-based nonviral gene therapy, including novel plasmids, nonviral delivery systems, clinical advances, and prospects. These developments hold great potential for enhancing the efficacy and safety of nonviral gene therapy and expanding its applications in the treatment of various diseases.
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Affiliation(s)
- Xiaocai Guan
- Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yufeng Pei
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, The Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou 310022, China
| | - Jie Song
- Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, The Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou 310022, China
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Sahayasheela VJ, Sugiyama H. RNA G-quadruplex in functional regulation of noncoding RNA: Challenges and emerging opportunities. Cell Chem Biol 2024; 31:53-70. [PMID: 37909035 DOI: 10.1016/j.chembiol.2023.08.010] [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: 04/18/2023] [Revised: 07/12/2023] [Accepted: 08/22/2023] [Indexed: 11/02/2023]
Abstract
G-quadruplexes (G4s) are stable, noncanonical structures formed in guanine (G)-rich sequences of DNA/RNA. G4 structures are reported to play a regulatory role in various cellular processes and, recently, a considerable number of studies have attributed new biological functions to these structures, especially in RNA. Noncoding RNA (ncRNA), which does not translate into a functional protein, is widely expressed and has been shown to play a key role in shaping cellular activity. There has been growing evidence of G4 formation in several ncRNA classes, and it has been identified as a key part for diverse biological functions and physio-pathological contexts in neurodegenerative diseases and cancer. This review discusses RNA G4s (rG4s) in ncRNA, focusing on the molecular mechanism underlying its function. This review also aims to highlight potential and emerging opportunities to identify and target the rG4s in ncRNA to understand its function and, ultimately, treat many diseases.
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Affiliation(s)
- Vinodh J Sahayasheela
- Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto 606-8502, Japan
| | - Hiroshi Sugiyama
- Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto 606-8502, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Ushinomaecho, Sakyo-Ku, Kyoto 606-8501, Japan.
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Hadi M, Qutaiba B Allela O, Jabari M, Jasoor AM, Naderloo O, Yasamineh S, Gholizadeh O, Kalantari L. Recent advances in various adeno-associated viruses (AAVs) as gene therapy agents in hepatocellular carcinoma. Virol J 2024; 21:17. [PMID: 38216938 PMCID: PMC10785434 DOI: 10.1186/s12985-024-02286-1] [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: 09/30/2023] [Accepted: 01/02/2024] [Indexed: 01/14/2024] Open
Abstract
Primary liver cancer, which is scientifically referred to as hepatocellular carcinoma (HCC), is a significant concern in the field of global health. It has been demonstrated that conventional chemotherapy, chemo-hormonal therapy, and conformal radiotherapy are ineffective against HCC. New therapeutic approaches are thus urgently required. Identifying single or multiple mutations in genes associated with invasion, metastasis, apoptosis, and growth regulation has resulted in a more comprehensive comprehension of the molecular genetic underpinnings of malignant transformation, tumor advancement, and host interaction. This enhanced comprehension has notably propelled the development of novel therapeutic agents. Therefore, gene therapy (GT) holds great promise for addressing the urgent need for innovative treatments in HCC. However, the complexity of HCC demands precise and effective therapeutic approaches. The adeno-associated virus (AAV) distinctive life cycle and ability to persistently infect dividing and nondividing cells have rendered it an alluring vector. Another appealing characteristic of the wild-type virus is its evident absence of pathogenicity. As a result, AAV, a vector that lacks an envelope and can be modified to transport DNA to specific cells, has garnered considerable interest in the scientific community, particularly in experimental therapeutic strategies that are still in the clinical stage. AAV vectors emerge as promising tools for HCC therapy due to their non-immunogenic nature, efficient cell entry, and prolonged gene expression. While AAV-mediated GT demonstrates promise across diverse diseases, the current absence of ongoing clinical trials targeting HCC underscores untapped potential in this context. Furthermore, gene transfer through hepatic AAV vectors is frequently facilitated by GT research, which has been propelled by several congenital anomalies affecting the liver. Notwithstanding the enthusiasm associated with this notion, recent discoveries that expose the integration of the AAV vector genome at double-strand breaks give rise to apprehensions regarding their enduring safety and effectiveness. This review explores the potential of AAV vectors as versatile tools for targeted GT in HCC. In summation, we encapsulate the multifaceted exploration of AAV vectors in HCC GT, underlining their transformative potential within the landscape of oncology and human health.
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Affiliation(s)
- Meead Hadi
- Department of Microbiology, Faculty of Basic Science, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | | | - Mansoureh Jabari
- Medical Campus, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Asna Mahyazadeh Jasoor
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Omid Naderloo
- Department of Laboratory Sciences, Faculty of Medicine, Islamic Azad University of Gorgan Breanch, Gorgan, Iran
| | | | | | - Leila Kalantari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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Chen W, Wu X, Hu J, Liu X, Guo Z, Wu J, Shao Y, Hao M, Zhang S, Hu W, Wang Y, Zhang M, Zhu M, Wang C, Wu Y, Wang J, Xing D. The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7. Cardiovasc Diabetol 2024; 23:21. [PMID: 38195542 PMCID: PMC10777520 DOI: 10.1186/s12933-024-02119-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/02/2024] [Indexed: 01/11/2024] Open
Abstract
Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3β, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1β, IL-6, JAG2, KCNJ2, MALT1, β-MHC, NF-κB, PCK1, PLCβ1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.
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Affiliation(s)
- Wujun Chen
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Xiaolin Wu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Jianxia Hu
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xiaolei Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Zhu Guo
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Jianfeng Wu
- Department of Cardiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, Hengyang, 421001, Hunan, China
| | - Yingchun Shao
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Minglu Hao
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Shuangshuang Zhang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Weichao Hu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
- Department of Endocrinology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266000, Shandong, China
| | - Yanhong Wang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Miao Zhang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Meng Zhu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266071, Shandong, China
| | - Chao Wang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
| | - Yudong Wu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
| | - Jie Wang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
| | - Dongming Xing
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
- School of Life Sciences, Tsinghua University, Beijing, 100084, China.
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36
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Yang X, Liang Y, Tong S. Advancing cancer treatment: in vivo delivery of therapeutic small noncoding RNAs. Front Mol Biosci 2024; 10:1297413. [PMID: 38234581 PMCID: PMC10791939 DOI: 10.3389/fmolb.2023.1297413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/15/2023] [Indexed: 01/19/2024] Open
Abstract
In recent years, small non-coding RNAs (ncRNAs) have emerged as a new player in the realm of cancer therapeutics. Their unique capacity to directly modulate genetic networks and target oncogenes positions them as valuable complements to existing small-molecule drugs. Concurrently, the advancement of small ncRNA-based therapeutics has rekindled the pursuit of efficacious in vivo delivery strategies. In this review, we provide an overview of the most current clinical and preclinical studies in the field of small ncRNA-based cancer therapeutics. Furthermore, we shed light on the pivotal challenges hindering the successful translation of these promising therapies into clinical practice, with a specific focus on delivery methods, aiming to stimulate innovative approaches to address this foundational aspect of cancer treatment.
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Affiliation(s)
- Xiaoyue Yang
- F. Joseph Halcomb III, MD Department of Biomedical Engineering, University of Kentucky, Lexington, KY, United States
| | - Ying Liang
- New York Blood Center, New York, NY, United States
| | - Sheng Tong
- F. Joseph Halcomb III, MD Department of Biomedical Engineering, University of Kentucky, Lexington, KY, United States
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Lv Y, Sun X. Role of miRNA in pathogenesis, diagnosis, and prognosis in hepatocellular carcinoma. Chem Biol Drug Des 2024; 103:e14352. [PMID: 37726253 DOI: 10.1111/cbdd.14352] [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: 08/01/2023] [Revised: 08/27/2023] [Accepted: 09/04/2023] [Indexed: 09/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and is responsible for the second cancer-related death globally. Many treatment regimens have been developed to cure the disease; however, life expectancy is still low. Therefore, there is an urgent need to explore new selective, specific, and robust diagnosis markers for efficient early recognition of the ailment. Along with the diagnosis, the treatment's effectiveness can be determined by prognostic markers, and miRNAs are excellent tools for the diagnosis and prognosis of HCC. In addition, the altered expression profile of a few miRNAs promotes HCC cell migration and invasion, and selective up- or downregulation of these responsible genes may help mitigate the disorder. On one hand, few of the miRNAs have been found to enhance angiogenesis, a crucial step of tumor growth; on the other hand, upregulation of specific miRNAs is reported to suppress angiogenesis and resulting tumor growth of HCC cells. Exosomal miRNAs have significant implications in promoting angiogenesis, increased endothelial cell permeability, tube formation, and metastasis to hepatic and pulmonary tissues. miRNA also attributes to drug resistance toward chemotherapy and the prevention of autophagy also. Identifying novel miRNA and determining their differential expression in HCC tissue may serve as a potential tool for diagnosis, prognosis, and therapy to enhance the life expectancy and quality of life of HCC patients. In the present review, we have summarized the recent advances in HCC-related research.
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Affiliation(s)
- Yi Lv
- Hepatobiliary and Pancreatic Surgery, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Xiujuan Sun
- Department of Pathology, Liuzhou People's Hospital, Liuzhou, Guangxi, China
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Vali R, Azadi A, Tizno A, Farkhondeh T, Samini F, Samarghandian S. miRNA contributes to neuropathic pains. Int J Biol Macromol 2023; 253:126893. [PMID: 37730007 DOI: 10.1016/j.ijbiomac.2023.126893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 08/29/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023]
Abstract
Neuropathic pain (NP) is a kind of chronic pain caused by direct injury to the peripheral or central nervous system (CNS). microRNAs (miRNAs) are small noncoding RNAs that mostly interact with the 3 untranslated region of messenger RNAs (mRNAs) to regulate the expression of multiple genes. NP is characterized by changes in the expression of receptors and mediators, and there is evidence that miRNAs may contribute to some of these alterations. In this review, we aimed to fully comprehend the connection between NP and miRNA; and also, to establish a link between neurology, biology, and dentistry. Studies have shown that targeting miRNAs may be an effective therapeutic strategy for the treatment of chronic pain and potential target for the prevention of NP.
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Affiliation(s)
- Reyhaneh Vali
- Department of Biology, Faculty of Modern Science, Tehran Medical Branch, Islamic Azad University, Tehran, Iran; Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Azadi
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ashkan Tizno
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Farkhondeh
- Neuroscience Research Center, Kamyab Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariborz Samini
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran.
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Ding N, Wang W, Teng J, Zeng Y, Zhang Q, Dong L, Tang H. miR-26a-5p Regulates Adipocyte Differentiation via Directly Targeting ACSL3 in Adipocytes. Adipocyte 2023; 12:1-10. [PMID: 36710425 PMCID: PMC9891161 DOI: 10.1080/21623945.2023.2166345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Preadipocytes become mature adipocytes after proliferation and differentiation, and although many genes and microRNAs have been identified in intramuscular fat, their physiological function and regulatory mechanisms remain largely unexplored. miR-26a-5p has been reported to be related to fat deposition, but its effect on porcine preadipocyte differentiation has not been explored. In this study, bioinformatics analysis and luciferase reporter assay identified that miR-26a-5p binds to the 3'UTR of Acyl-CoA synthetase long-chain family member 3 (ACSL3) mRNA. The model for porcine intramuscular preadipocyte differentiation was established to explore the function of miR-6a-5p-ACSL3 on adipocyte differentiation. ACSL3 knockdown markedly reduced the triglycerides (TG) content of cells, as well as the mRNA levels of adipogenic marker genes (PPAR-γ and SREBP-1c). The number of lipid droplets in cells transfected with a miR-26a-5p mimic is significantly reduced, consistent with ACSL3 knockdown results, while the miR-26a-5p inhibitor resulted in opposite results. Taken together, miR-26a-5p is a repressor of porcine preadipocyte differentiation and plays a vital role in ACSL3-mediated adipogenesis.
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Affiliation(s)
- Ning Ding
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science & Technology, Shandong Agricultural University, Taian, Shandong Province, China,Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, China
| | - Wenwen Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science & Technology, Shandong Agricultural University, Taian, Shandong Province, China,Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, China
| | - Jun Teng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science & Technology, Shandong Agricultural University, Taian, Shandong Province, China,Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, China
| | - Yongqing Zeng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science & Technology, Shandong Agricultural University, Taian, Shandong Province, China,Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, China
| | - Qin Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science & Technology, Shandong Agricultural University, Taian, Shandong Province, China,Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, China
| | - Licai Dong
- Shandong Futong Agriculture & Animal Husbandry Development Co. LTD, Linyi, China
| | - Hui Tang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science & Technology, Shandong Agricultural University, Taian, Shandong Province, China,Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, Taian, China,CONTACT Hui Tang No. 61, Daizong Street, Tai’an City, Shandong Province, 271018, China
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Wang Z, Zhang X, Liu Y, Shi X, Li L, Jia Y, Wu F, Cui H, Li L. MiR-5195-3p functions as a tumor suppressor by targeting RHBDD1 in ovarian cancer. Histol Histopathol 2023; 38:1403-1413. [PMID: 36825753 DOI: 10.14670/hh-18-595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
BACKGROUND Recent studies have reported the tumor suppressive role of miR-5195-3p in the progression of several cancers, but the potential roles of miR-5195-3p in ovarian cancer (OC) remain largely unknown. METHODS We first analyzed the expression levels of miR-5195-3p in 83 pairs of human OC tissues and adjacent specimens by reverse transcription-quantitative PCR. The correlation of miR-5195-3p/rhomboid domain containing 1 (RHBDD1) and clinicopathological parameters was analyzed by chi-square test. The prognostic value of miR-5195-3p was evaluated by Kaplan-Meier method Cox proportional hazards models. The effects of miR-5195-3p on cell proliferation, cell cycle distribution, migration and invasion were examined by CCK-8 assay, colony formation assay, flow cytometry and transwell assay. Tumor forming was evaluated by nude mice model in vivo. The association between miR-5195-3p and RHBDD1 was verified by luciferase reporter assay. RESULTS We observed that miR-5195-3p level was remarkably reduced in OC tissues as compared to adjacent tissues. The expression of miR-5195-3p was associated with FIGO stage, depth of invasion and poor survival prognosis in OC patients. Overexpression of miR-5195-3p significantly suppressed cell proliferation, cell cycle G1/S transition, migration and invasion in OC cell lines (SKOV-3 and OVCAR3), while knockdown of miR-5195-3p obtained the opposite results. We further confirmed miR-5195-3p as a negative post-transcriptional modulator of RHBDD1. RHBDD1 expression was upregulated in OC tissues compared with adjacent tissues, which was inversely correlated with miR-5195-3p expression. The expression of RHBDD1 was associated with FIGO stage and distant metastasis. RHBDD1 overexpression reversed the suppressive role of miR-5195-3p on OC cell proliferation, migration and invasion. Consistent with the in vitro results, miR-5195-3p overexpression decreased the growth of subcutaneously inoculated tumors in nude mice. CONCLUSIONS Taken together, the present results indicated that miR-5195-3p acts a tumor suppressor by targeting RHBDD1 in OC.
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Affiliation(s)
- Zhanyu Wang
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Xiaoping Zhang
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Yongying Liu
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Xiaoyan Shi
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Lijun Li
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Yun Jia
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Fangfang Wu
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Haosen Cui
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China
| | - Liang Li
- Department of Gynecology and Obstetrics, Fuyang Hospital of Anhui Medical University, Fuyang, Anhui Province, China.
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Saxena R, Chakrapani B, Sarath Krishnan MP, Gupta A, Gupta S, Das J, Gupta SC, Mirza AA, Rao S, Goyal B. Next generation sequencing uncovers multiple miRNAs associated molecular targets in gallbladder cancer patients. Sci Rep 2023; 13:19101. [PMID: 37925508 PMCID: PMC10625549 DOI: 10.1038/s41598-023-44767-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/12/2023] [Indexed: 11/06/2023] Open
Abstract
Gallbladder cancer (GBC) is a lethal disease with surgical resection as the only curative treatment. However, many patients are ineligible for surgery, and current adjuvant treatments exhibit limited effectiveness. Next-generation sequencing has improved our understanding of molecular pathways in cancer, sparking interest in microRNA-based gene regulation. The aim of the study is to identify dysregulated miRNAs in GBC and investigate their potential as therapeutic tools for effective and targeted treatment strategies. GBC and control tissue samples were sequenced for miRNA expression using the Illumina HiSeq platform. Biological processes and related pathways were determined using the Panther and Gene Ontology databases. 439 significantly differentially expressed miRNAs were identified; 19 of them were upregulated and 29 were downregulated. Key enriched biological processes included immune cell apoptosis, endoplasmic reticulum (ER) overload response, and negative regulation of the androgen receptor (AR) signaling pathway. Panther analysis revealed the insulin-like growth factor (IGF)-mitogen activated protein kinases (MAPK) cascade, p38 MAPK pathway, p53 pathway, and FAS (a subgroup of the tumor necrosis factor receptor) signaling pathway as highly enriched among dysregulated miRNAs. Kirsten rat sarcoma virus (KRAS), AR, and interferon gamma (IFN-γ) pathways were identified among the key pathways potentially amenable to targeted therapy. We concluded that a combination approach involving miRNA-based interventions could enhance therapeutic outcomes. Our research emphasizes the importance of precision medicine, targeting pathways using sense and anti-sense miRNAs as potential therapies in GBC.
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Affiliation(s)
- Rahul Saxena
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - Baskar Chakrapani
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - M P Sarath Krishnan
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - Amit Gupta
- Department of General Surgery, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Sweety Gupta
- Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Jayanta Das
- Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, India
| | - Subash C Gupta
- Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, India
| | - Anissa A Mirza
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - Shalinee Rao
- Department of Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Bela Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India.
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Yang G, Zhou J, Guo Z, Fan L, Chen B, Zhang D, Wen H. miR-26b Targets CEP135 Gene to Regulate Nasopharyngeal Carcinoma Proliferation and Migration by NF-κB Pathway. Mol Biotechnol 2023; 65:1857-1868. [PMID: 36820950 PMCID: PMC10518290 DOI: 10.1007/s12033-023-00691-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023]
Abstract
To screen microRNAs (miRNAs) and analyze their role in the nasopharyngeal carcinoma (NPC) development through differential analysis and cytological validation of the nasopharyngeal carcinoma dataset. The Gene Expression Omnibus (GEO) database of NPC-related data were utilized to screen for differential miRNAs, downstream target genes and relevant pathways, and the relationships among them were verified by luciferase reporter assay and cell co-culture. To analyze the function of miRNAs and downstream target genes, a series of mimics, inhibitors or Small interfering RNAs (siRNAs) targeting the downstream target genes were transfected into NPC cells or normal epithelial cells by cell transfection techniques. Cell Counting Kit-8 (CCK8), Transwell, Enzyme-linked immunosorbent assay (ELISA) apoptosis, and western blotting were adopted to determine the changes in cell activity, invasiveness, and apoptosis after differential miRNA and target gene overexpression or downregulation. Differential analysis of miRNA dataset showed that the expression of miR-26b was significantly downregulated in NPC, in agreement with the validation results of nasopharyngeal carcinoma cell lines. And downregulation of miR-26b expression in normal nasopharyngeal epithelial cells transformed the cells to tumors. CEP135 was identified as the miR-26b downstream target gene by mRNA dataset analysis, and a luciferase reporter test revealed a direct targeting link between the two. Upregulation of CEP135 levels in nasopharyngeal cancer cell lines increased cell activity, accelerated cell migration, and inhibited apoptosis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that CEP135 exerted the above effects on cells via the NF-κB pathway, and co-culture with NF-κB pathway blockers reversed cell biological behavior to the level of the control group. MiR-26b downregulation leads to CEP135 overexpression and NF-κB pathway activation in NPC, which enhances proliferation, migration, and prevents apoptosis of nasopharyngeal carcinoma cells. Therefore, the study further clarifies the biological behavior mechanism of NPC and suggests new therapeutic options for NPC.
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Affiliation(s)
- Guangrun Yang
- Department of Radiotherapy, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar City, China
| | - Jiafu Zhou
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Zhong Guo
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Lixia Fan
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Bowen Chen
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Dapeng Zhang
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China
| | - Haitao Wen
- Department of Otolaryngology, The Third Affiliated Hospital of Qiqihar Medical University, Tiefeng District, 27 Taishun Street, Qiqihar City 161000, China.
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Wong B, Birtch R, Rezaei R, Jamieson T, Crupi MJF, Diallo JS, Ilkow CS. Optimal delivery of RNA interference by viral vectors for cancer therapy. Mol Ther 2023; 31:3127-3145. [PMID: 37735876 PMCID: PMC10638062 DOI: 10.1016/j.ymthe.2023.09.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/28/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
In recent years, there has been a surge in the innovative modification and application of the viral vector-based gene therapy field. Significant and consistent improvements in the engineering, delivery, and safety of viral vectors have set the stage for their application as RNA interference (RNAi) delivery tools. Viral vector-based delivery of RNAi has made remarkable breakthroughs in the treatment of several debilitating diseases and disorders (e.g., neurological diseases); however, their novelty has yet to be fully applied and utilized for the treatment of cancer. This review highlights the most promising and emerging viral vector delivery tools for RNAi therapeutics while discussing the variables limiting their success and suitability for cancer therapy. Specifically, we outline different integrating and non-integrating viral platforms used for gene delivery, currently employed RNAi targets for anti-cancer effect, and various strategies used to optimize the safety and efficacy of these RNAi therapeutics. Most importantly, we provide great insight into what challenges exist in their application as cancer therapeutics and how these challenges can be effectively navigated to advance the field.
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Affiliation(s)
- Boaz Wong
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Rayanna Birtch
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Reza Rezaei
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Taylor Jamieson
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Mathieu J F Crupi
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Jean-Simon Diallo
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Carolina S Ilkow
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
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Zhang Y, Liu X, Sun K, Luo Y, Yang J, Li A, Kiupel M, Fenske S, Biel M, Mi QS, Wang H, Xiao H. Hyperpolarization-activated cyclic nucleotide-gated cation channel 3 promotes HCC development in a female-biased manner. Cell Rep 2023; 42:113157. [PMID: 37733590 PMCID: PMC10873026 DOI: 10.1016/j.celrep.2023.113157] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/17/2023] [Accepted: 09/06/2023] [Indexed: 09/23/2023] Open
Abstract
Sex differences in hepatocellular carcinoma (HCC) development are regulated by sex and non-sex chromosomes, sex hormones, and environmental factors. We previously reported that Ncoa5+/- mice develop HCC in a male-biased manner. Here we show that NCOA5 expression is reduced in male patient HCCs while the expression of an NCOA5-interacting tumor suppressor, TIP30, is lower in female HCCs. Tip30 heterozygous deletion does not change HCC incidence in Ncoa5+/- male mice but dramatically increases HCC incidence in Ncoa5+/- female mice, accompanied by hepatic hyperpolarization-activated cyclic nucleotide-gated cation channel 3 (HCN3) overexpression. HCN3 overexpression cooperates with MYC to promote mouse HCC development, whereas Hcn3 knockout preferentially hinders HCC development in female mice. Furthermore, HCN3 amplification and overexpression occur in human HCCs and correlate with a poorer prognosis of patients in a female-biased manner. Our results suggest that TIP30 and NCOA5 protect against female liver oncogenesis and that HCN3 is a female-biased HCC driver.
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Affiliation(s)
- Yueqi Zhang
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA
| | - Xinhui Liu
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Kairui Sun
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Yue Luo
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Jack Yang
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
| | - Aimin Li
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Matti Kiupel
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA
| | - Stefanie Fenske
- Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians Universität München, 81377 München, Germany
| | - Martin Biel
- Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians Universität München, 81377 München, Germany
| | - Qing-Sheng Mi
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA; Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202, USA
| | - Hongbing Wang
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
| | - Hua Xiao
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.
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Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, Tammaro C, Scafuro G, Iodice P, Federico A. Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications. Cancers (Basel) 2023; 15:5178. [PMID: 37958352 PMCID: PMC10647270 DOI: 10.3390/cancers15215178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.
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Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Flavia Scognamiglio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Lorenzo Ventriglia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Annachiara Coppola
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Chiara Tammaro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Giuseppe Scafuro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Patrizia Iodice
- Division of Medical Oncology, AORN Azienda dei Colli, Monaldi Hospital, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
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Hu J, Liu WF, Zhang XY, Shi GM, Yang XR, Zhou KQ, Hu B, Chen FY, Zhou C, Lau WY, Fan J, Wang Z, Zhou J. Synthetic miR-26a mimics delivered by tumor exosomes repress hepatocellular carcinoma through downregulating lymphoid enhancer factor 1. Hepatol Int 2023; 17:1265-1278. [PMID: 37115456 DOI: 10.1007/s12072-023-10527-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 03/18/2023] [Indexed: 04/29/2023]
Abstract
BACKGROUND The dysregulation of exosomal microRNAs plays an important role in the progression of hepatocarcinogenesis. In this study, we investigated the therapeutic potential of synthetic exosomal miR-26a against HCC cells and explored the feasibility of tumor-derived exosomes as drug delivery vehicles. METHODS Proliferation and migration assays were performed to examine the effects of miR-26a on HCC in vitro. The direct target gene of miR-26a was identified through miRecords analysis and target validation. The transferring efficiency and anti-HCC effect of exosomes with different origin were studied and the optimal miR-26a delivery method was established and verified in vitro and in vivo. In addition, the relationships between prognosis of HCC patients and miR-26a expression in HCC serum and exosomes were retrospectively analyzed. RESULTS Here, we found that tumor cell-derived exosomes were taken in preferentially by HCC cells and promoted HCC progression through Wnt pathway by low-density lipoprotein receptor-related protein 6 (LRP6). HCC cells with vacuolar protein sorting-associated protein 35 knocked down were adopted to generate engineered LRP6-exosomes. The engineered HCC-derived exosomes loading miR-26a inhibited HCC progression in vitro and in vivo effectively. Overexpression of miR-26a impaired the growth and migration of HCC by targeting lymphoid enhancer factor 1 (LEF1). Moreover, low expression of exosomal miR-26a was an independent prognostic factor for recurrence and survival in HCC patients. CONCLUSIONS Our findings suggested the exosomal miR-26a could serve as a non-invasive prognostic marker for HCC patients. Genetically modified tumor-derived exosomes showed preferable transfection efficiency but reduced Wnt activity, which provides a novel therapeutic strategy for HCC.
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Affiliation(s)
- Jie Hu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wei-Feng Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiang-Yu Zhang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Guo-Ming Shi
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin-Rong Yang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Kai-Qian Zhou
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Bo Hu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Fei-Yu Chen
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Cheng Zhou
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wan-Yee Lau
- Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China
| | - Jia Fan
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Zheng Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Jian Zhou
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200032, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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Qiu C, Feng YD, Yang X. MicroRNA-409-5p Inhibits GIST Tumorigenesis and Improves Imatinib Resistance by Targeting KDM4D Expression. Curr Med Sci 2023; 43:935-946. [PMID: 37828372 DOI: 10.1007/s11596-023-2715-8] [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: 09/15/2022] [Accepted: 05/11/2023] [Indexed: 10/14/2023]
Abstract
OBJECTIVE Gastrointestinal stromal tumors (GISTs) can rapidly proliferate through angiogenesis. Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis. This study aimed to explore the specific mechanism by which microRNA-409-5p (miR-409-5p) contributes to GIST. METHODS To identify genes potentially involved in the development and progression of GIST, the differences of miR-409-5p between tumors and adjacent tissues were first analyzed. Following this analysis, target genes were predicted. To further investigate the function of miRNA in GIST cells, two GIST cell lines (GIST-T1 and GIST882) were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA (negative control). Later, the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes. RESULTS In GISTs, there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues. It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β (HIF1β) and vascular endothelial growth factor A (VEGF-A). Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3'-UTR of Lysine-specific demethylase 4D (KDM4D) mRNA. Moreover, the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis. CONCLUSION This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.
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Affiliation(s)
- Cheng Qiu
- GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yong-Dong Feng
- GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xi Yang
- GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Mafi A, Mannani R, Khalilollah S, Hedayati N, Salami R, Rezaee M, Dehmordi RM, Ghorbanhosseini SS, Alimohammadi M, Akhavan-Sigari R. The Significant Role of microRNAs in Gliomas Angiogenesis: A Particular Focus on Molecular Mechanisms and Opportunities for Clinical Application. Cell Mol Neurobiol 2023; 43:3277-3299. [PMID: 37414973 DOI: 10.1007/s10571-023-01385-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/25/2023] [Indexed: 07/08/2023]
Abstract
MicroRNAs (miRNAs) are non-coding RNAs with only 20-22 nucleic acids that inhibit gene transcription and translation by binding to mRNA. MiRNAs have a diverse set of target genes and can alter most physiological processes, including cell cycle checkpoints, cell survival, and cell death mechanisms, affecting the growth, development, and invasion of various cancers, including gliomas. So optimum management of miRNA expression is essential for preserving a normal biological environment. Due to their small size, stability, and capability of specifically targeting oncogenes, miRNAs have emerged as a promising marker and new biopharmaceutical targeted therapy for glioma patients. This review focuses on the most common miRNAs associated with gliomagenesis and development by controlling glioma-determining markers such as angiogenesis. We also summarized the recent research about miRNA effects on signaling pathways, their mechanistic role and cellular targets in the development of gliomas angiogenesis. Strategies for miRNA-based therapeutic targets, as well as limitations in clinical applications, are also discussed.
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Affiliation(s)
- Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Mannani
- Department of Surgery, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shayan Khalilollah
- Department of Neurosurgery, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Raziyeh Salami
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Malihe Rezaee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rohollah Mousavi Dehmordi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyedeh Sara Ghorbanhosseini
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mina Alimohammadi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tübingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Warsaw, Poland
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Tan S, Tang H, Wang Y, Xie P, Li H, Zhang Z, Zhou J. Tumor cell-derived exosomes regulate macrophage polarization: Emerging directions in the study of tumor genesis and development. Heliyon 2023; 9:e19296. [PMID: 37662730 PMCID: PMC10474436 DOI: 10.1016/j.heliyon.2023.e19296] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 09/05/2023] Open
Abstract
As an extracellular vesicle, exosomes play an important role in intercellular information transmission, delivering cargos of the parent cell, such as RNA, DNA, proteins, and lipids, activating different signaling pathways in the target cell and regulating inflammation, angiogenesis, and tumor progression. In particular, exosomes secreted by tumor cells can change the function of surrounding cells, creating a microenvironment conducive to tumor growth and metastasis. For example, after macrophages phagocytose exosomes and accept their cargos, they activate macrophage polarization-related signaling pathways and polarize macrophages into M1 or M2 types to exert antitumor or protumor functions. Currently, the study of exosomes affecting the polarization of macrophages has attracted increasing attention. Therefore, this paper reviews relevant studies in this field to better understand the mechanism of exosome-induced macrophage polarization and provide evidence for exploring novel targets for tumor therapy and new diagnostic markers in the future.
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Affiliation(s)
- Siyuan Tan
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Haodong Tang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Yang Wang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Peng Xie
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Haifeng Li
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Zheng Zhang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Jiahua Zhou
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
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Mesa-Diaz N, Smith MT, Cardus DF, Du L. Development of Shortened miR-506-3p Mimics Exhibiting Strong Differentiation-Inducing Activity in Neuroblastoma Cells. Molecules 2023; 28:6295. [PMID: 37687123 PMCID: PMC10489042 DOI: 10.3390/molecules28176295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/09/2023] [Accepted: 08/16/2023] [Indexed: 09/10/2023] Open
Abstract
microRNA mimics are synthetic RNA molecules that imitate the mature miRNA duplexes and their functions. These mimics have shown promise in treating cancers. Nucleotide chemical modifications of microRNA mimics have been investigated and have improved the stability of miRNA mimics. However, the potential therapeutic benefit of mimic analogs based on sequence modifications has not been explored. miR-506-3p was identified as a differentiation-inducing microRNA in neuroblastoma cells, suggesting the potential of applying the miR-506-3p mimic in neuroblastoma differentiation therapy. In this study, we explored the possibility of developing shortened miR-506-3p analogs that can maintain differentiation-inducing activities comparable to the wild-type miR-506-3p mimic. We found that deleting up to two nucleotides at either the 3' end or within the middle region of the miR-506-3p sequence fully maintained the differentiation-inducing activity when compared to the wild-type mimic. Deleting up to four nucleotides from the 3' end or deleting three nucleotides in the middle positions diminished the differentiation-inducing activity, but the analogs still maintained differentiation-inducing activities that were significantly higher than the negative control oligo. The shortened analog designs potentially benefit patients from two perspectives: (1) the reduced cost of manufacturing shortened analogs, and (2) the reduced non-specific toxicity due to their smaller molecular sizes.
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Affiliation(s)
| | | | | | - Liqin Du
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA; (N.M.-D.); (M.T.S.); (D.F.C.)
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