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Tang S, Cheng H, Zang X, Tian J, Ling Z, Wang L, Xu W, Jiang J. Small extracellular vesicles: crucial mediators for prostate cancer. J Nanobiotechnology 2025; 23:230. [PMID: 40114183 PMCID: PMC11927207 DOI: 10.1186/s12951-025-03326-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025] Open
Abstract
Small extracellular vesicles (sEVs) play a critical role in the progression, diagnosis, and treatment of prostate cancer (PCa), particularly within the tumor microenvironment (TME). Acting as novel biomarkers and agents for targeted biological therapy, sEVs contribute significantly to improving patient survival. These vesicles transport a variety of biomolecules, including proteins, nucleic acids, and lipids, which are instrumental in remodeling the TME, facilitating intercellular communication, and influencing key processes such as tumor growth, metastasis, and therapy resistance. A thorough understanding of sEV heterogeneity, including their biogenesis, characteristics, and potential applications, is essential. Recent advances have illuminated the origins, formation processes, and molecular cargo of PCa-derived sEVs (PCa-sEVs), enhancing our understanding of their role in disease progression. Furthermore, sEVs show promise as diagnostic markers, with potential applications in early detection and prognostic assessment in PCa. Therapeutically, natural and engineered sEVs offer versatile applications, including drug delivery, gene therapy, and immunomodulation, underscoring their potential in PCa management. This review delves into the substantial potential of sEVs in clinical practices for PCa.
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Affiliation(s)
- Sijie Tang
- The Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
- Department of Urology, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, China
| | - Huiying Cheng
- The Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, China
| | - Xueyan Zang
- The Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, China
| | - Jiawei Tian
- The Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
- Department of Urology, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
| | - Zhongli Ling
- Department of Urology, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
| | - Lingling Wang
- The Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China
| | - Wenrong Xu
- The Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China.
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, China.
| | - Jiajia Jiang
- The Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Blvd, Zhangjiagang, Suzhou, 215600, China.
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, China.
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Ng CX, How CW, Lee SH. Precision-engineered PEGylated liposome for dual payload delivery: enhancing efficacy of Doxorubicin hydrochloride and miR-145 mimics in breast cancer cells. J Liposome Res 2025; 35:15-28. [PMID: 39101839 DOI: 10.1080/08982104.2024.2385457] [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: 05/02/2024] [Revised: 07/14/2024] [Accepted: 07/23/2024] [Indexed: 08/06/2024]
Abstract
Micro-145 down-regulation is frequently found in breast cancers, indicating its potential as a therapeutic target. The introduction of exogenous miR-145 directly to the tumor sites has been a hurdle due to limited delivery, low bioavailability, and hence lower therapeutic efficacy. Thus, this study aims to synthesize and characterize PEGylated liposome co-loaded with Dox-HCl and miR-145 mimics to investigate its in-vitro anti-proliferative activity against MDA-MB-231 cells. The formulations were developed using a composite central design to optimize nanoparticle size and encapsulation efficiency (EE%) of Dox-HCl and miR-145 mimics. The optimized formulation exhibited the highest desirability function (D = 0.814) and displayed excellent stability over 60 days at 4 °C, maintaining a stable nanoparticle size and zeta potential, with relative EE% of Dox-HCl and miR-145 mimics on the final incubation day 94.97 ± 0.53% and 51.96 ± 2.67%, respectively. The system displayed a higher rate of drug release within 4 h of incubation at an acidic condition. Additionally, the optimized formulation demonstrated a higher toxicity (IC50 = 0.58 μM) against MDA-MB-231 cells than the free Dox- HCl and miR-145 regimen (IC50 = 1.00 μM). Our findings suggest that PEGylated liposome is tunable for effective concurrent delivery of anticancer drugs and therapeutic miRNAs into tumor cells, necessitating further investigation.
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Affiliation(s)
- Chu Xin Ng
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Lakeside Campus, Selangor, Malaysia
| | - Chee Wun How
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | - Sau Har Lee
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Lakeside Campus, Selangor, Malaysia
- Digital Health and Medical Advancements Impact Lab, Taylor's University, Subang Jaya, Selangor, Malaysia
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3
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Beňačka R, Szabóová D, Guľašová Z, Hertelyová Z. Non-Coding RNAs in Breast Cancer: Diagnostic and Therapeutic Implications. Int J Mol Sci 2024; 26:127. [PMID: 39795985 PMCID: PMC11719911 DOI: 10.3390/ijms26010127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Breast cancer (BC) is one of the most prevalent forms of cancer globally, and has recently become the leading cause of cancer-related mortality in women. BC is a heterogeneous disease comprising various histopathological and molecular subtypes with differing levels of malignancy, and each patient has an individual prognosis. Etiology and pathogenesis are complex and involve a considerable number of genetic alterations and dozens of alterations in non-coding RNA expression. Non-coding RNAs are part of an abundant family of single-stranded RNA molecules acting as key regulators in DNA replication, mRNA processing and translation, cell differentiation, growth, and overall genomic stability. In the context of breast cancer, non-coding RNAs are involved in cell cycle control and tumor cell migration and invasion, as well as treatment resistance. Alterations in non-coding RNA expression may contribute to the development and progression of breast cancer, making them promising biomarkers and targets for novel therapeutic approaches. Currently, the use of non-coding RNAs has not yet been applied to routine practice; however, their potential has been very well studied. The present review is a literature overview of current knowledge and its objective is to delineate the function of diverse classes of non-coding RNAs in breast cancer, with a particular emphasis on their potential utility as diagnostic and prognostic markers or as therapeutic targets and tools.
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Affiliation(s)
- Roman Beňačka
- Department of Pathophysiology, Medical Faculty, Pavol Jozef Šafarik University, 04011 Košice, Slovakia;
| | - Daniela Szabóová
- Department of Pathophysiology, Medical Faculty, Pavol Jozef Šafarik University, 04011 Košice, Slovakia;
| | - Zuzana Guľašová
- Center of Clinical and Preclinical Research MEDIPARK, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (Z.G.); (Z.H.)
| | - Zdenka Hertelyová
- Center of Clinical and Preclinical Research MEDIPARK, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (Z.G.); (Z.H.)
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Chen X, Li D, Su Q, Ling X, Ding S, Xu R, Liu Z, Qin Y, Zhang J, Yang Z, Kang X, Qi Y, Wu H. MicroRNA-145-5p inhibits the tumorigenesis of breast cancer through SENP2-regulated ubiquitination of ERK2. Cell Mol Life Sci 2024; 81:461. [PMID: 39578257 PMCID: PMC11584840 DOI: 10.1007/s00018-024-05505-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 10/04/2024] [Accepted: 11/11/2024] [Indexed: 11/24/2024]
Abstract
Breast carcinoma exhibits the highest incidence among various cancers and is the foremost cause of mortality in women. Increasing evidence shows that SUMOylation of proteins plays a critical role in the progression of breast cancer; however, the role of SENP2 and its molecular mechanism in breast cancer remain underexplored. Here, we discerned that SENP2 promoted the tumorigenesis of breast cancer both in vitro and in vivo. Furthermore, we identified that ERK2 was SUMOylated and that SENP2 played a role by deconjugating ERK2 SUMOylation in breast cancer. SUMOylation of ERK2 promoted its ubiquitin-proteasomal degradation, thus inhibiting the epithelial-to-mesenchymal transition in breast cancer cells. Furthermore, microRNA-145-5p (miR-145-5p) has emerged as a scarce commodity in breast cancer and binds to the 3'-untranslated region of SENP2 mRNA to govern the regulatory dynamics of SENP2 expression. Finally, miR-145-5p inhibits SENP2 transcription, enhances ERK2 SUMOylation, and ultimately suppresses the progression of breast cancer. These revelations suggest evolving ideas for the miR-145-5p-SENP2 axis in therapeutic intervention, thus heralding transformative prospects for the clinical management of breast cancer.
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Affiliation(s)
- Xu Chen
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Danqing Li
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Qi Su
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Xing Ling
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Siyu Ding
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Runxiao Xu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Zhaoxia Liu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Yuanyuan Qin
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Jinping Zhang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhihui Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Xunlei Kang
- Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA
| | - Yitao Qi
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China.
| | - Hongmei Wu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China.
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Mishra J, Chakraborty S, Nandi P, Manna S, Baral T, Niharika, Roy A, Mishra P, Patra SK. Epigenetic regulation of androgen dependent and independent prostate cancer. Adv Cancer Res 2024; 161:223-320. [PMID: 39032951 DOI: 10.1016/bs.acr.2024.05.007] [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: 07/23/2024]
Abstract
Prostate cancer is one of the most common malignancies among men worldwide. Besides genetic alterations, epigenetic modulations including DNA methylation, histone modifications and miRNA mediated alteration of gene expression are the key driving forces for the prostate tumor development and cancer progression. Aberrant expression and/or the activity of the epigenetic modifiers/enzymes, results in aberrant expression of genes involved in DNA repair, cell cycle regulation, cell adhesion, apoptosis, autophagy, tumor suppression and hormone response and thereby disease progression. Altered epigenome is associated with prostate cancer recurrence, progression, aggressiveness and transition from androgen-dependent to androgen-independent phenotype. These epigenetic modifications are reversible and various compounds/drugs targeting the epigenetic enzymes have been developed that are effective in cancer treatment. This chapter focuses on the epigenetic alterations in prostate cancer initiation and progression, listing different epigenetic biomarkers for diagnosis and prognosis of the disease and their potential as therapeutic targets. This chapter also summarizes different epigenetic drugs approved for prostate cancer therapy and the drugs available for clinical trials.
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Affiliation(s)
- Jagdish Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Subhajit Chakraborty
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Piyasa Nandi
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Soumen Manna
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Tirthankar Baral
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Prahallad Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India.
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Ni C, Li D. Ferroptosis and oxidative stress in endometriosis: A systematic review of the literature. Medicine (Baltimore) 2024; 103:e37421. [PMID: 38489713 PMCID: PMC10939684 DOI: 10.1097/md.0000000000037421] [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: 05/12/2023] [Revised: 10/19/2023] [Accepted: 02/07/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Endometriosis (EMT) a common gynecological condition in women, an inflammatory disease characterized by the presence of endometrial tissue on organs and tissues in the pelvis, and is mainly associated with chronic pelvic pain and infertility. As the etiology has not been fully elucidated, current treatment is limited to surgery, hormones and painkillers, with more side effects and difficulty in achieving long-term relief. Oxidative stress manifests itself as an overproduction of reactive oxygen species, which has an integral impact in the pathology of female reproductive disorders. In this review, we evaluate the mechanisms of iron overload-induced oxidative stress and ferroptosis in EMT and their pathophysiological implications. METHODS Because the etiology has not been fully elucidated, current treatments are limited to surgery, hormones, and painkillers, which have many side effects and are difficult to achieve long-term relief. RESULTS We interpreted that antioxidants as well as ferroptosis inducers show promising results in the treatment of EMT, but their application in this population needs to be further investigated. CONCLUSION In combination with the interpretation of previous studies, it was shown that iron overload is present in the peritoneal fluid, endometriotic lesions, peritoneum and macrophages in the abdominal cavity. However, the programmed cellular ferroptosis associated with iron overload is resisted by endometriotic foci, which is critical to the pathophysiology of EMT with local iron overload and inflammation.
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Affiliation(s)
- Chenghong Ni
- Department of Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Dingheng Li
- Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital, Hangzhou, Zhejiang Province, China
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Wang G, Chen Y, Wei Y, Zheng L, Jiao J, Guo Y. Highly Sensitive Labeling, Clickable Functionalization, and Glycoengineering of the MUC1 Neighboring System. JACS AU 2024; 4:828-836. [PMID: 38425906 PMCID: PMC10900198 DOI: 10.1021/jacsau.3c00803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/25/2024] [Accepted: 01/25/2024] [Indexed: 03/02/2024]
Abstract
This study introduces a novel wash-type affinity-primed proximity labeling (WAPL) strategy for labeling and surface engineering of the MUC1 protein neighboring system. The strategy entails the utilization of peroxidase in conjunction with a MUC1-selective aptamer, facilitating targeted binding to MUC1 and inducing covalent labeling of the protein neighboring system. This study reveals a novel finding that the WAPL strategy demonstrates superior labeling efficiency in comparison to nonwash-type affinity-primed proximity labeling, marking the first instance of such observations. The WAPL strategy provides signal amplification by converting a single recognition event into multiple covalent labeling events, thereby improving the detection sensitivity for subtle changes in MUC1. The WAPL platform employs two levels of labeling upgrades, modifying the biotin handles of the conventional labeling substrate, biotin-phenol. The first level involves a range of clickable molecules, facilitating dibenzoazacyclooctynylation, alkynylation, and trans-cyclooctenylation of the protein neighboring system. The second level utilizes lactose as a post-translational modification model, enabling rapid and reliable glycoengineering of the MUC1 neighboring system while remaining compatible with cell-based assays. The implementation of the WAPL strategy in protein neighboring systems has resulted in the establishment of a versatile platform that can effectively facilitate diverse monitoring and regulation techniques. This platform offers valuable insights into the regulation of relevant signaling pathways and promotes the advancement of novel therapeutic approaches, thereby bringing substantial implications for human health.
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Affiliation(s)
- Gang Wang
- Medical
Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
- Nanjing
University School of Life Sciences, Nanjing
University, Nanjing 210023, China
| | - Ying Chen
- School
of Clinical and Basic Medical Sciences, Shandong First Medical University, Jinan 250117, China
| | - Yuan Wei
- Medical
Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
| | - Lei Zheng
- Medical
Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
| | - Jianwei Jiao
- Medical
Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
- Laboratory
of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yuna Guo
- Medical
Science and Technology Innovation Center, Shandong First Medical University, Jinan 250117, China
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Luo L, Xu N, Fan W, Wu Y, Chen P, Li Z, He Z, Liu H, Lin Y, Zheng G. The TGFβ2-Snail1-miRNA TGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer. Clin Transl Med 2024; 14:e1558. [PMID: 38299307 PMCID: PMC10831563 DOI: 10.1002/ctm2.1558] [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: 09/08/2023] [Revised: 01/04/2024] [Accepted: 01/09/2024] [Indexed: 02/02/2024] Open
Abstract
There have been contradictory reports on the biological role of transforming growth factor-βs (TGFβs) in breast cancer (BC), especially with regard to their ability to promote epithelial-mesenchymal transition (EMT). Here, we show that TGFβ2 is preferentially expressed in mesenchymal-like BCs and maintains the EMT phenotype, correlating with cancer stem cell-like characteristics, growth, metastasis and chemo-resistance and predicting worse clinical outcomes. However, this is only true in ERα- BC. In ERα+ luminal-type BC, estrogen receptor interacts with p-Smads to block TGFβ signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFβ2 ) that is weakened in TGFβ2-overexpressing BC cells. We discover that TGFβ2-Snail1 recruits enhancer of zeste homolog-2 to convert miRNAsTGFβ2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFβ2 overexpression reverses the mesenchymal-like traits in agreement with the inhibition of TGFβ2-Snail1 signalling in BC cells. These findings clarify the roles of TGFβ2 in BC and suggest novel therapeutic strategies based on the TGFβ2-Snail1-miRNAsTGFβ2 loop for a subset type of human BCs.
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Affiliation(s)
- Liyun Luo
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Ning Xu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Weina Fan
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Yixuan Wu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Pingping Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Zhihui Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Zhimin He
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Hao Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Ying Lin
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
| | - Guopei Zheng
- Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseGuangzhouChina
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Zhang Y, Sun X, Li Z, Han X, Wang W, Xu P, Liu Y, Xue Y, Wang Z, Xu S, Wang X, Li G, Tian Y, Zhao Q. Interactions between miRNAs and the Wnt/β-catenin signaling pathway in endometriosis. Biomed Pharmacother 2024; 171:116182. [PMID: 38262146 DOI: 10.1016/j.biopha.2024.116182] [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: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/25/2024] Open
Abstract
Endometriosis is a disease characterized by the ectopic growth of endometrial tissue (glands and stroma) outside the confines of the uterus and often involves vital organs such as the intestines and urinary system. Endometriosis is considered a refractory disease owing to its enigmatic etiology, propensity for recurrence following conservative or surgical interventions, and the absence of radical treatment and long-term management. In recent years, the incidence of endometriosis has gradually increased, rendering it a pressing concern among women of childbearing age. A more profound understanding of its pathogenesis can significantly improve prognosis. Recent research endeavors have spotlighted the molecular mechanisms by which microRNAs (miRNAs) regulate the occurrence and progression of endometriosis. Many miRNAs have been reported to be aberrantly expressed in the affected tissues of both patients and animal models. These miRNAs actively participate in the regulation of inflammatory reactions, cellular proliferation, angiogenesis, and tissue remodeling. Their capacity to modulate crucial signaling pathways, such as the Wnt/β-catenin signaling pathway, reinforces their potential utility as diagnostic markers or therapeutic agents for endometriosis. In this review, we provide the latest insights into the role of miRNAs that interact with the Wnt/β-catenin pathway to regulate the biological behaviors of endometriosis cells and disease-related symptoms, such as pain and infertility. We hope that this review will provide novel insights and promising targets for innovative therapies addressing endometriosis.
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Affiliation(s)
- Yu Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Xueyu Sun
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China; Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Zhongkang Li
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China
| | - Xianhong Han
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Wenjun Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Penglin Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yangyang Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yuna Xue
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Zhe Wang
- Department of Basic Medicine, Chengde Medical College, Chengde, Hebei 067000, PR China
| | - Shuling Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Xueying Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Gailing Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yanpeng Tian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
| | - Qian Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
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Patel K, Rao DM, Sundersingh S, Velusami S, Rajkumar T, Nair B, Pandey A, Chatterjee A, Mani S, Gowda H. MicroRNA Expression Profile in Early-Stage Breast Cancers. Microrna 2024; 13:71-81. [PMID: 37873952 DOI: 10.2174/0122115366256479231003064842] [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: 05/12/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND Breast cancer is one of the leading causes of cancer deaths in women. Early diagnosis offers the best hope for a cure. Ductal carcinoma in situ is considered a precursor of invasive ductal carcinoma of the breast. In this study, we carried out microRNA sequencing from 7 ductal carcinoma in situ (DCIS), 6 infiltrating ductal carcinomas (IDC Stage IIA) with paired normal, and 5 unpaired normal breast tissue samples. METHODS We have deployed miRge for microRNA analysis, DESeq for differential expression analysis, and Cytoscape for competing endogenous RNA network investigation. RESULTS Here, we identified 76 miRNAs that were differentially expressed in DCIS and IDC. Additionally, we provide preliminary evidence of miR-365b-3p and miR-7-1-3p being overexpressed, and miR-6507-5p, miR-487b-3p, and miR-654-3p being downregulated in DCIS relative to normal breast tissue. We also identified a miRNA miR-766-3p that was overexpressed in earlystage IDCs. The overexpression of miR-301a-3p in DCIS and IDC was confirmed in 32 independent breast cancer tissue samples. CONCLUSION Higher expression of miR-301a-3p is associated with poor overall survival in The Cancer Genome Atlas Breast Cancer (TCGA-BRCA) dataset, indicating that it may be associated with DCIS at high risk of progressing to IDC and warrants deeper investigation.
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MESH Headings
- Humans
- Female
- MicroRNAs/genetics
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/mortality
- Gene Expression Regulation, Neoplastic/genetics
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/pathology
- Middle Aged
- Neoplasm Staging
- Gene Expression Profiling
- Biomarkers, Tumor/genetics
- Transcriptome/genetics
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Affiliation(s)
- Krishna Patel
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 691001, India
| | - Deva Magendhra Rao
- Department of Molecular Oncology, Cancer Institute (WIA), Chennai 600036, India
| | | | - Sridevi Velusami
- Department of Surgical Oncology, Cancer Institute (WIA), Chennai, India
| | | | - Bipin Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 691001, India
| | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore 560029, India
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore 560066 India
- Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Samson Mani
- Department of Molecular Oncology, Cancer Institute (WIA), Chennai 600036, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 691001, India
- Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
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11
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Chakraborty S, Banerjee S. Understanding crosstalk of organ tropism, tumor microenvironment and noncoding RNAs in breast cancer metastasis. Mol Biol Rep 2023; 50:9601-9623. [PMID: 37792172 DOI: 10.1007/s11033-023-08852-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/26/2023] [Indexed: 10/05/2023]
Abstract
Cancer metastasis is one of the major clinical challenges worldwide due to limited existing effective treatments. Metastasis roots from the host organ of origin and gradually migrates to different regional and distant organs. In different breast cancer subtypes, different organs like bones, liver, lungs and brain are targeted by the metastatic tumor cells. Cancer renders mortality to their respective metastasizing sites like bones, brain, liver, and lungs. Metastatic breast cancers are best treated and managed if detected at an early stage. Metastasis is regulated by various molecular activators and suppressors. The conventional theory of 'seed and soil' states that metastatic tumor cells move to tumor microenvironment that has favorable conditions like blood flow for them to grow just like seeds grows when planted in fertile land. Additionally, different coding as well as non-coding RNAs play a very significant role in the process of metastasis by modulating their expression levels leading to a crosstalk of various tumorigenic cascades. Treatments for metastasis is also very critical in controlling this lethal process. Detecting breast cancer metastasis at an early stage is crucial for managing and predicting metastatic progression. In this review, we have compiled several factors that can be targeted to manage the onset and gradual stages of breast cancer metastasis.
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Affiliation(s)
- Sohini Chakraborty
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Satarupa Banerjee
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
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12
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Chen Y, Scully M. The Tumorigenicity of Breast Cancer Cells Is Reduced upon Treatment with Small Extracellular Vesicles Isolated from Heparin Treated Cell Cultures. Int J Mol Sci 2023; 24:15736. [PMID: 37958720 PMCID: PMC10649933 DOI: 10.3390/ijms242115736] [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: 09/01/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
As a member of the HPSG family, heparin is often used as a specific probe of their role in cell physiology; indeed, we have previously shown a reduction in the tumorigenicity of breast cancer cells when cultured in its presence. However, a partial reversal of the anti-tumorigenic effect occurred when the treated cells were cultured in fresh medium without heparin, which led us to consider whether a more persistent effect could be achieved by treatment of the cells with small extracellular vesicles (sEV) from heparin-treated cells. The tumorigenicity was analyzed using sEV isolated from the culture medium of heparin-treated MCF-7 and MDA-MB231 breast cancer cells (sEV-HT) or from conditioned medium following the termination of treatment (heparin discontinued, sEV-HD). Tumorigenicity was reduced in cells cultured in the presence of sEV-HT compared to that of cells cultured in the presence of sEV from untreated cells (sEV-Ctrl). sEV-HD were also observed to exert an anti-tumorigenic effect on the expression of pro-tumorigenic and cell cycle regulatory proteins, as well as signaling activities when added to fresh cultures of MCF-7 and MDA-MB231 cells. The anti-tumorigenic activity of the heparin-derived sEV may arise from observed changes in the miRNA content or from heparin, which was observed to be bound to the sEV. sEV may constitute a relatively stable reservoir of circulating heparin, allowing heparin activity to persist in the circulation even after therapy has been discontinued. These findings can be considered as a special additional pharmacological characteristic of heparin clinical therapy.
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Affiliation(s)
- Yunliang Chen
- Thrombosis Research Institute, 1b Manresa Road, London SW3 6LR, UK;
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13
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Khamis T, Diab AAAA, Zahra MH, El-Dahmy SE, Abd Al-Hameed BA, Abdelkhalek A, Said MA, Abdellatif H, Fericean LM, Banatean-Dunea I, Arisha AH, Attia MS. The Antiproliferative Activity of Adiantum pedatum Extract and/or Piceatannol in Phenylhydrazine-Induced Colon Cancer in Male Albino Rats: The miR-145 Expression of the PI-3K/ Akt/ p53 and Oct4/ Sox2/ Nanog Pathways. Molecules 2023; 28:5543. [PMID: 37513415 PMCID: PMC10383735 DOI: 10.3390/molecules28145543] [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: 06/04/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Colon cancer is one of the most common types of cancer worldwide, and its incidence is increasing. Despite advances in medical science, the treatment of colon cancer still poses a significant challenge. This study aimed to investigate the potential protective effects of Adiantum pedatum (AP) extract and/or piceatannol on colon cancer induced via phenylhydrazine (PHZ) in terms of the antioxidant and apoptotic pathways and histopathologic changes in the colons of male albino rats. The rats were randomly divided into eight groups: control, AP extract, piceatannol (P), PHZ, PHZ and AP treatments, PHZ and P treatments, PHZ and both AP and P, and PHZ and prophylaxis with both AP and P. The results demonstrated that PHZ induced oxidative damage, apoptosis, and histopathological changes compared to the control group. However, the administration of AP or P or AP + P as therapy or prophylaxis significantly ameliorated these changes and upregulated the colonic mir-145 and mRNA expression of P53 and PDCD-4 while downregulating the colonic mRNA expression of PI3K, AKT, c-Myc, CK-20, SOX-2, OCT-4, and NanoG compared to the PHZ group. These findings suggest that the candidate drugs may exert their anti-cancer effects through multiple mechanisms, including antioxidant and apoptotic activities.
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Affiliation(s)
- Tarek Khamis
- Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | | | - Mansour H Zahra
- Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| | - Samih Ebrahim El-Dahmy
- Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | | | - Adel Abdelkhalek
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt
| | - Mahmoud A Said
- Zagazig University Hospital, Zagazig University, Zagazig 44511, Egypt
| | - Hussein Abdellatif
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
- Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Liana Mihaela Fericean
- Department of Biology, Faculty of Agriculture, University of Life Sciences, King Mihai I" from Timisoara [ULST], Aradului St. 119, 300645 Timisoara, Romania
| | - Ioan Banatean-Dunea
- Department of Biology, Faculty of Agriculture, University of Life Sciences, King Mihai I" from Timisoara [ULST], Aradului St. 119, 300645 Timisoara, Romania
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt
- Department of Physiology, Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mai S Attia
- Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
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14
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Hu C, Liu T, Zhang W, Sun Y, Jiang D, Zhang X, Liu Y, Mao S, Xu Y, Pan J, Wang J, Huang Y, Yang S, Yang K. miR-145 inhibits aerobic glycolysis and cell proliferation of cervical cancer by acting on MYC. FASEB J 2023; 37:e22839. [PMID: 36946075 DOI: 10.1096/fj.202201189rr] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 01/04/2023] [Accepted: 02/13/2023] [Indexed: 03/23/2023]
Abstract
Nearly half a million women are diagnosed with cervical cancer (CC) each year, with the incidence of CC stabilizing or rising in low-income and middle-income countries. Cancer cells use metabolic reprogramming to meet the needs of rapid proliferation, known as the Warburg effect, but the mechanism of the Warburg effect in CC remains unclear. microRNAs (miRNAs) have a wide range of effects on gene expression and diverse modes of action, and they regulate genes for metabolic reprogramming. Dysregulation of miRNA expression leads to metabolic abnormalities in tumor cells and promotes tumorigenesis and tumor progression. In this study, we found that miR-145 was negatively correlated with metabolic reprogramming-related genes and prevented the proliferation and metastasis of CC cell lines by impeding aerobic glycolysis. A dual-luciferase reporter assay showed that miR-145 can bind to the 3'-untranslated region (3'-UTR) of MYC. Chromatin Immunoprecipitation-quantitative real-time PCR indicated that MYC was involved in the regulation of glycolysis-related genes. In addition, miR-145 mimics significantly suppressed the growth of CC cell xenograft tumor, prolonged the survival time of mice, and dramatically silenced the expression of tumor proliferation marker Ki-67. Therefore, the results suggested that miR-145 affects aerobic glycolysis through MYC, which may be a potential target for the treatment of CC.
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Affiliation(s)
- Chenchen Hu
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Tianyue Liu
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Wenxin Zhang
- School of Basic Medicine, The Fourth Military Medical University, Xi'an, China
| | - Yuanjie Sun
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Dongbo Jiang
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Xiyang Zhang
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Yang Liu
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Siyi Mao
- School of Basic Medicine, The Fourth Military Medical University, Xi'an, China
| | - Yiming Xu
- School of Basic Medicine, The Fourth Military Medical University, Xi'an, China
| | - Jingyu Pan
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Jing Wang
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Yinan Huang
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Shuya Yang
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
| | - Kun Yang
- Department of Immunology, The Fourth Military Medical University, Xi'an, China
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15
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Shinde SS, Ahmed S, Malik JA, Hani U, Khanam A, Ashraf Bhat F, Ahmad Mir S, Ghazwani M, Wahab S, Haider N, Almehizia AA. Therapeutic Delivery of Tumor Suppressor miRNAs for Breast Cancer Treatment. BIOLOGY 2023; 12:467. [PMID: 36979159 PMCID: PMC10045434 DOI: 10.3390/biology12030467] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023]
Abstract
The death rate from breast cancer (BC) has dropped due to early detection and sophisticated therapeutic options, yet drug resistance and relapse remain barriers to effective, systematic treatment. Multiple mechanisms underlying miRNAs appear crucial in practically every aspect of cancer progression, including carcinogenesis, metastasis, and drug resistance, as evidenced by the elucidation of drug resistance. Non-coding RNAs called microRNAs (miRNAs) attach to complementary messenger RNAs and degrade them to inhibit the expression and translation to proteins. Evidence suggests that miRNAs play a vital role in developing numerous diseases, including cancer. They affect genes critical for cellular differentiation, proliferation, apoptosis, and metabolism. Recently studies have demonstrated that miRNAs serve as valuable biomarkers for BC. The contrast in the expression of miRNAs in normal tissue cells and tumors suggest that miRNAs are involved in breast cancer. The important aspect behind cancer etiology is the deregulation of miRNAs that can specifically influence cellular physiology. The main objective of this review is to emphasize the role and therapeutic capacity of tumor suppressor miRNAs in BC and the advancement in the delivery system that can deliver miRNAs specifically to cancerous cells. Various approaches are used to deliver these miRNAs to the cancer cells with the help of carrier molecules, like nanoparticles, poly D, L-lactic-co-glycolic acid (PLGA) particles, PEI polymers, modified extracellular vesicles, dendrimers, and liposomes. Additionally, we discuss advanced strategies of TS miRNA delivery techniques such as viral delivery, self-assembled RNA-triple-helix hydrogel drug delivery systems, and hyaluronic acid/protamine sulfate inter-polyelectrolyte complexes. Subsequently, we discuss challenges and prospects on TS miRNA therapeutic delivery in BC management so that miRNAs will become a routine technique in developing individualized patient profiles.
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Affiliation(s)
- Sonali S. Shinde
- Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, India
| | - Sakeel Ahmed
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad 382355, India
| | - Jonaid Ahmad Malik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati 781101, India
- Department of Biomedical Engineering, Indian Institute of Technology, Rupnagar 140001, India
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Afreen Khanam
- Department of Pharmacognosy and Phytochemistry, Jamia Hamdard, New Delhi 110062, India
| | | | - Suhail Ahmad Mir
- Department of Pharmaceutical Sciences, University of Kashmir, Jammu and Kashmir, Hazratbal, Srinagar 190006, India
| | - Mohammed Ghazwani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Nazima Haider
- Department of Pathology, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Abdulrahman A. Almehizia
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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16
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Zhu L, Gong P, Liu Y, Shi Y, Wang W, Zhang W, Hu Z, Li X. A retrospective case-series of influence of chronic hepatitis B on synchronous liver metastasis of colorectal cancer. Front Oncol 2023; 13:1109464. [PMID: 36910607 PMCID: PMC9995980 DOI: 10.3389/fonc.2023.1109464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/14/2023] [Indexed: 02/25/2023] Open
Abstract
Main point Our retrospective analysis of a large number of cases found in patients with primary colorectal cancer (CRC) carrying positive HBsAg inhibited the occurrence of synchronous liver metastases (SLM). However, liver cirrhosis caused by non-HBV factors promoted the occurrence of SLM. Objectives This study aimed to investigate the effect of HBV on the occurrence of synchronous liver metastases (SLM) of colorectal cancer (CRC). Methods Univariate and multivariate analyses were used to analyze the influence of clinical parameters on the occurrence of SLM. Results A total of 6, 020 patients with primary CRC were included in our study, of which 449 patients carrying HBsAg(+) accounted for 7.46%. 44 cases of SLM occurred in the HBsAg(+) group, accounting for 9.80%, which was much lower than 13.6% (758/5571) in the HBsAg(-) group (X=5.214, P=0.022). Among CRC patients with HBsAg(-), the incidence of SLM was 24.9% and 14.9% in the group with high APRI and FIB-4 levels, respectively, which were significantly higher than that in the compared groups (12.3% and 12.5%, all P<0.05). Compared with the control group, female patients, late-onset patients, and HBV-infective patients had lower risks of SLM (HR=0.737, 95%CI: 0.614-0.883, P<0.001; HR=0.752, 95%CI: 0.603-0.943, P=0.013; HR=0.682, 95%CI: 0.473-0.961, P=0.034). Conclusions The carriage of HBsAg(+) status inhibited the occurrence of SLM from CRC. HBV-causing liver cirrhosis did not further influence the occurrence of SLM, whereas non-HBV-factor cirrhosis promoted the occurrence of SLM. Nevertheless, this still required prospective data validation.
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Affiliation(s)
- Lin Zhu
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
| | - Piqing Gong
- Department of Anorectal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Ye Liu
- Department of Blood Transfusion, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Yunjie Shi
- Department of Anorectal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wenqiang Wang
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
| | - Wei Zhang
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
| | - Zhiqian Hu
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China.,Department of Anorectal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xinxing Li
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
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17
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Tumour-associated Mucin1 correlates with the procoagulant properties of cancer cells of epithelial origin. THROMBOSIS UPDATE 2022. [DOI: 10.1016/j.tru.2022.100123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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18
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Abdolrahmani A, Kardouni Khoozestani N, Azmoudeh-Ardalan F, Shamshiri AR. Prognostic impact of MUC1 and potential regulatory miR-145 and miR-21 expression in salivary mucoepidermoid carcinoma. Head Neck Pathol 2022; 16:1134-1145. [PMID: 35980523 PMCID: PMC9729488 DOI: 10.1007/s12105-022-01475-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/29/2022] [Accepted: 07/01/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Salivary gland mucoepidermoid carcinoma (MEC) poses a considerable risk of locoregional and distant metastasis after conventional treatments. There is an evident need for specifying prognostic biomarkers to identify patients who are in need of more intensive and prolonged follow-ups. This study aimed to assess the mucin 1 (MUC1) expression level and its potential regulatory microRNAs in salivary gland MEC and their prognostic potentials. MATERIALS AND METHODS The expression of MUC1 in salivary gland MEC tissues was assessed in 47 samples using immunohistochemistry. Related microRNA (miR-145 and miR-21) were evaluated using quantitative Reverse Transcription PCR. The associations between MUC1 and microRNAs expressions and clinicopathological parameters were investigated. RESULTS MUC1 expression levels positively correlated with histologic grade (p < 0.001), clinical stage (p = 0.04), risk of nodal metastasis (p = 0.02), as well as the likelihood of opting for radical treatment (p = 0.01). Increased expression of miR-21 (p < 0.001) and decreased expression of miR-145 (p < 0.001) were observed in MECs compared to normal salivary gland tissue. MiR-145 negatively (p = 0.01) and miR-21 positively (p = 0.01) correlated with MUC1 overexpression. Based on the univariate cox proportional hazard model, histologic grade and MUC1 expression level were significantly associated with disease-free, cancer-specific, and overall survival. However, the multivariable cox proportional hazard model indicated tumor grade as the only prognostic factor associated with disease-free survival. CONCLUSION Our results support the tumor suppressor role of miR-145 and the oncogenic role of miR-21 in salivary gland MEC. Also, MUC1 and miR-145 overexpression, as well as miR-21 suppression, show promising association with histologic tumor grade and clinical stage.
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Affiliation(s)
- Ali Abdolrahmani
- Dental Research Center, Dentistry Research Institute, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Kardouni Khoozestani
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, North Kargar St, Tehran, Iran
- Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pathology, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Farid Azmoudeh-Ardalan
- Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pathology, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Shamshiri
- Research Center for Caries Prevention, Dental Research Institute, Department of Community Oral Health, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
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19
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Li S, Chen H, Jiang X, Hu F, Li Y, Xu G. Adeno-associated virus-based caveolin-1 delivery via different routes for the prevention of cholesterol gallstone formation. Lipids Health Dis 2022; 21:109. [PMID: 36303150 PMCID: PMC9609467 DOI: 10.1186/s12944-022-01718-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatic caveolin-1 (CAV1) is reduced in cholesterol gallstone disease (CGD). Mice with CAV1 deficiency were prone to develop CGD. However, it remains unknown whether restored hepatic CAV1 expression prevents the development of CGD. METHODS C57BL/6 mice were injected with adeno-associated virus 2/8 (AAV2/8) vectors carrying the CAV1 gene (AAV2/8CAV1) via intravenous (i.v.) or intraperitoneal (i.p.) route and then subjected to a lithogenic diet (LD) for 8 weeks. Uninjected mice were used as controls. The functional consequences of rescuing CAV1 expression by either i.v. or i.p. AAV2/8CAV1 treatment for CGD prevention and its subsequent molecular mechanisms were examined. RESULTS CAV1 expression was reduced in the liver and gallbladder of LD-fed CGD mice. We discovered that AAV2/8CAV1 i.p. delivery results in higher transduction efficiency in the gallbladder than tail vein administration. Although either i.v. or i.p. injection of AAV2/8CAV1 improved liver lipid metabolic abnormalities in CGD mice but did not affect LD feeding-induced bile cholesterol supersaturation. In comparison with i.v. administration route, i.p. administration of AAV2/8CAV1 obviously increased CAV1 protein levels in the gallbladder of LD-fed mice, and i.p. delivery of AAV2/8CAV1 partially improved gallbladder cholecystokinin receptor (CCKAR) responsiveness and impeded bile cholesterol nucleation via the activation of adenosine monophosphate-activated protein kinase (AMPK) signaling, which induced a reduction in gallbladder mucin-1 (MUC1) and MUC5ac expression and gallbladder cholesterol accumulation. CONCLUSION CGD prevention by i.p. AAV2/8CAV1 injection in LD-fed mice was associated with the improvement of gallbladder stasis, which again supported the notion that supersaturated bile is required but not sufficient for the formation of cholesterol gallstones. Additionally, AAV treatment via the local i.p. injection offers particular advantages over the systemic i.v. route for much more effective gallbladder gene delivery, which will be an excellent tool for conducting preclinical functional studies on the maintenance of normal gallbladder function to prevent CGD.
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Affiliation(s)
- Sha Li
- grid.13402.340000 0004 1759 700XDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, 310006 Hangzhou, Zhejiang China
| | - Hongtan Chen
- grid.13402.340000 0004 1759 700XDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, 310006 Hangzhou, Zhejiang China
| | - Xin Jiang
- grid.13402.340000 0004 1759 700XDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, 310006 Hangzhou, Zhejiang China
| | - Fengling Hu
- grid.13402.340000 0004 1759 700XDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, 310006 Hangzhou, Zhejiang China
| | - Yiqiao Li
- grid.417401.70000 0004 1798 6507Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital and Hangzhou Medical College Affiliated People’s Hospital, 158 Shangtang Road, 310014 Hangzhou, Zhejiang China
| | - Guoqiang Xu
- grid.13402.340000 0004 1759 700XDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, 310006 Hangzhou, Zhejiang China
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20
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Zou Y, Zhang X, Liang J, Peng L, Qin J, Zhou F, Liu T, Dai L. Mucin 1 aggravates synovitis and joint damage of rheumatoid arthritis by regulating inflammation and aggression of fibroblast-like synoviocytes. Bone Joint Res 2022; 11:639-651. [PMID: 36048147 PMCID: PMC9533250 DOI: 10.1302/2046-3758.119.bjr-2021-0398.r2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Aims To explore the synovial expression of mucin 1 (MUC1) and its role in rheumatoid arthritis (RA), as well as the possible downstream mechanisms. Methods Patients with qualified synovium samples were recruited from a RA cohort. Synovium from patients diagnosed as non-inflammatory orthopaedic arthropathies was obtained as control. The expression and localization of MUC1 in synovium and fibroblast-like synoviocytes were assessed by immunohistochemistry and immunofluorescence. Small interfering RNA and MUC1 inhibitor GO-203 were adopted for inhibition of MUC1. Lysophosphatidic acid (LPA) was used as an activator of Rho-associated pathway. Expression of inflammatory cytokines, cell migration, and invasion were evaluated using quantitative real-time polymerase chain reaction (PCR) and Transwell chamber assay. Results A total of 63 RA patients and ten controls were included. Expression of MUC1 was observed in both the synovial lining and sublining layer. The percentage of MUC1+ cells in the lining layer of synovium was significantly higher in RA than that in control, and positively correlated to joint destruction scores of RA. Meanwhile, MUC1+ cells in the sublining layer were positively correlated to the Krenn subscore of inflammatory infiltration. Knockdown of MUC1, rather than GO-203 treatment, ameliorated the expression of proinflammatory cytokines, cell migration, and invasion of rheumatoid synoviocytes. Knockdown of MUC1 decreased expression of RhoA, Cdc42, and Rac1. Treatment with LPA compromised the inhibition of migration and invasion, but not inflammation, of synoviocytes by MUC1 knockdown. Conclusion Upregulated MUC1 promotes the aggression of rheumatoid synoviocytes via Rho guanosine triphosphatases (GTPases), thereby facilitating synovitis and joint destruction during the pathological process of RA. Cite this article: Bone Joint Res 2022;11(9):639–651.
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Affiliation(s)
- Yaoyao Zou
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Xuepei Zhang
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Jinjian Liang
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Liqin Peng
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Jiale Qin
- Zhong Shan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Feng Zhou
- Zhong Shan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Ting Liu
- Zhong Shan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Lie Dai
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
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21
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Toraih EA, Fawzy MS, Ning B, Zerfaoui M, Errami Y, Ruiz EM, Hussein MH, Haidari M, Bratton M, Tortelote GG, Hilliard S, Nilubol N, Russell JO, Shama MA, El-Dahr SS, Moroz K, Hu T, Kandil E. A miRNA-Based Prognostic Model to Trace Thyroid Cancer Recurrence. Cancers (Basel) 2022; 14:cancers14174128. [PMID: 36077665 PMCID: PMC9454675 DOI: 10.3390/cancers14174128] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/12/2022] [Accepted: 08/21/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Some thyroid tumors elected for surveillance remain indolent, while others progress. The mechanism responsible for this difference is poorly understood, making it challenging to devise patient surveillance plans. Early prediction is important for tailoring treatment and follow-up in high-risk patients. The aim of our study was to identify predictive markers for progression. We leveraged a highly sensitive test that accurately predicts which thyroid nodules are more likely to develop lymph node metastasis, thereby improving care and outcomes for cancer patients. Abstract Papillary thyroid carcinomas (PTCs) account for most endocrine tumors; however, screening and diagnosing the recurrence of PTC remains a clinical challenge. Using microRNA sequencing (miR-seq) to explore miRNA expression profiles in PTC tissues and adjacent normal tissues, we aimed to determine which miRNAs may be associated with PTC recurrence and metastasis. Public databases such as TCGA and GEO were utilized for data sourcing and external validation, respectively, and miR-seq results were validated using quantitative real-time PCR (qRT-PCR). We found miR-145 to be significantly downregulated in tumor tissues and blood. Deregulation was significantly related to clinicopathological features of PTC patients including tumor size, lymph node metastasis, TNM stage, and recurrence. In silico data analysis showed that miR-145 can negatively regulate multiple genes in the TC signaling pathway and was associated with cell apoptosis, proliferation, stem cell differentiation, angiogenesis, and metastasis. Taken together, the current study suggests that miR-145 may be a biomarker for PTC recurrence. Further mechanistic studies are required to uncover its cellular roles in this regard.
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Affiliation(s)
- Eman A. Toraih
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Correspondence: ; Tel.: +1-346-907-4237
| | - Manal S. Fawzy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar P.O. Box 1321, Saudi Arabia
| | - Bo Ning
- Department of Biochemistry and Molecular Biology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Mourad Zerfaoui
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Youssef Errami
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Emmanuelle M. Ruiz
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Mohammad H. Hussein
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Muhib Haidari
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Melyssa Bratton
- Biospecimen Core Laboratory, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Giovane G. Tortelote
- Section of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Sylvia Hilliard
- Section of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Naris Nilubol
- Endocrine Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20814, USA
| | - Jonathon O. Russell
- Division of Head and Neck Endocrine Surgery, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins, Baltimore, MD 21287, USA
| | - Mohamed A. Shama
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Samir S. El-Dahr
- Section of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Tony Hu
- Department of Biochemistry and Molecular Biology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Emad Kandil
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
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Tao S, Li J, Wang H, Ding S, Han W, He R, Ren Z, Wei G. Anti-colon Cancer Effects of Dendrobium officinale Kimura & Migo Revealed by Network Pharmacology Integrated With Molecular Docking and Metabolomics Studies. Front Med (Lausanne) 2022; 9:879986. [PMID: 35847793 PMCID: PMC9280342 DOI: 10.3389/fmed.2022.879986] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/23/2022] [Indexed: 11/26/2022] Open
Abstract
Objective The present study aimed to investigate the potential mechanism of Dendrobium officinale (D. officinale) on colorectal cancer and the relevant targets in the pathway using a network pharmacological approach. Methods (1) We identified the major bioactive components of D. officinale by UPLC-ESI-MS/MS and established the in-house library by using the literature mining method. (2) Target prediction was performed by SwissADME and SwissTargetPrediction. (3) A protein–protein interaction (PPI) network and component–target–pathway network (C-T-P network) were constructed. (4) The GO pathways and the KEGG pathway enrichment analysis were carried out by the Metascape database. (5) Molecular docking was performed by AutoDock software. (6) A series of experimental assays including cell proliferation, cell invasion and migration, and TUNEL staining in CRC were performed in CRC cell lines (HT-29, Lovo, SW-620, and HCT-116) to confirm the inhibitory effects of D. officinale. Results (1) In total, 396 candidate active components of D. officinale were identified by UPLC-ESI-MS/MS and selected from the database. (2) From OMIM, GeneCards, DrugBank, and TTD databases, 1,666 gene symbols related to CRC were gathered, and (3) 34 overlapping gene symbols related to CRC and drugs were obtained. (4) These results suggested that the anti-CRC components of D. officinale were mainly apigenin, naringenin, caffeic acid, γ-linolenic acid, α-linolenic acid, cis-10-heptadecenoic acid, etc., and the core targets of action were mainly ESR1, EGFR, PTGS2, MMP9, MMP2, PPARG, etc. (5) The proliferation of muscle cells, the regulation of inflammatory response, the response of cells to organic cyclic compounds, and the apoptotic signaling pathway might serve as principal pathways for CRC treatment. (6) The reliability of some important active components and targets was further validated by molecular docking. The molecular docking analysis suggested an important role of apigenin, naringenin, PTGS2, and MMP9 in delivering the pharmacological activity of D. officinale against CRC. (7) These results of the evaluation experiment in vitro suggested that D. officinale had a strong inhibitory effect on CRC cell lines, and it exerted anti-CRC activity by activating CRC cell apoptosis and inhibiting CRC cell migration and invasion. Conclusion This study may provide valuable insights into exploring the mechanism of action of D. officinale against CRC.
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Affiliation(s)
- Shengchang Tao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Jinyan Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- The Research Centre of Chinese Herbal Resource, Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Huan Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- The Research Centre of Chinese Herbal Resource, Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Shaobo Ding
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Weichao Han
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Ruirong He
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Zhiyao Ren
- The Research Centre of Chinese Herbal Resource, Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China
- NHC Key Laboratory of Male Reproduction and Genetics, Guangzhou, China
- Department of Central Laboratory, Family Planning Research Institute of Guangdong Province, Guangzhou, China
| | - Gang Wei
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Gang Wei
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Silencing of lncRNA MALAT1 facilitates erastin-induced ferroptosis in endometriosis through miR-145-5p/MUC1 signaling. Cell Death Dis 2022; 8:190. [PMID: 35399101 PMCID: PMC8995383 DOI: 10.1038/s41420-022-00975-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 02/19/2022] [Accepted: 03/23/2022] [Indexed: 12/18/2022]
Abstract
Endometriosis is a chronic disorder characterized by the implantation of endometrial glands and stroma outside the uterus. However, the pathogenesis of endometriosis is still unclear. To date, there is no fully effective treatment without trauma because of various side effects. Recent data suggest that ferroptosis is a novel recognized form of nonapoptosis-regulated cell death characterized by iron-dependent and lethal lipid peroxidation accumulation, showing great promise in the treatment of many diseases. In the present study, we verified that erastin induced ferroptosis in ectopic endometrial stromal cells (EESCs). Furthermore, we found that the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was decreased during erastin-induced ferroptosis. Knockdown of MALAT1 significantly aggravated the inhibition of cell viability and increased intracellular iron, Liperfluo, and MDA levels in EESCs upon erastin treatment. Mechanistically, we demonstrated that MALAT1 served as a competing endogenous RNA of miR-145-5p to regulate the expression of MUC1, a suppressor of ferroptosis. MALAT1 knockdown-mediated ferroptotic cell death and MUC1 downregulation could be abrogated by inhibition of miR-145-5p. In addition, miR-145-5p inhibition-mediated ferroptotic cell death could be abolished by MUC1 knockdown. Furthermore, erastin-induced ferroptosis shrunk endometriotic lesions via the MALAT1/miR-145-5p/MUC1 axis in vivo. Taken together, our data indicate that knockdown of MALAT1 facilitates ferroptosis upon erastin treatment via miR-145-5p/MUC1 signaling. The synergistic effect of MALAT1 knockdown and erastin induction in ferroptosis may be a new therapeutic strategy for endometriosis.
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Fan W, Fan L, Wang Z, Yang L. Limonoids From the Genus Melia (Meliaceae): Phytochemistry, Synthesis, Bioactivities, Pharmacokinetics, and Toxicology. Front Pharmacol 2022; 12:795565. [PMID: 35140606 PMCID: PMC8819599 DOI: 10.3389/fphar.2021.795565] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/06/2021] [Indexed: 12/17/2022] Open
Abstract
Limonoids, as the vital bioactive chemical compounds in genus Melia plants, have attracted significant attention owing to their exclusive structural characteristics and remarkable biological activity. These compounds can be usually classified into two categories, including the ring-intact group and the ring-C-seco group. Benefiting from the development of separation and analysis technology, more than 200 limonoids have been isolated and identified from this genus. There is growing evidence that limonoids from genus Melia possess diverse pharmacological activities, especially anti-cancer effects, insecticidal activities, and anti-botulism effects. Toosendanin, one of the paramount limonoids, was considered as the pivotal bioactive marker in two medicinal herbs, including Melia toosendan Sieb. et Zucc and Melia azedarach L. In particular, limonoids are found to exhibit non-negligible toxic effects, a finding which needs further research. Besides this, the lack of clinical research data seriously hinders its further development and utilization, and necessary clinical trials should be taken into consideration. In this review, we systematically summarized the phytochemical compounds and their synthesis methods, pharmacological activities, and the structure–activity relationship, pharmacokinetics, and toxicology of genus Melia-derived limonoids. We believe that this up-to-date review could provide scientific evidence for the application of limonoids as agents beneficial to health in future clinical practice.
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Affiliation(s)
- Wenxiang Fan
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Linhong Fan
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhengtao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Zhengtao Wang, ; Li Yang,
| | - Li Yang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Zhengtao Wang, ; Li Yang,
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Zeng H, Li L, Gao Y, Wu G, Hou Z, Liu S. Long noncoding RNA UCA1 regulates HCV replication and antiviral response via miR-145-5p/SOCS7/IFN pathway. Int J Biol Sci 2021; 17:2826-2840. [PMID: 34345210 PMCID: PMC8326114 DOI: 10.7150/ijbs.59227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 06/21/2021] [Indexed: 12/25/2022] Open
Abstract
Hepatitis C virus (HCV) infection involves a variety of viral and host factors, which leads to the dysregulation of number of relevant genes including long noncoding RNAs (LncRNAs). LncRNA urothelial carcinoma-associated 1 (UCA1) has been reported to be upregulated in HCV-infected individuals. In a bid to elucidate on the contribution of UCA1 on HCV replication, we infected Huh7.5 cells with cell culture-derived HCV and found that UCA1 expression was elevated in time- and dose-dependent manners. Functionally, UCA1 knockdown by siRNA upregulated interferon (IFN) responses, thereby increasing the expression of interferon-stimulating genes (ISGs), and subsequently suppressing HCV replication. Bioinformatics analysis and experimental results indicated that, functioning as competitive endogenous RNA, UCA1 could sponge microRNA (miR)-145-5p, which targeted suppressor of cytokine signaling 7 (SOCS7) mRNA and subsequently mediated SOCS7 silencing. Moreover, SOCS7 protein exerted an inhibitory effect on IFN responses, thereby facilitating HCV replication. Taken together, at first, our findings demonstrate that UCA1 can counteract the expression of miR-145-5p, thereby upregulating the level of SOCS7, and in turn leading to the suppression of antiviral response in Huh7.5 cells.
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Affiliation(s)
- Haiyan Zeng
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Lei Li
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100010, China
| | - Yi Gao
- Department of Infectious Disease, the Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, China
| | - Guojun Wu
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Zhouhua Hou
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shuiping Liu
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
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Sheykhhasan M, Kalhor N, Sheikholeslami A, Dolati M, Amini E, Fazaeli H. Exosomes of Mesenchymal Stem Cells as a Proper Vehicle for Transfecting miR-145 into the Breast Cancer Cell Line and Its Effect on Metastasis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5516078. [PMID: 34307654 PMCID: PMC8263260 DOI: 10.1155/2021/5516078] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/10/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Despite recent advances in scientific knowledge and clinical practice, management, and treatment of breast cancer, as one of the leading causes of female mortality, breast cancer remains a major burden. Recently, methods employing stem cells and their derivatives, i.e., exosomes, in gene-based therapies hold great promise. Since these natural nanovesicles are able to transmit crucial cellular information which can be engineered to have robust delivery and targeting capacity, they are considered one of the modes of intercellular communication. miR-145, one of the downregulated microRNAs (miRNAs) in various cancers, can regulate tumor cell invasion, metastasis, apoptosis, and proliferation and stem cell differentiation. OBJECTIVES The aim of this study was to investigate the role of exosomes secreted from adipose tissue-derived mesenchymal stem cells (MSCs) for miR-145 transfection into breast cancer cells in order to weaken their expansion and metastasis. METHODS Here, we exploited the exosomes from adipose tissue-derived mesenchymal stem cells (MSC-Exo) to deliver miR-145 in the T-47D breast cancer cell line. Lentiviral vectors of miR-145-pLenti-III-enhanced green fluorescent protein (eGFP) and empty pLenti-III-eGFP as the backbone were used to transfect MSCs and T-47D cells. In order to find the efficiency of exosomes as a delivery vehicle, the expression level of some miR-145 target genes, including Rho-Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1), Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), Matrix Metalloproteinase 9 (MMP9), and Tumor Protein p53 (TP53), was compared in all treatment groups (T-47D cells treated by miR-145-transfected MSCs and their derivatives or their backbone) and control group (untransfected T-47D cells) using real-time PCR. RESULTS The obtained data represented the inhibitory effect of miR-145 on apoptosis induction and metastasis in both direct miR-treated groups. However, exosome-mediated delivery caused an improved anticancer property of miR-145. CONCLUSION Restoration of miR-145 using MSC-Exo can be considered a potential novel therapeutic strategy in breast cancer in the future.
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Affiliation(s)
- Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Masoumeh Dolati
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Elaheh Amini
- Department of Cellular & Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Hoda Fazaeli
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
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Jara D, Carvajal P, Castro I, Barrera MJ, Aguilera S, González S, Molina C, Hermoso M, González MJ. Type I Interferon Dependent hsa-miR-145-5p Downregulation Modulates MUC1 and TLR4 Overexpression in Salivary Glands From Sjögren's Syndrome Patients. Front Immunol 2021; 12:685837. [PMID: 34149728 PMCID: PMC8208490 DOI: 10.3389/fimmu.2021.685837] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/12/2021] [Indexed: 12/19/2022] Open
Abstract
Sjögren’s syndrome (SS) is an autoimmune disease that mainly affects salivary glands (SG) and is characterized by overactivation of the type I interferon (IFN) pathway. Type I IFNs can decrease the levels of hsa-miR-145-5p, a miRNA with anti-inflammatory roles that is downregulated in SG from SS-patients. Two relevant targets of hsa-miR-145-5p, mucin 1 (MUC1) and toll-like receptor 4 (TLR4) are overexpressed in SS-patients and contribute to SG inflammation and dysfunction. This study aimed to evaluate if hsa-miR-145-5p modulates MUC1 and TLR4 overexpression in SG from SS-patients in a type I IFN dependent manner. Labial SG (LSG) biopsies from 9 SS-patients and 6 controls were analyzed. We determined hsa-miR-145-5p levels by TaqMan assays and the mRNA levels of MUC1, TLR4, IFN-α, IFN-β, and IFN-stimulated genes (MX1, IFIT1, IFI44, and IFI44L) by real time-PCR. We also performed in vitro assays using type I IFNs and chemically synthesized hsa-miR-145-5p mimics and inhibitors. We validated the decreased hsa-miR-145-5p levels in LSG from SS-patients, which inversely correlated with the type I IFN score, mRNA levels of IFN-β, MUC1, TLR4, and clinical parameters of SS-patients (Ro/La autoantibodies and focus score). IFN-α or IFN-β stimulation downregulated hsa-miR-145-5p and increased MUC1 and TLR4 mRNA levels. Hsa-miR-145-5p overexpression decreased MUC1 and TLR4 mRNA levels, while transfection with a hsa-miR-145-5p inhibitor increased mRNA levels. Our findings show that type I IFNs decrease hsa-miR-145-5p expression leading to upregulation of MUC1 and TLR4. Together, this suggests that type I interferon-dependent hsa-miR-145-5p downregulation contributes to the perpetuation of inflammation in LSG from SS-patients.
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Affiliation(s)
- Daniela Jara
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Patricia Carvajal
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Isabel Castro
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | | | | | - Sergio González
- Escuela de Odontología, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - Claudio Molina
- Facultad de Odontología, Universidad San Sebastián, Santiago, Chile
| | - Marcela Hermoso
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - María-Julieta González
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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Abstract
MicroRNAs orchestrate the tight regulation of numerous cellular processes and the deregulation in their activities has been implicated in many diseases, including diabetes and cancer. There is an increasing amount of epidemiological evidence associating diabetes, particularly type 2 diabetes mellitus, to an elevated risk of various cancer types, including breast cancer. However, little is yet known about the underlying molecular mechanisms and even less about the role miRNAs play in driving the tumorigenic potential of the cell signaling underlying diabetes pathogenesis. This article reviews the role of miRNA in bridging the diabetes–breast cancer association by discussing specific miRNAs that are implicated in diabetes and breast cancer and highlighting the overlap between the disease-specific regulatory miRNA networks to identify a 20-miRNA signature that is common to both diseases. Potential therapeutic targeting of these molecular players may help to alleviate the socioeconomic burden on public health that is imposed by the type 2 diabetes mellitus (T2DM)–breast cancer association.
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Rodrigues MA, Caldeira-Brant AL, Gomes DA, Silveira TL, Chiarini-Garcia H, Cassali GD. Characterization of neoplastic cells outlining the cystic space of invasive micropapillary carcinoma of the canine mammary gland. BMC Vet Res 2021; 17:130. [PMID: 33761962 PMCID: PMC7992814 DOI: 10.1186/s12917-021-02807-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 02/19/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Invasive micropapillary carcinoma (IMPC) is a rare malignant breast tumor and a variant form of invasive ductal carcinoma that is an aggressive neoplasm of the human breast and canine mammary gland. The importance of the tumor microenvironment in cancer development has gradually been recognized, but little is known about the cell types outlining the cystic space of canine IMPC. This study aimed to characterize the neoplastic cells outlining the cystic space of IMPC. RESULTS Immunohistochemistry (IHC), immunofluorescence (IF), superresolution and transmission electron microscopy (TEM) were used to assess the cell types in the cystic areas of IMPCs. Cells expressing the mesenchymal markers alpha-smooth muscle actin (αSMA), Vimentin, and S100A4 outlined the cystic space of IMPC. Furthermore, loss of epithelial cell polarity in IMPC was shown by the localization of MUC1 at the stroma-facing surface. This protein modulates lumen formation and inhibits the cell-stroma interaction. Immunohistochemical and IF staining for the myoepithelial cell marker p63 were negative in IMPC samples. Furthermore, associated with peculiar morphology, such as thin cytoplasmic extensions outlining cystic spaces, was observed under TEM. These observations suggested cells with characteristics of myoepithelial-like cells. CONCLUSIONS The cells outlining the cystic space of IMPC in the canine mammary gland were characterized using IHC, IF and TEM. The presence of cells expressing αSMA, Vimentin, and S100A4 in the IMPC stroma suggested a role for tumor-associated fibroblasts in the IMPC microenvironment. The reversal of cell polarity revealed by the limited basal localization of MUC1 may be an important factor contributing to the invasiveness of IMPC. For the first time, the cystic space of canine mammary gland IMPC was shown to be delimited by myoepithelial-like cells that had lost p63 expression. These findings may enhance our understanding of the cellular microenvironment of invasive tumors to improve cancer diagnosis and treatment.
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Affiliation(s)
- Michele A Rodrigues
- Department of General Pathology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil
| | - Andre L Caldeira-Brant
- Department of Morphology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil
| | - Dawidson A Gomes
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil
| | - Tatiany L Silveira
- Department of General Pathology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil
| | - Hélio Chiarini-Garcia
- Department of Morphology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil
| | - Geovanni D Cassali
- Department of General Pathology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, CEP: 31270-901, Brazil.
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30
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Zhang Q, Ni Y, Zhi X, Wang J, Li Z, Tang J, Wang L, Wang W, Xu Z. Involvement of APRIL in Helicobacter pylori-related gastric cancer. J Cancer Res Clin Oncol 2021; 147:1685-1697. [PMID: 33738544 DOI: 10.1007/s00432-021-03574-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 02/17/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND/AIMS A proliferation-inducing ligand (APRIL, also known as TNFSF13, CD256) is a member of the tumor necrosis factor (TNF) superfamily and involved in a diverse set of diseases. In this work, we explored the potential associations and underlying mechanism in patients suffered from gastric cancer between the expression of APRIL and H. pylori infection. METHODS We analyzed APRIL expression levels in 200 GC tissue samples by immunohistochemistry staining. H. pylori infection was detected by modified Giemsa staining. The biological effects of APRIL on human GC cells in vitro and in vivo were tested by CCK-8 assay, colony formation, flow cytometry detection, transwell migration assay, matrigel invasion assay, and tumor xenograft assay in animals. RESULTS APRIL reactivity was positively correlated with H. pylori infection in vitro and vivo. It turned out that the decrease of miR-145 expression was dose-dependent and time-dependent on H. pylori infection and in consistent with APRIL expression. MiR-145 significantly attenuated the effect of H. pylori infection on APRIL gene expression in SGC7901 and BGC823 cell lines. Furthermore, APRIL overexpression promoted the proliferation, migration, invasion, and transfer of GC cells and decreased apoptosis, while APRIL knockdown suppressed these effects. We confirmed that APRIL activated the canonical NF-κB pathway through phosphorylation of AKT. CONCLUSION The expression of APRIL, which promoted the proliferation, migration, invasion, viability, and metastasis of GC cells, was upregulated in human H. pylori-infected GC through miR-145. Besides, APRIL-induced gastric tumorigenicity via activating NF-κB pathway. These results may provide a framework for the deeper analysis of APRIL in GC risk and prognosis.
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Affiliation(s)
- Qun Zhang
- Department of Oncological Surgery, Minhang Branch of Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ying Ni
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaofei Zhi
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jiwei Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Tang
- Department of Pediatric Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
| | - Linjun Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Nair MG, Somashekaraiah VM, Ramamurthy V, Prabhu JS, Sridhar TS. miRNAs: Critical mediators of breast cancer metastatic programming. Exp Cell Res 2021; 401:112518. [PMID: 33607102 DOI: 10.1016/j.yexcr.2021.112518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
MicroRNA mediated aberrant gene regulation has been implicated in several diseases including cancer. Recent research has highlighted the role of epigenetic modulation of the complex process of breast cancer metastasis by miRNAs. miRNAs play a crucial role in the process of metastatic evolution by facilitating alterations in the phenotype of tumor cells and the tumor microenvironment that promote this process. They act as critical determinants of the multi-step progression starting from carcinogenesis all the way to organotropism. In this review, we focus on the current understanding of the compelling role of miRNAs in breast cancer metastasis.
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Affiliation(s)
- Madhumathy G Nair
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
| | | | - Vishakha Ramamurthy
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - T S Sridhar
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
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Abstract
Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in U.S. women. The invasion-metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules. The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment. Each of these processes is regulated by changes in gene expression. Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression. miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs). The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer. We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade. We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis. It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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Gougousis S, Mouchtaropoulou E, Besli I, Vrochidis P, Skoumpas I, Constantinidis I. HPV-Related Oropharyngeal Cancer and Biomarkers Based on Epigenetics and Microbiome Profile. Front Cell Dev Biol 2021; 8:625330. [PMID: 33521000 PMCID: PMC7841258 DOI: 10.3389/fcell.2020.625330] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022] Open
Abstract
H uman papillomavirus (HPV) is considered the main cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC), and soon, the global burden of HPV-related OPSCC is predicted to exceed that of cervical cancer. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new promising targeted therapies and immunotherapy approaches. Epigenetic and microbiome-based exploration of biomarkers has gained growing interest with a view to the primary oropharyngeal cancer (OPC) screening. Understanding the role of the epigenetic mechanism and the changes that occur during pathogenesis shows appreciable progress in recent years. The different methylation status of DNA and miRNAs demonstrates the value of possible biomarkers discriminating even in different stages of dysplasia. Through whole-genome bisulfite sequencing, differentially methylated regions (DMRs) hold the key to recover missing information. O n the other hand, the microbiota investigation signifies a new biomarker approach for the evaluation of OPC. Along with known cofactors playing a major role in microbiota differentiation, HPV-related cases must be explored further for better understanding. The dynamic approach of the shotgun metagenomic sequencing will robustly fill the gap especially in species/strain level and consequently to biomarker detection. The constantly growing incidence of HPV-related OPC should lead us in further investigation and understanding of the unique features of the disease, more accurate diagnostic methods, along with the development and implementation of new, targeted therapies. This paper comprehensively reviews the significance of biomarkers based on epigenetics and microbiome profile in the accuracy of the diagnosis of the HPV-related cancer in the oropharynx.
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Affiliation(s)
- Spyridon Gougousis
- GH "G. Papanikolaou," ENT, Head and Neck Department, Thessaloniki, Greece
| | | | - Ioanna Besli
- GH "G. Papanikolaou," ENT, Head and Neck Department, Thessaloniki, Greece
| | | | - Ioannis Skoumpas
- GH "G. Papanikolaou," ENT, Head and Neck Department, Thessaloniki, Greece
| | - Ioannis Constantinidis
- 1st Department of Otorhinolaryngology, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Salimimoghadam S, Taefehshokr S, Loveless R, Teng Y, Bertoli G, Taefehshokr N, Musaviaroo F, Hajiasgharzadeh K, Baradaran B. The role of tumor suppressor short non-coding RNAs on breast cancer. Crit Rev Oncol Hematol 2020; 158:103210. [PMID: 33385514 DOI: 10.1016/j.critrevonc.2020.103210] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 12/15/2020] [Accepted: 12/20/2020] [Indexed: 12/11/2022] Open
Abstract
Characterized by remarkable levels of aggression and malignancy, BC remains one of the leading causes of death in females world wide. Accordingly, significant efforts have been made to develop early diagnostic tools, increase treatment efficacy, and improve patient prognosis. Hopefully, many of the molecular mechanisms underlying BC have been detected and show promising targeting potential. In particular, short and long non-coding RNAs (ncRNAs) are a class of endogenous BC controllers and include a number of different species including microRNAs, Piwi-interacting RNAs, small nucleolar RNA, short interfering RNAs, and tRNA-derivatives. In this review, we discuss the tumor suppressing roles of ncRNAs in the context of BC, and the mechanisms by which ncRNAs target tumor hallmarks, including apoptosis, proliferation, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis, and cell cycle progression, in addition to their diagnostic and prognostic significance in cancer treatment.
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Affiliation(s)
| | - Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Reid Loveless
- Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
| | - Yong Teng
- Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
| | - Gloria Bertoli
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Segrate, Milan, Italy.
| | - Nima Taefehshokr
- Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, Ontario, Canada.
| | | | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Chen C, Zhang M, Li Y, Wang S, Xie D, Wen X, Hu Y, Shen J, He X, You C, Tocher DR, Monroig Ó. Identification of miR-145 as a Key Regulator Involved in LC-PUFA Biosynthesis by Targeting hnf4α in the Marine Teleost Siganus canaliculatus. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:15123-15133. [PMID: 33291871 DOI: 10.1021/acs.jafc.0c04649] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Fish, particularly marine species, are considered as the major source of long-chain polyunsaturated fatty acids (LC-PUFA) in the human diet. The extent to which fish can synthesize LC-PUFA varies with species and is regulated by dietary fatty acids and ambient salinity. Therefore, to enable fish to produce more LC-PUFA, comprehending the mechanisms underlying the regulation of LC-PUFA biosynthesis is necessary. Here, the regulatory roles of miR-145 were investigated in the marine teleost rabbitfish Siganus canaliculatus. The hepatic abundance of miR-145 was lower in rabbitfish reared in low salinity (10 ppt) in comparison with that of those cultured in seawater (32 ppt), while the opposite pattern was observed for the transcripts of the transcription factor hepatocyte nuclear factor 4 alpha (Hnf4α), known to affect rabbitfish LC-PUFA biosynthesis. Rabbitfish hnf4α was identified as a target of miR-145 by luciferase reporter assays, and overexpression of miR-145 in the S. canaliculatus hepatocyte line (SCHL) markedly reduced the expression of Hnf4α and its target genes involved in LC-PUFA biosynthesis, namely, Δ4 fads2, Δ6Δ5 fads2, and elovl5. The opposite pattern was observed when miR-145 was knocked down in SCHL cells, with these effects being attenuated by subsequent hnf4α knockdown. Moreover, increasing endogenous Hnf4α by the knockdown of miR-145 increased the expression of LC-PUFA biosynthesis genes and enhanced the synthesis of LC-PUFA in both SCHL cells and rabbitfish in vivo. This is the first report to identify miR-145 as a key effector of LC-PUFA biosynthesis by targeting hnf4α, providing a novel insight into the mechanisms of the regulation of LC-PUFA biosynthesis in vertebrates.
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Affiliation(s)
- Cuiying Chen
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
| | - Mei Zhang
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
| | - Yuanyou Li
- Guangdong Laboratory for Lingnan Modern Agriculture, School of Marine Sciences of South China Agricultural University, Guangzhou 510642, China
| | - Shuqi Wang
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
- Research Center for Nutrition & Feed and Healthy Breeding of Aquatic Animals of Guangdong Province, Shantou 515063, China
| | - Dizhi Xie
- Guangdong Laboratory for Lingnan Modern Agriculture, School of Marine Sciences of South China Agricultural University, Guangzhou 510642, China
| | - Xiaobo Wen
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
- Guangdong Laboratory for Lingnan Modern Agriculture, School of Marine Sciences of South China Agricultural University, Guangzhou 510642, China
| | - Yu Hu
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
| | - Jiajian Shen
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
| | - Xianda He
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
| | - Cuihong You
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, 243 DaXue Road, Shantou 515063, China
| | - Douglas R Tocher
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling, Scotland FK9 4LA, UK
| | - Óscar Monroig
- Instituto de Acuicultura Torre de la Sal, Consejo Superior de Investigaciones Científicas (IATS-CSIC), Ribera de Cabanes, 12595 Castellón, Spain
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Grzywa TM, Klicka K, Włodarski PK. Regulators at Every Step-How microRNAs Drive Tumor Cell Invasiveness and Metastasis. Cancers (Basel) 2020; 12:E3709. [PMID: 33321819 PMCID: PMC7763175 DOI: 10.3390/cancers12123709] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial-mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.
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Affiliation(s)
- Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Paweł K. Włodarski
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
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Sawant D, Lilly B. MicroRNA-145 targets in cancer and the cardiovascular system: evidence for common signaling pathways. VASCULAR BIOLOGY 2020; 2:R115-R128. [PMID: 33283158 PMCID: PMC7709916 DOI: 10.1530/vb-20-0012] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/01/2022]
Abstract
miRNAs are small regulatory RNAs which govern gene expression post-transcriptionally by primarily binding to the 3'-UTR of mRNA target genes. miR-145 is a well-studied miRNA that has been implicated in controlling a range of biological processes. miR-145 is expressed in a variety of tissues and cell types and acts as a tumor-suppressor by regulating target gene signaling pathways involved in different aspects of tumor growth and progression. There is also strong evidence that highlights the important functions of miR-145 in the cardiovascular system. Here, we review the mechanisms of miR-145 in tumorigenesis and cancer progression and compare and contrast with the roles of miR-145 in cardiovascular development and disease. We discuss the important targets of miR-145 in cancer and their possible link to the cardiovascular system.
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Affiliation(s)
- Dwitiya Sawant
- Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Brenda Lilly
- Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA.,Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
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Kandettu A, Radhakrishnan R, Chakrabarty S, Sriharikrishnaa S, Kabekkodu SP. The emerging role of miRNA clusters in breast cancer progression. Biochim Biophys Acta Rev Cancer 2020; 1874:188413. [PMID: 32827583 DOI: 10.1016/j.bbcan.2020.188413] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/01/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
Micro RNAs (miRNAs) are small non-coding RNAs that are essential for regulation of gene expression of the target genes. Large number of miRNAs are organized into defined units known as miRNA clusters (MCs). The MCs consist of two or more than two miRNA encoding genes driven by a single promoter, transcribed together in the same orientation, that are not separated from each other by a transcription unit. Aberrant miRNA clusters expression is reported in breast cancer (BC), exhibiting both pro-tumorogenic and anti-tumorigenic role. Altered MCs expression facilitates to breast carcinogenesis by promoting the breast cells to acquire the various hallmarks of the cancer. Since miRNA clusters contain multiple miRNA encoding genes, targeting cluster may be more attractive than targeting individual miRNAs. Besides targeting dysregulated miRNA clusters in BC, studies have focused on the mechanism of action, and its contribution to the progression of the BC. The present review provides a comprehensive overview of dysregulated miRNA clusters and its role in the acquisition of cancer hallmarks in BC. More specifically, we have presented the regulation, differential expression, classification, targets, mechanism of action, and signaling pathways of miRNA clusters in BC. Additionally, we have also discussed the potential utility of the miRNA cluster as a diagnostic and prognostic indicator in BC.
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Affiliation(s)
- Amoolya Kandettu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - S Sriharikrishnaa
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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Tao S, Ju X, Zhou H, Zeng Q. Circulating microRNA-145 as a diagnostic biomarker for non-small-cell lung cancer: A systemic review and meta-analysis. Int J Biol Markers 2020; 35:51-60. [PMID: 33103527 DOI: 10.1177/1724600820967124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs), a class of small non-coding, highly stable RNAs, have been reported to have diagnostic value for variety types of cancers. OBJECTIVES To assess the diagnostic value of circulating miR-145 for non-small cell lung cancer (NSCLC) by using systemic review and meta-analysis. METHODS A systematic literature search was conducted in five databases until 20 February 2020 to identify diagnostic trials of miR-145 in the diagnosis of NSCLC. The quality of included studies was assessed by the QUADAS-2 tool with Review Manager 5.3, and the summary receiver operating characteristic (SROC) curve was plotted by STATA 13.1 software. RESULTS A total of 1394 patients from 11 data sets in trials (published in nine studies) were recruited. The area under the curve of the SROC was 0.83. According to the meta regression, the specimen selection was considered the source of heterogeneity, the SROC in serum (0.90 (95% CI 0.87, 0.92), the sensitivity was 0.84 (95% CI 0.79, 0.89), and the specificity was 0.80 (95% CI 0.71, 0.89)) was obviously higher than that in plasma (SROC=0.75). CONCLUSION Serum miR-145 might be served as a potentially useful biomarker for NSCLC diagnosis. However, due to the existing limited-quality research, more large-scale and multicenter studies are required for further verification.
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Affiliation(s)
- Shaohua Tao
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital/Clinical College, Chengdu University, Chengdu, China
| | - Xuegui Ju
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Hui Zhou
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital/Clinical College, Chengdu University, Chengdu, China
| | - Qianglin Zeng
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital/Clinical College, Chengdu University, Chengdu, China
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Cao D, Zhu H, Zhao Q, Huang J, Zhou C, He J, Liang Y. MiR-128 suppresses metastatic capacity by targeting metadherin in breast cancer cells. Biol Res 2020; 53:43. [PMID: 32993809 PMCID: PMC7526227 DOI: 10.1186/s40659-020-00311-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 09/17/2020] [Indexed: 01/17/2023] Open
Abstract
Background Breast cancer, the most common cancer in women worldwide, causes the vast majority of cancer-related deaths. Undoubtedly, tumor metastasis and recurrence are responsible for more than 90 percent of these deaths. MicroRNAs are endogenous noncoding RNAs that have been integrated into almost all the physiological and pathological processes, including metastasis. In the present study, the role of miR-128 in breast cancer was investigated. Results Compared to the corresponding adjacent normal tissue, the expression of miR-128 was significantly suppressed in human breast cancer specimens. More importantly, its expression level was reversely correlated to histological grade of the cancer. Ectopic expression of miR-128 in the aggressive breast cancer cell line MDA-MB-231 could inhibit cell motility and invasive capacity remarkably. Afterwards, Metadherin (MTDH), also known as AEG-1 (Astrocyte Elevated Gene 1) and Lyric that implicated in various aspects of cancer progression and metastasis, was further identified as a direct target gene of miR-128 and its expression level was up-regulated in clinical samples as expected. Moreover, knockdown of MTDH in MDA-MB-231 cells obviously impaired the migration and invasion capabilities, whereas re-expression of MTDH abrogated the suppressive effect caused by miR-128. Conclusions Overall, these findings demonstrate that miR-128 could serve as a novel biomarker for breast cancer metastasis and a potent target for treatment in the future.
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Affiliation(s)
- Danxia Cao
- Comprehensive Breast Health Center, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Rui-Jin Er Road, Shanghai, 200025, China
| | - Han Zhu
- Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800, Gong-Wei Road, Shanghai, 201399, China
| | - Qian Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, No. 280, Chong-Qing South Road, Shanghai, 200025, China
| | - Jianming Huang
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800, Gong-Wei Road, Shanghai, 201399, China
| | - Cixiang Zhou
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, No. 280, Chong-Qing South Road, Shanghai, 200025, China
| | - Jianrong He
- Comprehensive Breast Health Center, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Rui-Jin Er Road, Shanghai, 200025, China.
| | - Yongjun Liang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800, Gong-Wei Road, Shanghai, 201399, China.
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Khalife H, Skafi N, Fayyad-Kazan M, Badran B. MicroRNAs in breast cancer: New maestros defining the melody. Cancer Genet 2020; 246-247:18-40. [PMID: 32805688 DOI: 10.1016/j.cancergen.2020.08.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/07/2020] [Accepted: 08/03/2020] [Indexed: 02/06/2023]
Abstract
MicroRNAs, short non-coding single-stranded RNAs, are important regulators and gatekeepers of the coding genes in the human genome. MicroRNAs are highly conserved among species and expressed in different tissues and cell types. They are involved in almost all the biological processes as apoptosis, proliferation, cell cycle arrest and differentiation. Playing all these roles, it is not surprising that the deregulation of the microRNA profile causes a number of diseases including cancer. Breast cancer, the most commonly diagnosed malignancy in women, accounts for the highest cancer-related deaths worldwide. Different microRNAs were shown to be up or down regulated in breast cancer. MicroRNAs can function as oncogenes or tumor suppressors according to their targets. In this review, the most common microRNAs implicated in breast cancer are fully illustrated with their targets. Besides, the review highlights the effect of exosomal microRNA on breast cancer and the effect of microRNAs on drug and therapies resistance as well as the miRNA-based therapeutic strategies used until today.
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Affiliation(s)
- Hoda Khalife
- Laboratory of Cancer biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut, Lebanon.
| | - Najwa Skafi
- Laboratory of Cancer biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut, Lebanon.
| | - Mohammad Fayyad-Kazan
- Laboratory of Cancer biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut, Lebanon; Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.
| | - Bassam Badran
- Laboratory of Cancer biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut, Lebanon.
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Li Y, Jiang B, He Z, Zhu H, He R, Fan S, Wu X, Xie L, He X. circIQCH sponges miR-145 to promote breast cancer progression by upregulating DNMT3A expression. Aging (Albany NY) 2020; 12:15532-15545. [PMID: 32756009 PMCID: PMC7467367 DOI: 10.18632/aging.103746] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/25/2020] [Indexed: 12/16/2022]
Abstract
As a unique type of RNA, circular RNAs (circRNAs) are important regulators of multiple biological processes in the progression of cancer. However, the potential role of most circRNAs in breast cancer lung metastasis is still unknown. In this study, we characterized and further investigated circIQCH (hsa_circ_0104345) by analyzing the circRNA microarray profiling in our previous study. circIQCH was upregulated in breast cancer tissues, especially in the metastatic sites. CCK-8, transwell, wound-healing and mouse xenograft assays were carried out to investigate the functions of circIQCH. Knockdown of circIQCH inhibited breast cancer cell proliferation and migration to lung. Moreover, luciferase reporter assays and RNA immunoprecipitation assays were performed to elucidate the underlying molecular mechanism of circIQCH. The results showed that circIQCH sponges miR-145 and promotes breast cancer progression by upregulating DNMT3A. In summary, our study demonstrated the pivotal role of circIQCH-miR-145-DNMT3A axis in breast cancer growth and metastasis via the mechanism of competing endogenous RNAs. Thus, circIQCH could be a potential therapeutic target for breast cancer.
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Affiliation(s)
- Yuehua Li
- Department of Medical Oncology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan Province, China
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Baohong Jiang
- Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan Province, China
| | - Zhengxi He
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Hongbo Zhu
- Department of Medical Oncology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan Province, China
| | - Rongfang He
- Department of Pathology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan Province, China
| | - Shanji Fan
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital, University of South China, Hengyang, 421001 Hunan Province, China
| | - Xiaoping Wu
- Department of Medical Oncology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan Province, China
| | - Liming Xie
- Department of Medical Oncology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan Province, China
| | - Xiusheng He
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
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43
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Wong JS, Cheah YK. Potential miRNAs for miRNA-Based Therapeutics in Breast Cancer. Noncoding RNA 2020; 6:E29. [PMID: 32668603 PMCID: PMC7549352 DOI: 10.3390/ncrna6030029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/04/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that can post-transcriptionally regulate the genes involved in critical cellular processes. The aberrant expressions of oncogenic or tumor suppressor miRNAs have been associated with cancer progression and malignancies. This resulted in the dysregulation of signaling pathways involved in cell proliferation, apoptosis and survival, metastasis, cancer recurrence and chemoresistance. In this review, we will first (i) provide an overview of the miRNA biogenesis pathways, and in vitro and in vivo models for research, (ii) summarize the most recent findings on the roles of microRNAs (miRNAs) that could potentially be used for miRNA-based therapy in the treatment of breast cancer and (iii) discuss the various therapeutic applications.
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Affiliation(s)
- Jun Sheng Wong
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Yoke Kqueen Cheah
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia
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Urdinez J, Boro A, Mazumdar A, Arlt MJ, Muff R, Botter SM, Bode-Lesniewska B, Fuchs B, Snedeker JG, Gvozdenovic A. The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1. J Bone Miner Res 2020; 35:1077-1091. [PMID: 32027760 DOI: 10.1002/jbmr.3976] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/17/2022]
Abstract
Chondrosarcoma is the second most frequent bone sarcoma. Due to the inherent chemotherapy and radiotherapy resistance and absence of known therapeutic targets, clinical management is limited to surgical resection. Consequently, patients with advanced disease face a poor prognosis. Hence, elucidating regulatory networks governing chondrosarcoma pathogenesis is vital for development of effective therapeutic strategies. Here, miRNA and mRNA next generation sequencing of different subtypes of human chondrogenic tumors in combination with in silico bioinformatics tools were performed with the aim to identify key molecular factors. We identified miR-143/145 cluster levels to inversely correlate with tumor grade. This deregulation was echoed in the miRNA plasma levels of patients and we provided the first evidence that circulating miR-145 is a potential noninvasive diagnostic biomarker and can be valuable as an indicator to improve the currently challenging diagnosis of cartilaginous bone tumors. Additionally, artificial upregulation of both miRNAs impelled a potent tumor suppressor effect in vitro and in vivo in an orthotopic xenograft mouse model. A combined in silico/sequencing approach revealed FSCN1 as a direct target of miR-143/145, and its depletion phenotypically resembled miR-143/145 upregulation in vitro. Last, FSCN1 is a malignancy-promoting factor associated with aggressive chondrosarcoma progression. Our findings underscore miR-143/145/FSCN1 as important players in chondrosarcoma and may potentially open new avenues for specific therapeutic intervention options. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Joaquin Urdinez
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Aleksandar Boro
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Alekhya Mazumdar
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Matthias Je Arlt
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Roman Muff
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Sander M Botter
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Beata Bode-Lesniewska
- Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Bruno Fuchs
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Jess G Snedeker
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Ana Gvozdenovic
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
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45
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Li Y, Luo JT, Liu YM, Wei WB. miRNA-145/miRNA-205 inhibits proliferation and invasion of uveal melanoma cells by targeting NPR1/CDC42. Int J Ophthalmol 2020; 13:718-724. [PMID: 32420217 DOI: 10.18240/ijo.2020.05.04] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 03/15/2020] [Indexed: 12/14/2022] Open
Abstract
AIM To investigate the role of microRNA-145 (miRNA-145) and microRNA-205 (miRNA-205) in proliferation and invasion of uveal melanoma (UM) cells. METHODS The expression level of miRNA-145 and miRNA-205 from samples of UM patients were determined by real-time polymerase chain reaction (RT-PCR). The growth and invasion inhibitory effects were observed by the transfection of UM cells with miRNA-145 and miRNA-205. Several epithelial-to-mesenchymal transition (EMT)-related proteins were screened by Western blotting. UM clinical samples from The Cancer Genome Atlas (TCGA) were applied to search for potential protein interaction. Pearson's correlation analysis was applied to estimate co-expression between genes. Dual-luciferase reporter assay was used to verify the binding sites on target protein for miRNA-145 and miRNA-205. RESULTS The expression levels of miRNA-145 and miRNA-205 in the samples from patients with UM were significantly lower than those in the normal tissue samples. Significant growth and invasion inhibitory effects were observed in human UM cells with miRNA-145 and miRNA-205 overexpression. The miRNA-145 and miRNA-205 could decrease the expression level of cell division control protein 42 (CDC42). After database searching and sequence alignment, we identified that Neuropilin 1 (NRP1) had binding sites for both miRNA-145 and miRNA-205. CONCLUSION The miRNA-145 and miRNA-205 can reduce the proliferation, migration and invasion of UM cells by targeting the mRNA of its upstream protein NRP1 to down-regulate the expression level of CDC42.
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Affiliation(s)
- Yang Li
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Jing-Ting Luo
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Yue-Ming Liu
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Wen-Bin Wei
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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46
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Zhao L, Liu Y, Liu Y, Zhang M, Zhang X. Microfluidic Control of Tumor and Stromal Cell Spheroids Pairing and Merging for Three-Dimensional Metastasis Study. Anal Chem 2020; 92:7638-7645. [PMID: 32374153 DOI: 10.1021/acs.analchem.0c00408] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Three-dimensional cell culture provides an efficient way to simulate the in vivo tumorigenic microenvironment where tumor-stroma interaction intrinsically plays a pivotal role. Conventional three-dimensional (3D) culture is inadequate to address precise coexistential heterogeneous pairing and quantitative measurement in a parallel algorithm format. Herein, we implemented a set of microwell array microfluidic devices to study the cell spheroids-based tumor-stromal metastatic process in vitro. This approach enables accurate one-to-one pairing between tumor and fibroblast spheroid for dissecting 3D tumor invasion in the manner of high-content imaging. On one single device, 240 addressable tumor-stroma pairings can be formed with convenient pipetting and centrifugation within a small area of 1 cm2. Consequential confocal imaging analysis disclosed that the tumor spheroid could envelop the fibroblast spheroid. Specific chemicals can effectively hamper or promote this 3D metastasis. Due to the addressable time-resolved measurements of the merging process of hundreds of doublets, our approach allows us to decipher the metastatic phenotype between different tumor spheroids. Compared with traditional protocols, massive heterogeneous cellular spheroids pairing and merging using this method is well-defined with microfluidic control, which leads to a favorable high-content tumor-stroma doublet metastasis analysis. This simple technique will be a useful tool for investigating heterotypic spheroid-spheroid interactions.
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Affiliation(s)
- Liang Zhao
- Institute of Precision Medicine and Health, Research Center for Bioengineering and Sensing Technology, Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China, 100083
| | - Yingying Liu
- Institute of Precision Medicine and Health, Research Center for Bioengineering and Sensing Technology, Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China, 100083
| | - Yang Liu
- Institute of Precision Medicine and Health, Research Center for Bioengineering and Sensing Technology, Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China, 100083
| | - Meiqin Zhang
- Institute of Precision Medicine and Health, Research Center for Bioengineering and Sensing Technology, Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China, 100083
| | - Xueji Zhang
- Institute of Precision Medicine and Health, Research Center for Bioengineering and Sensing Technology, Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China, 100083
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lncRNA AFAP1-AS1 promotes triple negative breast cancer cell proliferation and invasion via targeting miR-145 to regulate MTH1 expression. Sci Rep 2020; 10:7662. [PMID: 32376943 PMCID: PMC7203232 DOI: 10.1038/s41598-020-64713-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/20/2020] [Indexed: 12/13/2022] Open
Abstract
The actin fiber-associated protein 1-antisense RNA1 (AFAP1-AS1) is upregulated in various cancers and associated with cancer proliferation and metastasis. Several cancer-related pathways have been linked to up-expression of this long non-coding (lnc)RNA, but the underlying mechanisms are yet unknown. In triple negative breast cancer (TNBC), AFAP1-AS1 expression is also significantly overexpressed compared to that in other subtypes of breast cancer from the TCGA dataset. In this study, we performed bioinformatic RNAhybrid analyses and identified that miR-145 is a potential target of AFAP1-AS1 and able to reduce MutT homolog-1 (MTH1) expression. Thus, this study investigated the oncogenic activity of AFAP1-AS1 in TNBC cells and the underlying mechanisms that are yet poorly understood. The results showed that miR-145 expression was low, whereas AFAP1-AS1 and MTH1 expression was high in TNBC cells and that miR-145 mimics reduced TNBC cell proliferation and invasion, whereas miR-145 knockdown exerted the opposite activity in TNBC cells. Moreover, knockdown of AFAP1-AS1 reduced tumor cell proliferation and invasion, but miR-145 co-transfection rescued tumor cell viability and colony formation ability. The dual luciferase reporter assay showed that AFAP1-AS1 could directly target miR-145, while miR-145 could directly target MTH1. After knockdown of ATF6, AFAP1-AS1 was reduced along with AFAP1-AS1 promoter activity. This study revealed that AFAP1-AS1 could promote TNBC cell proliferation and invasion via regulation of MTH1 expression through targeting of miR-145.
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Li J, Zhang S, Zou Y, Wu L, Pei M, Jiang Y. miR-145 promotes miR-133b expression through c-myc and DNMT3A-mediated methylation in ovarian cancer cells. J Cell Physiol 2020; 235:4291-4301. [PMID: 31612498 DOI: 10.1002/jcp.29306] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 09/30/2019] [Indexed: 12/11/2022]
Abstract
Ovarian cancer presents as malignant tumors in the female reproductive system with high mortality. MicroRNAs are involved in the progression of ovarian cancer; however, the regulatory relationship among miRs remains unclear. In our study, we verified that both miR-145 and miR-133b messenger RNA (mRNA) levels in ovarian cancer tissues were lower than in normal ovarian tissues, and their mRNA level in serum of patients with ovarian cancer was reduced. We demonstrated miR-145 targeted c-myc, and c-myc interacted physically with DNMT3A in ovarian cancer cells. We confirmed that c-myc recruited DNMT3A to the miR-133b promoter. miR-133b overexpression also inhibited target gene PKM2 expression along with the Warburg effect. Our results indicate that miR-145 inhibited the Warburg effect through miR-133b/PKM2 pathways, which may improve approaches to ovarian cancer diagnosis and treatment.
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Affiliation(s)
- Jie Li
- Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Songlin Zhang
- Department of Structural Heart Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuliang Zou
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lei Wu
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Meili Pei
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yu Jiang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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49
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Reciprocal control of ADAM17/EGFR/Akt signaling and miR-145 drives GBM invasiveness. J Neurooncol 2020; 147:327-337. [PMID: 32170633 DOI: 10.1007/s11060-020-03453-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 03/07/2020] [Indexed: 01/04/2023]
Abstract
INTRODUCTION Glioblastoma multiforme (GBM) is one of the most devastating brain malignancies worldwide and is considered to be incurable. However, the mechanisms underlying its aggressiveness remain unclear. METHODS The expression of ADAM17 in tissue samples was detected by immunohistochemistry. Knockdown and rescue experiments were used to demonstrate the regulatory effect of ADAM17 on the invasion ability of GBM cells. Western Blot and qPCR were used to detect the expression of related proteins and RNAs. Moreover, a luciferase reporter assay was performed to verify whether miR-145 directly binds to the 3'-UTR of ADAM17. RESULTS We revealed that ADAM17 was overexpressed in GBM tissues and correlated positively with poor prognosis. The knockdown of ADAM17 obviously suppressed the invasiveness of GBM cell lines. Furthermore, we found that knockdown of ADAM17 decreased activation of EGFR/Akt/C/EBP-β signaling, and consequently upregulated miR-145 expression in GBM cell lines. Notably, miR-145 directly targeted the ADAM17 3'-UTR and suppressed expression levels of ADAM17. CONCLUSIONS Our findings define an ADAM17/EGFR/miR-145 feedback loop that drives the GBM invasion. Reciprocal regulation between ADAM17 and miR-145 results in aberrant activation of EGFR signaling, suggesting that inhibition of ADAM17 expression can be an ideal therapeutic strategy for the treatment of GBM.
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Niu C, Wang L, Ye W, Guo S, Bao X, Wang Y, Xia Z, Chen R, Liu C, Lin X, Huang X. CCAT2 contributes to hepatocellular carcinoma progression via inhibiting miR-145 maturation to induce MDM2 expression. J Cell Physiol 2020; 235:6307-6320. [PMID: 32037568 DOI: 10.1002/jcp.29630] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/30/2020] [Indexed: 12/19/2022]
Abstract
Long noncoding RNA colon cancer-associated transcript 2 (CCAT2) has been recently found to function as an oncogene in hepatocellular carcinoma (HCC). However, the mechanisms of CCAT2 in HCC development remain to be further explored. In the present study, we found that CCAT2 was abnormally upregulated in HCC cells and tissue specimens, exhibiting an inverse correlation with microRNA (miR)-145 expression. Mechanistic investigation showed that CCAT2 selectively blocked miR-145 processing, leading to decreased mature miR-145 presence. Both the in vitro and in vivo effects of CCAT2 knockdown on the proliferation and metastasis of HCC cells were reversed by miR-145 inhibitor, indicating that miR-145 modulation accounts for CCAT2-meditated HCC progression. Furthermore, miR-145 mimic dramatically suppressed HCC cells' proliferation and metastasis, revealing a tumor suppressor role of miR-145 in HCC. Mechanistically, MDM2 was predicted to be a potential target of miR-145. The luciferase and western blot assay demonstrated that miR-145 mimic largely inhibited MDM2 3'-untranslated region luciferase activity and MDM2 expression, followed by the upregulation of p53/p21 expression. Finally, the coexpression of MDM2 in miR-145 mimic-transfected HCC cells was able to largely compromise the inhibitory effects of miR-145 mimic on HCC cells' proliferation and metastasis in vitro and tumor formation in a xenograft model, confirming MDM2 is the critical mediator of miR-145 in HCC. In summary, our findings indicated that CCAT2 selectively blocks the miR-145 maturation process and plays an oncogene in HCC. Furthermore, a novel CCAT2/miR-145/MDM2 axis was revealed in HCC development and might provide a new target in the molecular treatment of HCC.
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Affiliation(s)
- Chao Niu
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Linlin Wang
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Weijian Ye
- Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shikun Guo
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaozhou Bao
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yongbiao Wang
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhaobo Xia
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Randong Chen
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chong Liu
- Department of Cardiology, The Central Hospital of Lishui City, Lishui, China
| | - Xiaokun Lin
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaozhong Huang
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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