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Yang Z, Niu R, Han J, Guo J, Lv Y. Hedgehog inhibitors exert anti-proliferation effects and synergistically interact with trastuzumab in HER2-positive gastric cancer models. Acta Oncol 2025; 64:715-728. [PMID: 40426308 DOI: 10.2340/1651-226x.2025.42219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 03/17/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND Gastric cancer (GC) remains a significant health concern with limited therapeutic options. While trastuzumab, a Human Epidermal Growth Factor Receptor 2 (HER2)-targeting antibody, has shown efficacy in HER2-positive GC, its therapeutic response is moderate. Hedgehog (Hh) signalling plays a critical role in the progression of GC. METHODS We evaluated the sensitivity of various GC cell lines to trastuzumab. The HER2-positive HGC-27 cell line was identified as the most sensitive. In addition, the effects of two Hedgehog inhibitors, vismodegib and cyclopamine, were assessed on cell growth by monitoring SMO expression. Both in vitro and in vivo assays were conducted to explore the combination of Hh inhibitors and trastuzumab. RESULTS Both vismodegib and cyclopamine exerted anti-proliferative effects, and synergistically enhanced the anti-tumour activity of trastuzumab in HER2-positive GC models. Mechanistically, Hh inhibitors inhibited the AKT/mTOR signalling pathway through Smoothened (SMO) depletion, contributing to their anti-growth effects. INTERPRETATION This study highlights the potential of combining Hh inhibitors with trastuzumab as a therapeutic strategy for HER2-positive GC by targeting the AKT/mTOR pathway.
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Affiliation(s)
- Zixin Yang
- The second department of Oncology, The Second Hospital of Hebei Medical University, Hebei, China
| | - Ren Niu
- The second department of Oncology, The Second Hospital of Hebei Medical University, Hebei, China
| | - Jinzhu Han
- The second department of Oncology, The Second Hospital of Hebei Medical University, Hebei, China
| | - Jie Guo
- The second department of Oncology, The Second Hospital of Hebei Medical University, Hebei, China
| | - Yingqian Lv
- The second department of Oncology, The Second Hospital of Hebei Medical University, Hebei, China.
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2
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Ji CF, Ji JF, Yu XB, Wang ZX. N‑methyladenosine reader YTHDF2‑mediated AC026691.1 degradation promotes gastric cancer cell proliferation, migration and M2 macrophage polarization. Mol Med Rep 2025; 31:120. [PMID: 40052573 PMCID: PMC11914866 DOI: 10.3892/mmr.2025.13485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 01/03/2025] [Indexed: 03/20/2025] Open
Abstract
The present study aimed to explore the effects of key N6‑methyladenosine (m6A)‑related long non‑coding RNAs (lncRNAs) on the malignant behavior and macrophage polarization of gastric cancer cells, and their preliminary mechanisms. Gastric cancer‑related lncRNA datasets were downloaded from The Cancer Genome Atlas database, and m6A‑related differentially expressed lncRNAs (DElncRNAs) were analyzed. Subsequently, Cox regression and lasso regression analyses were used to screen the m6A‑related DElncRNAs associated with the prognosis of patients with gastric cancer. Additionally, reverse transcription‑quantitative polymerase chain reaction (qPCR) was employed to detect the expression levels of m6A‑related lncRNAs in normal gastric epithelial cells (GES‑1) and human gastric cancer cells (AGS and MKN‑45). In addition, the methylation levels of lncRNAs were measured using a methylated RNA immunoprecipitation qPCR assay kit, and the interaction between m6A‑related lncRNAs and m6A‑related proteins was observed by RNA pull‑down assay. Subsequently, m6A‑related lncRNAs and proteins were knocked down separately or simultaneously in gastric cancer cell lines. Bioinformatics analysis revealed that m6A‑related AC026691.1 was significantly associated with the prognosis of patients with gastric cancer and had a potential binding site for YT521‑B homology domain family member 2 (YTHDF2). The RNA pull‑down assay indicated that YTHDF2 not only had binding sites with AC026691.1 but could also markedly promote the degradation of m6A‑related AC026691.1. Furthermore, AC026691.1 was lowly expressed in gastric cancer cells, whereas YTHDF2 was highly expressed. Knockdown of YTHDF2 inhibited the proliferation, migration and epithelial‑mesenchymal transition of gastric cancer cells, and reduced M2 macrophage polarization. By contrast, knocking down AC026691.1 showed the opposite trend. Knockdown of YTHDF2 and AC026691.1 further confirmed the stable impact of YTHDF2 on AC026691.1. In conclusion, the degradation of AC026691.1 modified by YTHDF2‑mediated m6A may promote gastric cancer cell proliferation, migration, epithelial‑mesenchymal transition and M2 macrophage polarization.
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Affiliation(s)
- Cong-Fei Ji
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu 226006, P.R. China
| | - Jin-Feng Ji
- Department of Integrative Chinese and Western Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu 226006, P.R. China
| | - Xiao-Bing Yu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhen-Xin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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3
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Li L, An Z, Lin C, Xu Q, Tang C. An update on regulation and function of G protein-coupled receptors in cancer: A promising strategy for cancer therapy. Biochim Biophys Acta Rev Cancer 2025; 1880:189266. [PMID: 39864470 DOI: 10.1016/j.bbcan.2025.189266] [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: 08/19/2024] [Revised: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 01/28/2025]
Abstract
G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that play a crucial role in signal transduction and cellular communication. GPCR proteins are involved in a wide range of physiological processes, including cell growth, migration, and survival. Dysregulation of GPCR protein expression has been implicated in the pathogenesis of various diseases, including cancer, and GPCR proteins have been shown to modulate these processes in various types of cancer, highlighting their importance as potential therapeutic targets. In this review, we summarize the expression regulation of GPCRs in cancer cells, update the various ways by which the abnormal expression of GPCR protein affects the behavior of tumor cells, and discuss the current research directions and potentially facing problems of strategies on GPCR-targeting therapy.
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Affiliation(s)
- Lin Li
- National Clinical Research Center for Child Health of Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; Department of Urology, Third Affiliated Hospital of Naval Medical University, Shanghai 201805, China
| | - Zihao An
- National Clinical Research Center for Child Health of Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Chao Lin
- Department of Neurosurgery, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Xu
- National Clinical Research Center for Child Health of Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Chao Tang
- National Clinical Research Center for Child Health of Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China.
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Mirzaei Z, Barati T, Ebrahimi A, Derakhshan SM, Khaniani MS. The role of mir-7-5p in cancer: function, prognosis, diagnosis, and therapeutic implications. Mol Biol Rep 2024; 52:12. [PMID: 39585455 DOI: 10.1007/s11033-024-10107-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024]
Abstract
One of the important and conserved microRNAs (miRNAs), miR-7-5p, is involved in several pathological mechanisms, including cell proliferation, apoptosis, migration, and metastasis. Dysregulation of this miRNA's expression is correlated with multiple diseases, especially cancer. Its role as a tumor suppressor has been demonstrated in various types of cancer, such as colorectal cancer, lung cancer, bladder cancer, breast cancer, and glioblastoma. Furthermore, several studies have highlighted the prognostic and diagnostic value of this miRNA, which could be valuable for the diagnosis and treatment of certain disorders. We present an overview of the latest findings regarding miR-7-5p's role in the development of cancer, its action mechanisms, and expression, based on in vivo, in vitro, and human research. Additionally, we discuss the function of miR-7-5p as a prognostic biomarker in cancer and explore its potential as a therapeutic target.
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Affiliation(s)
- Zohreh Mirzaei
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tahereh Barati
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Ebrahimi
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran
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5
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Kane E, Mak TC, Latreille M. MicroRNA-7 regulates endocrine progenitor delamination and endocrine cell mass in developing pancreatic islets. iScience 2024; 27:110332. [PMID: 39055950 PMCID: PMC11269303 DOI: 10.1016/j.isci.2024.110332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/28/2024] [Accepted: 06/18/2024] [Indexed: 07/28/2024] Open
Abstract
β-cell replenishment in patients with diabetes through cadaveric islet transplantation has been successful; however, it requires long-term immunosuppression and suitable islet donors are scarce. Stepwise in vitro differentiation of pluripotent stem cells into β-cells represents a viable alternative, but limitations in our current understanding of in vivo islet endocrine differentiation constrains its clinical use. Here, we show that microRNA-7 (miR-7) is highly expressed in embryonic pancreatic endocrine progenitors. Genetic deletion of the miR-7 gene family in endocrine progenitors leads to reduced islet endocrine cell mass, due to endocrine progenitors failing to delaminate from the epithelial plexus. This is associated with a reduction in neurogenin-3 levels and increased expression of Sry-box transcription factor 9. Further, we observe that a significant number of endocrine progenitors lacking miR-7 differentiate into ductal cells. Our study suggests that increasing miR-7 expression could improve efficiency of in vitro differentiation and augment stem cell-derived β-cell terminal maturity.
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Affiliation(s)
- Eva Kane
- MRC Laboratory of Medical Sciences, Du Cane Road, London W12 0NN, UK
| | - Tracy C.S. Mak
- MRC Laboratory of Medical Sciences, Du Cane Road, London W12 0NN, UK
| | - Mathieu Latreille
- MRC Laboratory of Medical Sciences, Du Cane Road, London W12 0NN, UK
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Tayanloo-Beik A, Eslami A, Sarvari M, Jalaeikhoo H, Rajaeinejad M, Nikandish M, Faridfar A, Rezaei-Tavirani M, Mafi AR, Larijani B, Arjmand B. Extracellular vesicles and cancer stem cells: a deadly duo in tumor progression. Oncol Rev 2024; 18:1411736. [PMID: 39091989 PMCID: PMC11291337 DOI: 10.3389/or.2024.1411736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/27/2024] [Indexed: 08/04/2024] Open
Abstract
The global incidence of cancer is increasing, with estimates suggesting that there will be 26 million new cases and 17 million deaths per year by 2030. Cancer stem cells (CSCs) and extracellular vesicles (EVs) are key to the resistance and advancement of cancer. They play a crucial role in tumor dynamics and resistance to therapy. CSCs, initially discovered in acute myeloid leukemia, are well-known for their involvement in tumor initiation, progression, and relapse, mostly because of their distinct characteristics, such as resistance to drugs and the ability to self-renew. EVs, which include exosomes, microvesicles, and apoptotic bodies, play a vital role in facilitating communication between cells within the tumor microenvironment (TME). They have a significant impact on cellular behaviors and contribute to genetic and epigenetic changes. This paper analyzes the mutually beneficial association between CSCs and EVs, emphasizing their role in promoting tumor spread and developing resistance mechanisms. This review aims to investigate the interaction between these entities in order to discover new approaches for attacking the complex machinery of cancer cells. It highlights the significance of CSCs and EVs as crucial targets in the advancement of novel cancer treatments, which helps stimulate additional research, promote progress in ideas for cancer treatment, and provide renewed optimism in the effort to reduce the burden of cancer.
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Affiliation(s)
- Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azin Eslami
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hasan Jalaeikhoo
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Mohsen Rajaeinejad
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
- Student Research Committee, Aja University of medical sciences, Tehran, Iran
| | - Mohsen Nikandish
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Ali Faridfar
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | | | - Ahmad Rezazadeh Mafi
- Department of Radiation Oncology, Imam Hossein Hospital, Shaheed Beheshti Medical University, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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7
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Sun QH, Kuang ZY, Zhu GH, Ni BY, Li J. Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers. World J Gastrointest Oncol 2024; 16:300-313. [PMID: 38425402 PMCID: PMC10900144 DOI: 10.4251/wjgo.v16.i2.300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/31/2023] [Accepted: 01/19/2024] [Indexed: 02/02/2024] Open
Abstract
MicroRNAs (miRNAs) have received much attention in the past decade as potential key epigenomic regulators of tumors and cancer stem cells (CSCs). The abnormal expression of miRNAs is responsible for different phenotypes of gastric cancer stem cells (GCSCs). Some specific miRNAs could be used as promising biomarkers and therapeutic targets for the identification of GCSCs. This review summarizes the coding process and biological functions of miRNAs and demonstrates their role and efficacy in gastric cancer (GC) metastasis, drug resistance, and apoptosis, especially in the regulatory mechanism of GCSCs. It shows that the overexpression of onco-miRNAs and silencing of tumor-suppressor miRNAs can play a role in promoting or inhibiting tumor metastasis, apart from the initial formation of GC. It also discusses the epigenetic regulation and potential clinical applications of miRNAs as well as the role of CSCs in the pathogenesis of GC. We believe that this review may help in designing novel therapeutic approaches for GC.
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Affiliation(s)
- Qian-Hui Sun
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Zi-Yu Kuang
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Guang-Hui Zhu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Bao-Yi Ni
- Department of Oncology, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Jie Li
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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8
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Zou Y, Yuan Y, Zhou Q, Yue Z, Liu J, Fan L, Xu H, Xin L. The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity. Biomolecules 2024; 14:161. [PMID: 38397398 PMCID: PMC10887009 DOI: 10.3390/biom14020161] [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: 12/09/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang 330006, China; (Y.Z.); (Y.Y.); (Q.Z.); (Z.Y.); (J.L.); (L.F.); (H.X.)
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9
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Akyüz N, Janjetovic S, Ghandili S, Bokemeyer C, Dierlamm J. EBV and 1q Gains Affect Gene and miRNA Expression in Burkitt Lymphoma. Viruses 2023; 15:1808. [PMID: 37766215 PMCID: PMC10537407 DOI: 10.3390/v15091808] [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: 07/18/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 09/29/2023] Open
Abstract
Abnormalities of the long arm of chromosome 1 (1q) represent the most frequent secondary chromosomal aberrations in Burkitt lymphoma (BL) and are observed almost exclusively in EBV-negative BL cell lines (BL-CLs). To verify chromosomal abnormalities, we cytogenetically investigated EBV-negative BL patient material, and to elucidate the 1q gain impact on gene expression, we performed qPCR with six 1q-resident genes and analyzed miRNA expression in BL-CLs. We observed 1q aberrations in the form of duplications, inverted duplications, isodicentric chromosome idic(1)(q10), and the accumulation of 1q12 breakpoints, and we assigned 1q21.2-q32 as a commonly gained region in EBV-negative BL patients. We detected MCL1, ARNT, MLLT11, PDBXIP1, and FCRL5, and 64 miRNAs, showing EBV- and 1q-gain-dependent dysregulation in BL-CLs. We observed MCL1, MLLT11, PDBXIP1, and 1q-resident miRNAs, hsa-miR-9, hsa-miR-9*, hsa-miR-92b, hsa-miR-181a, and hsa-miR-181b, showing copy-number-dependent upregulation in BL-CLs with 1q gains. MLLT11, hsa-miR-181a, hsa-miR-181b, and hsa-miR-183 showed exclusive 1q-gains-dependent and FCRL5, hsa-miR-21, hsa-miR-155, hsa-miR-155*, hsa-miR-221, and hsa-miR-222 showed exclusive EBV-dependent upregulation. We confirmed previous data, e.g., regarding the EBV dependence of hsa-miR-17-92 cluster members, and obtained detailed information considering 1q gains in EBV-negative and EBV-positive BL-CLs. Altogether, our data provide evidence for a non-random involvement of 1q gains in BL and contribute to enlightening and understanding the EBV-negative and EBV-positive BL pathogenesis.
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Affiliation(s)
| | | | | | | | - Judith Dierlamm
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Clinic Hamburg-Eppendorf, 20251 Hamburg, Germany; (N.A.); (S.J.); (S.G.); (C.B.)
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10
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Jing J, Wu Z, Wang J, Luo G, Lin H, Fan Y, Zhou C. Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies. Signal Transduct Target Ther 2023; 8:315. [PMID: 37596267 PMCID: PMC10439210 DOI: 10.1038/s41392-023-01559-5] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 07/05/2023] [Indexed: 08/20/2023] Open
Abstract
The past decade has seen significant advances in our understanding of Hedgehog (HH) signaling pathway in various biological events. HH signaling pathway exerts its biological effects through a complex signaling cascade involved with primary cilium. HH signaling pathway has important functions in embryonic development and tissue homeostasis. It plays a central role in the regulation of the proliferation and differentiation of adult stem cells. Importantly, it has become increasingly clear that HH signaling pathway is associated with increased cancer prevalence, malignant progression, poor prognosis and even increased mortality. Understanding the integrative nature of HH signaling pathway has opened up the potential for new therapeutic targets for cancer. A variety of drugs have been developed, including small molecule inhibitors, natural compounds, and long non-coding RNA (LncRNA), some of which are approved for clinical use. This review outlines recent discoveries of HH signaling in tissue homeostasis and cancer and discusses how these advances are paving the way for the development of new biologically based therapies for cancer. Furthermore, we address status quo and limitations of targeted therapies of HH signaling pathway. Insights from this review will help readers understand the function of HH signaling in homeostasis and cancer, as well as opportunities and challenges of therapeutic targets for cancer.
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Affiliation(s)
- Junjun Jing
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Zhuoxuan Wu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Jiahe Wang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Guowen Luo
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Hengyi Lin
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
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Saviana M, Le P, Micalo L, Del Valle-Morales D, Romano G, Acunzo M, Li H, Nana-Sinkam P. Crosstalk between miRNAs and DNA Methylation in Cancer. Genes (Basel) 2023; 14:1075. [PMID: 37239435 PMCID: PMC10217889 DOI: 10.3390/genes14051075] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
miRNAs are some of the most well-characterized regulators of gene expression. Integral to several physiological processes, their aberrant expression often drives the pathogenesis of both benign and malignant diseases. Similarly, DNA methylation represents an epigenetic modification influencing transcription and playing a critical role in silencing numerous genes. The silencing of tumor suppressor genes through DNA methylation has been reported in many types of cancer and is associated with tumor development and progression. A growing body of literature has described the crosstalk between DNA methylation and miRNAs as an additional layer in the regulation of gene expression. Methylation in miRNA promoter regions inhibits its transcription, while miRNAs can target transcripts and subsequently regulate the proteins responsible for DNA methylation. Such relationships between miRNA and DNA methylation serve an important regulatory role in several tumor types and highlight a novel avenue for potential therapeutic targets. In this review, we discuss the crosstalk between DNA methylation and miRNA expression in the pathogenesis of cancer and describe how miRNAs influence DNA methylation and, conversely, how methylation impacts the expression of miRNAs. Finally, we address how these epigenetic modifications may be leveraged as biomarkers in cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, 1250 E. Marshall Street, Richmond, VA 23298, USA
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An Update of G-Protein-Coupled Receptor Signaling and Its Deregulation in Gastric Carcinogenesis. Cancers (Basel) 2023; 15:cancers15030736. [PMID: 36765694 PMCID: PMC9913146 DOI: 10.3390/cancers15030736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/15/2023] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
G-protein-coupled receptors (GPCRs) belong to a cell surface receptor superfamily responding to a wide range of external signals. The binding of extracellular ligands to GPCRs activates a heterotrimeric G protein and triggers the production of numerous secondary messengers, which transduce the extracellular signals into cellular responses. GPCR signaling is crucial and imperative for maintaining normal tissue homeostasis. High-throughput sequencing analyses revealed the occurrence of the genetic aberrations of GPCRs and G proteins in multiple malignancies. The altered GPCRs/G proteins serve as valuable biomarkers for early diagnosis, prognostic prediction, and pharmacological targets. Furthermore, the dysregulation of GPCR signaling contributes to tumor initiation and development. In this review, we have summarized the research progress of GPCRs and highlighted their mechanisms in gastric cancer (GC). The aberrant activation of GPCRs promotes GC cell proliferation and metastasis, remodels the tumor microenvironment, and boosts immune escape. Through deep investigation, novel therapeutic strategies for targeting GPCR activation have been developed, and the final aim is to eliminate GPCR-driven gastric carcinogenesis.
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13
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Liang L, Xu WY, Shen A, Cen HY, Chen ZJ, Tan L, Zhang LM, Zhang Y, Fu JJ, Qin AP, Lei XP, Li SP, Qin YY, Huang JH, Yu XY. Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9. Acta Pharmacol Sin 2022; 43:2946-2955. [PMID: 35388129 PMCID: PMC9622742 DOI: 10.1038/s41401-022-00893-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 02/21/2022] [Indexed: 01/27/2023]
Abstract
Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 (MAP3K9) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9. This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications.
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Affiliation(s)
- Lu Liang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Wen-Yan Xu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Ao Shen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Hui-Yu Cen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhi-Jun Chen
- Department of Medical Imaging, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Lin Tan
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Ling-Min Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yu Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Ji-Jun Fu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Ai-Ping Qin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xue-Ping Lei
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Song-Pei Li
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yu-Yan Qin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Jiong-Hua Huang
- Department of Cardiovascular Disease, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China.
| | - Xi-Yong Yu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
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LINC02389/miR-7-5p Regulated Cisplatin Resistance of Non-Small-Cell Lung Cancer via Promoting Oxidative Stress. Anal Cell Pathol (Amst) 2022; 2022:6100176. [PMID: 36311891 PMCID: PMC9605833 DOI: 10.1155/2022/6100176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 09/03/2022] [Accepted: 09/17/2022] [Indexed: 11/17/2022] Open
Abstract
Background Non-small-cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and cisplatin-based chemotherapy is the main treatment for NSCLC. However, cisplatin resistance of NSCLC cells is a major challenge for NSCLC treatment. Materials and Methods qRT-PCR and Western blot were performed to detect the expression of LINC02389 and miR-7-5p in NSCLC tissues and cell lines. Cell counting kit-8 (CCK-8) assay and flow cytometry assay were applied to exam cell proliferation and apoptosis rate of NSCLC cells. The interaction between LINC02389 and miR-7-5p was verified by dual luciferase reporter gene assay, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay. Additionally, cisplatin-resistant NSCLC cells were generated to assess the biological function of LINC02389 and miR-7-5p in cisplatin resistance of NSCLC. Results LINC02389 was highly expressed in NSCLC tissues and was correlated with poor prognosis of NSCLC patients. Knockdown of LINC02389 inhibited cell proliferation and promoted cell apoptosis of NSCLC, whereas miR-7-5p knockdown exerted the opposite effects. Moreover, LINC02389 negatively regulated the expression of miR-7-5p. In addition, LINC02389 was overexpressed, yet miR-7-5p was downregulated in cisplatin-resistant NSCLC cells compared with their parental cells. Moreover, oxidative stress biomarkers were overexpressed in cisplatin-resistant cells and were regulated by LINC02389. Besides, LINC02389 could reverse the inhibitory effect of cisplatin on NSCLC cells, which was partially reversed by attenuating the expression of miR-7-5p. Conclusion Our research firstly demonstrated that lncRNA LINC02389 acted as an oncogene to promote progression, oxidative stress, and cisplatin resistance through sponging miR-7-5p and may provide therapeutic targets for NSCLC.
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Yang Y, Meng WJ, Wang ZQ. The origin of gastric cancer stem cells and their effects on gastric cancer: Novel therapeutic targets for gastric cancer. Front Oncol 2022; 12:960539. [PMID: 36185219 PMCID: PMC9520244 DOI: 10.3389/fonc.2022.960539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/30/2022] [Indexed: 11/25/2022] Open
Abstract
Gastric cancer (GC) is one of the most prevalent malignancies and the most common causes of cancer-related mortality worldwide. Furthermore, the prognosis of advanced GC remains poor even after surgery combined with chemoradiotherapy. As a small group of cells with unlimited differentiation and self-renewal ability in GC, accumulating evidence shows that GC stem cells (GCSCs) are closely associated with the refractory characteristics of GC, such as drug resistance, recurrence, and metastasis. With the extensive development of research on GCSCs, GCSCs seem to be promising therapeutic targets for GC. However, the relationship between GCSCs and GC is profound and intricate, and its mechanism of action is still under exploration. In this review, we elaborate on the source and key concepts of GCSCs, systematically summarize the role of GCSCs in GC and their underlying mechanisms. Finally, we review the latest information available on the treatment of GC by targeting GCSCs. Thus, this article may provide a theoretical basis for the future development of the novel targets based on GCSCs for the treatment of GC.
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16
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Rao X, Zhang C, Luo H, Zhang J, Zhuang Z, Liang Z, Wu X. Targeting Gastric Cancer Stem Cells to Enhance Treatment Response. Cells 2022; 11:cells11182828. [PMID: 36139403 PMCID: PMC9496718 DOI: 10.3390/cells11182828] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer stem cell theory defines cancer stem cells (CSCs) as a key factor in the metastasis, recurrence, and chemotherapy resistance of cancer. It considers targeting gastric cancer stem cells (GCSCs) to be an effective method for the treatment of GC. For GCSCs, genes or noncoding RNAs are important regulatory factors. Many experimental studies have found that some drugs can target the stemness of gastric cancer by regulating these genes or noncoding RNAs, which may bring new directions for the clinical treatment of gastric cancer. Therefore, this review mainly discusses related genes or noncoding RNAs in GCSCs and drugs that target its stemness, thereby providing some information for the treatment of GC.
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17
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HajiEsmailPoor Z, Tabnak P, Ahmadzadeh B, Ebrahimi SS, Faal B, Mashatan N. Role of hedgehog signaling related non-coding RNAs in developmental and pathological conditions. Biomed Pharmacother 2022; 153:113507. [DOI: 10.1016/j.biopha.2022.113507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/23/2022] [Accepted: 07/30/2022] [Indexed: 11/02/2022] Open
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18
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Han X, Li B. The emerging role of noncoding RNAs in the Hedgehog signaling pathway in cancer. Biomed Pharmacother 2022; 154:113581. [PMID: 36037783 DOI: 10.1016/j.biopha.2022.113581] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Hedgehog (HH), a conserved signaling pathway, is involved in embryo development, organogenesis, and other biological functions. Dysregulation and abnormal activation of HH are involved in tumorigenesis and tumor progression. With the emergence of interest in noncoding RNAs, studies on their involvement in abnormal regulation of biological processes in tumors have been published one after another. In this review, we focus on the crosstalk between noncoding RNAs and the HH pathway in tumors and elaborate the mechanisms by which long noncoding RNAs and microRNAs regulate or are regulated by HH signaling in cancer. We also discuss the interaction between noncoding RNAs and the HH pathway from the perspective of cancer hallmarks, presenting this complex network as concisely as possible and organizing ideas for cancer diagnosis and treatment.
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Affiliation(s)
- Xue Han
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, China
| | - Bo Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, China. libo--
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19
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Song J, Ge Y, Sun X, Guan Q, Gong S, Wei M, Niu J, Zhao L. Noncoding RNAs related to the hedgehog pathway in cancer: clinical implications and future perspectives. Mol Cancer 2022; 21:115. [PMID: 35581586 PMCID: PMC9112456 DOI: 10.1186/s12943-022-01591-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/10/2022] [Indexed: 12/27/2022] Open
Abstract
Cancer is a type of malignant affliction threatening human health worldwide; however, the molecular mechanism of cancer pathogenesis remains to be elusive. The oncogenic hedgehog (Hh) pathway is a highly evolutionarily conserved signaling pathway in which the hedgehog-Patched complex is internalized to cellular lysosomes for degradation, resulting in the release of Smoothened inhibition and producing downstream intracellular signals. Noncoding RNAs (ncRNAs) with diversified regulatory functions have the potency of controlling cellular processes. Compelling evidence reveals that Hh pathway, ncRNAs, or their crosstalk play complicated roles in the initiation, metastasis, apoptosis and drug resistance of cancer, allowing ncRNAs related to the Hh pathway to serve as clinical biomarkers for targeted cancer therapy. In this review, we attempt to depict the multiple patterns of ncRNAs in the progression of malignant tumors via interactions with the Hh crucial elements in order to better understand the complex regulatory mechanism, and focus on Hh associated ncRNA therapeutics aimed at boosting their application in the clinical setting.
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Affiliation(s)
- Jia Song
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China
| | - Yuexin Ge
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China
| | - Xiaoyu Sun
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China
| | - Qiutong Guan
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China
| | - Shiqiang Gong
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China.,Shenyang Kangwei Medical Laboratory Analysis Co. LTD, Shenyang, 110000, People's Republic of China
| | - Jumin Niu
- Department of Gynecology, Shenyang Women's and Children's Hospital, Shenyang, 110011, People's Republic of China.
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China. .,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China.
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20
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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21
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Liu C, Wang JL, Wu DZ, Yuan YW, Xin L. Methionine restriction enhances the chemotherapeutic sensitivity of colorectal cancer stem cells by miR-320d/c-Myc axis. Mol Cell Biochem 2022; 477:2001-2013. [PMID: 35394639 DOI: 10.1007/s11010-022-04416-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 03/16/2022] [Indexed: 11/25/2022]
Abstract
Chemotherapy resistance of colorectal cancer stem cells (CRC-SCs) has become a major challenge in clinical treatment of cancer. Methionine restriction (MR) enhances the therapeutic effect of chemotherapeutic agents. The aim of this study was to explore the molecular pathways that MR affects the chemotherapeutic sensitivity of CRC-SCs. CD133+ and CD133- SW480 or SW620 cells were isolated by magnetic-activated cell sorting (MACS). Mouse xenograft tumor model was established by subcutaneous inoculation of CD133+ SW480. MTT assay was used to detect cell viability. Phase distribution of cell cycle was detected by flow cytometry. Western blotting was used to detect drug-resistant related protein expression. miR-320d and transcription factor c-Myc expressions were detected by qRT-PCR. The interaction between miR-320d and c-Myc was verified by luciferase assay. CD133+ SW480 and SW620 cells were more resistant to 5-fluorouracil (5-FU) than CD133- cells. In vitro and in vivo experiments showed that 5-FU and MR combined therapy further inhibited CD133+ cell activity and ATP binding cassette subfamily G member 2 (ABCG2) expression, and reduced tumor volume compared with drug administration alone. Interference with miR-320d or overexpression of c-Myc reversed the increased chemotherapeutic sensitivity of CRC-SCs induced by synergistic therapy with 5-FU and MR. miR-320d can target and regulate c-Myc. Interference with c-Myc could reverse the increase in cell viability and ABCG2 expression caused by down-regulation of miR-320d. In conclusion, the combined chemotherapy with MR can enhance the chemotherapeutic sensitivity of CRC-SCs by up-regulation of miR-320d to inhibit c-Myc expression, which lays a molecular basis for MR regulation of chemotherapeutic sensitivity of CRC-SCs.
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Affiliation(s)
- Chuan Liu
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Jin-Liang Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Deng-Zhong Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Yi-Wu Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China.
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22
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Wang C, Tang Z, Zhang Z, Liu T, Zhang J, Huang H, Li Y. MiR-7-5p suppresses invasion via downregulation of the autophagy-related gene ATG7 and increases chemoresistance to cisplatin in BCa. Bioengineered 2022; 13:7328-7339. [PMID: 35300572 PMCID: PMC9278970 DOI: 10.1080/21655979.2022.2037323] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/15/2022] Open
Abstract
Bladder cancer (BCa) is one of the most common cancers in men and is a major threat to the lives and health of older men. Many studies have shown that miR-7, as an important tumor suppressor gene, could directly inhibit some pathways involved in the development of cancer. MiR-7-5p, which was assessed in this study, consists of one arm of miR-7 and acts as a cancer suppressor gene in multiple cancer types. Autophagy, as a common biological process, plays dual roles in the process of cancer. Chemotherapy resistance is a problem in the treatment of BCa. In this study, the data showed that miR-7-5p was obviously down-regulated in BCa tissues and cells compared to their respective controls. In addition, miR-7-5p mimic effectively inhibited migration, invasion and autophagy both in vitro and in vivo. In the mechanistic study, miR-7-5p targeted autophagy-related gene ATG7 to inhibit its expression, which in turn inhibited autophagy. Finally, the migration of BCa cells was inhibited, and chemosensitivity was improved. Overall, our results provide evidence of the role of miR-7-5p as a cancer suppressor gene in BCa and provide new opportunities for the treatment of BCa.
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Affiliation(s)
- Chong Wang
- Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding Rna Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, People’s Republic of China
| | - Zhao Tang
- Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Ze Zhang
- Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding Rna Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, People’s Republic of China
| | - Tiantian Liu
- Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding Rna Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, People’s Republic of China
| | - Jingwei Zhang
- Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Houbao Huang
- Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Yawei Li
- CONTACT Yawei Li Department of Urology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
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Integrated Analysis of miR-7-5p-Related ceRNA Network Reveals Potential Biomarkers for the Clinical Outcome of Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:8204818. [PMID: 35466319 PMCID: PMC9023173 DOI: 10.1155/2022/8204818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/22/2022] [Accepted: 01/27/2022] [Indexed: 11/17/2022]
Abstract
Gastric cancer (GC) is the second leading cause of tumor-associated death and the fourth most commonly seen tumor across the world. Abnormal ncRNAs have been verified to be involved in potential metastasis via modulating epithelial-to-mesenchymal transition progression and are vital for the progression of cancers. Tumor-infiltrating immune cells (TICs) are a vital indicator of whether cancer patients will benefit from immunotherapy. Nonetheless, the association between ceRNAs and immune cells remained largely unclear. We used the ceRNA network combined with TICs for the prediction of the clinical outcome of GC patients based on TCGA datasets. The percentage of immunocytes in GC was speculated by the use of CIBERSORT. Via Lasso and multivariate assays, prognostic models were established applying survival-related genes and immune cells. Nomograms were developed, and the accuracy of the nomograms was determined using calibration curves. The association between ceRNAs and TICs was validated by the use of integration analysis. In this study, there were 2219 mRNAs (1308 increased and 911 decreased), 171 lncRNAs (51 decreased and 120 increased), and 123 miRNAs (55 decreased and 68 increased) differentially expressed between tumor groups and nontumor groups. Five lncRNAs, six miRNAs, and 64 mRNAs were used for ceRNA network construction. Eight genes including LOX, SPARC, MASTL, PI15, BMPR1B, ANKRD13B, PVT1, and miR-7-5p were applied for the development of the prognostic model. Survival assays suggested that tumor cases with high risk exhibited a shorter overall survival. In addition, we included T-cell CD4 memory activated, monocytes, and neutrophils for the development of a prognosis model. Eventually, our team demonstrated the possible associations between the ceRNA prognosis model and prognostic model based on immune cells. To sum up, the ceRNA network could be used for gene regulation and predict clinical outcomes of GC patients.
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Cheng M, Zhan X, Xu Y, Wang S, Zhang H, Fang L, Jin H, Chen W. DNA methylation of RNA-binding protein for multiple splicing 2 functions as diagnosis biomarker in gastric cancer pathogenesis and its potential clinical significance. Bioengineered 2022; 13:4347-4360. [PMID: 35137653 PMCID: PMC8973754 DOI: 10.1080/21655979.2022.2032965] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Higher methylation levels of RNA-binding protein for multiple splicing 2 (RBPMS2) was reported to be related with unfavorable outcome in gastric cancer (GC). However, molecular function and diagnostic significance of DNA methylation of RBPMS2 remains indistinct. Here we aimed to whether DNA methylation of RBPMS2 acts as a diagnosis biomarker in GC pathogenesis and its potential clinical significance. Western blot and immunochemistry assays were carried out to explore the level of RBPMS2. GC malignancy behaviors were determined by cell counting kit-8, Transwell, flow cytometry analysis and terminal-deoxynucleoitidyl transferase mediated nick end labeling staining. The inflammatory cell infiltration in xenograft model was observed by hematoxylin and eosin staining. CpG Islands was predicted by MethPrimer and the DNA methylation of RBPMS2 was evaluated by methylation-specific polymerase chain reaction. The results showed that RBPMS2 was downregulated in GC specimens. Poor survival rates were associated with low RBPMS2 expression. Overexpression of RBPMS2 inhibited GC growth while facilitated apoptosis in GC cells. In addition, level of DNA methylation of RBPMS2 in GC tissues was increased and DNA methylation of RBPMS2 was strongly associated with tumor invasion, Borrmann classification and TNM stage. We also observed that DNA methylation inhibitors counteracted the role of RBPMS2 in restraining GC development and tumorigenesis. To sum, our data demonstrated that DNA methylation of RBPMS2 was responsible for its downregulation in GC and promoted tumor progression, indicating DNA methylation of RBPMS2 might serve as a valuable potential parameter in GC pathogenesis.
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Affiliation(s)
- Ming Cheng
- Department of Gastroenterology, Zhejiang Jinhua Guangfu Tumor Hospital, Jinhua, Zhejiang, China
| | - Xiaoan Zhan
- Department of Gastrointestinal Surgery, Zhejiang Jinhua Guangfu Tumor Hospital, Jinhua, Zhejiang, China
| | - Yi Xu
- Department of Gastroenterology, Zhejiang Jinhua Guangfu Tumor Hospital, Jinhua, Zhejiang, China
| | - Saishan Wang
- Department of Gastroenterology, Zhejiang Jinhua Guangfu Tumor Hospital, Jinhua, Zhejiang, China
| | - Hongcheng Zhang
- Department of Gastroenterology, Zhejiang Jinhua Guangfu Tumor Hospital, Jinhua, Zhejiang, China
| | - Limin Fang
- Department of Gastroenterology, Zhejiang Jinhua Guangfu Tumor Hospital, Jinhua, Zhejiang, China
| | - Hao Jin
- Department of Gastroenterology, Zhejiang Jinhua Guangfu Tumor Hospital, Jinhua, Zhejiang, China
| | - Wei Chen
- Department of Cardiology, Jinhua Fifth Hospital, Jinhua, Zhejiang, China
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Dastmalchi N, Safaralizadeh R, Teimourian S. An updated review of the contribution of noncoding RNAs to the progression of gastric cancer stem cells: Molecular mechanisms of viability, invasion, and chemoresistance of gastric cancer stem cells. Curr Stem Cell Res Ther 2022; 17:440-445. [PMID: 35081895 DOI: 10.2174/1574888x17666220126143302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/07/2021] [Accepted: 11/29/2021] [Indexed: 11/22/2022]
Abstract
Gastric cancer (GC) is a leading cause of death and cancer mortality in the world, with poor survival for cases with higher stages of GC. During the past decade, GC stem cells (GCSCs) - a group of cancer cells- have been the focus of numerous cancer researches. GCSCs have the capability of self-renewal and are identified to be participated in GC development, invasion, chemoresistance, and tumor relapse. Research projects have indicated the main activities of noncoding RNAs in cellular pathways. Micro (mi)RNAs and lncRNAs play important functions in the modulation of different cellular pathways in the post-transcriptional form, through their dysregulated expression in several cancers, including GC. In this paper, we highlight the impact of dysregulated expression of micro-and lncRNAs and their downstream transcripts on GCSCs. Data collection about the progression of GCSCs may be beneficial for the introduction of new insights to the GC treatment.
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Affiliation(s)
- Narges Dastmalchi
- Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Safaralizadeh
- Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran
| | - Shahram Teimourian
- Department of Medical Genetics, Iran University of Medical Sciences (IUMS), Tehran, Iran
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Zhang W, Wang B, Lin Y, Yang Y, Zhang Z, Wang Q, Zhang H, Jiang K, Ye Y, Wang S, Shen Z. hsa_circ_0000231 Promotes colorectal cancer cell growth through upregulation of CCND2 by IGF2BP3/miR-375 dual pathway. Cancer Cell Int 2022; 22:27. [PMID: 35033075 PMCID: PMC8760675 DOI: 10.1186/s12935-022-02455-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 01/04/2022] [Indexed: 12/15/2022] Open
Abstract
Background Circular RNAs (circRNAs) have emerged as vital regulators of the initiation and progression of diverse kinds of human cancers. In this study, we explored the role of hsa_circ_0000231 and its downstream pathway in CRC. Methods The expression profile of circRNAs in 5 pairs of CRC tissues and adjacent normal tissues were analyzed by Microarray. Quantitative real-time PCR and in situ hybridization and Base Scope Assay were used to determine the level and prognostic values of hsa_circ_0000231. Then, functional experiments in vitro and in vivo were performed to investigate the effects of hsa_circ_0000231 on cell proliferation. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between hsa_circ_0000231 and IGF2BP3 or has_miR-375. Results We acquired data through circRNA microarray profiles, showing that the expression of hsa_circ_0000231 was upregulated in CRC primary tissues compared to adjacent normal tissues, which was indicated poor prognosis of patients with CRC. Functional analysis indicated that inhibition of hsa_circ_0000231 in CRC cell lines could suppress CRC cell proliferation as well as tumorigenesis in vitro and in vivo. The mechanistic analysis showed that hsa_circ_0000231 might, on the one hand, act as a competing endogenous RNA of miR-375 to promote cyclin D2 (CCND2) and, on the other hand, bind to the IGF2BP3 protein to prevent CCND2 degradation. Conclusions The findings suggested that hsa_circ_0000231 facilitated CRC progression by sponging miR-375 or binding to IGF2BP3 to modulate CCND2, implying that hsa_circ_0000231 might be a potential new diagnostic and therapeutic biomarker of CRC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02455-8.
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Affiliation(s)
- Wei Zhang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Bo Wang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Yilin Lin
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Yang Yang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Zhen Zhang
- Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Quan Wang
- Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Haoran Zhang
- Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Kewei Jiang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China
| | - Yingjiang Ye
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China
| | - Shan Wang
- Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China
| | - Zhanlong Shen
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China. .,Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, People's Republic of China. .,Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Xizhimen South Street, Xicheng, Beijing, 100044, People's Republic of China.
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Xin L, Lu H, Liu C, Zeng F, Yuan YW, Wu Y, Wang JL, Wu DZ, Zhou LQ. Methionine deficiency promoted mitophagy via lncRNA PVT1-mediated promoter demethylation of BNIP3 in gastric cancer. Int J Biochem Cell Biol 2021; 141:106100. [PMID: 34678458 DOI: 10.1016/j.biocel.2021.106100] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND The occurrence of recurrence and metastasis after treatment is a major challenge in the treatment of gastric cancer. This study was based on the methionine (Met)-dependent characteristics of gastric cancer cells to explore the effect of Met deficiency on the occurrence and development of gastric cancer. METHODS Human gastric cancer cell lines MKN45 and AGS and nude mice model were used to explore how Met affects gastric cancer by regulating lncRNA PVT1. RESULTS The levels of lncRNA PVT1 in gastric cancer cells and human gastric cancer xenografts of nude mice were down-regulated under the condition of Met deficiency. The cell viability and cell proliferation were declined after MKN45 and SGC-790 cells were cultured in Met-deficient medium. LncRNA PVT1 could affect BNIP3 promoter DNA methylation level through its interaction with DNMT1. Moreover, the silence of lncRNA PVT1 and the up-regulation of BNIP3 level inhibited the gastric cancer cell proliferation. Met deficiency could up-regulate BNIP3 expression by inhibiting the binding of lncRNA PVT1 to DNMT1, and activate mitophagy, thus inhibiting gastric cancer cell proliferation. CONCLUSION Our study suggested that Met deficiency could down-regulate the expression of lncRNA PVT1, further demethylated the promoter of BNIP3, thus inhibiting the proliferation of gastric cancer cells by activating mitophagy.
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Affiliation(s)
- Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China.
| | - Hao Lu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Chuan Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Fei Zeng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yi-Wu Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - You Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jin-Liang Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Deng-Zhong Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Li-Qiang Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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Tu W, Hong Y, Huang M, Chen M, Gan H. Effect of kaempferol on hedgehog signaling pathway in rats with --chronic atrophic gastritis - Based on network pharmacological screening and experimental verification. Biomed Pharmacother 2021; 145:112451. [PMID: 34839256 DOI: 10.1016/j.biopha.2021.112451] [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: 09/10/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The effect of active ingredients of Chaishaoliujun Decoction (CD) on chronic atrophic gastritis (CAG) was screened by network pharmacological method and verified by preliminary experiment. METHODS Firstly, the active ingredients and drug targets of CD were retrieved in TCMSP database; CAG-related targets from PharmGkb, OMIM, GeneCards and DrugBank databases were collected as well. Secondly, the drug targets and disease targets were mapped to obtain the intersection targets. PPI network and active ingredient-common target network were constructed for the intersection targets obtained and KEGG enrichment analysis was also carried out. Finally, the core active ingredient (kaempferol), effective targets (IL-1β、IL-6) and hedgehog signaling pathway were verified by animal experiments. RESULTS There were 137 active ingredients, 243 potential target so and 48 intersection targets with CAG in CD. 147 KEGG enrichment pathways were obtained, mainly involving JAK/STAT signaling pathway, PI3K/Akt signaling pathway, hedgehog signaling pathway, etc. The results of animal experiments showed: The content of IL-1β and IL-6 in model group was significantly increased compared with the normal group, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were also significantly decreased (P < 0.05); compared with model group, the content of IL-1β and IL-6 in the vitacoenzyme group, the CD group and the kaempferol group were significantly decreased, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were significantly increased (P < 0.05). CONCLUSION Kaempferol, the active ingredient of CD, could reduce the levels of IL-6 and IL-1β by regulating hedgehog signaling pathway so as to play a role in the treatment of CAG. Hence this paper could provide the methodological basis and theoretical basis for further revealing the pharmacological mechanism of CD.
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Affiliation(s)
- Wenling Tu
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Yinjie Hong
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Miaoan Huang
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Meimei Chen
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Huijuan Gan
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
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Wang LL, Zhu XL, Han SH, Xu L. Hypoxia Upregulates NOTCH3 Signaling Pathway to Promote Endothelial-Mesenchymal Transition in Pulmonary Artery Endothelial Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:1525619. [PMID: 34868328 PMCID: PMC8639273 DOI: 10.1155/2021/1525619] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/14/2021] [Accepted: 10/22/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND To investigate the effect of hypoxia on pulmonary artery endothelial cells and the role of NOTCH3 in endothelial-mesenchymal transition (EnMT) and to provide a research model for pulmonary disease and explain the pathogenesis of the pulmonary disease. METHODS Pulmonary artery endothelial cells were divided into two groups and cultured in normoxic and hypoxic environments, respectively. QPCR, western blot, and immunofluorescence were used to detect endothelial cell-specific marker protein and mRNA expression in each group, and the ability of endothelial cells migration was evaluated by scratch and transwell experiment. RESULTS The pulmonary artery endothelial cells in the normoxic group presented a typical pebble-like arrangement, and the endothelial cells in hypoxic culture showed a long spindle appearance. Hypoxia induced high expression of NOTCH3, Jagged-1, Hes1, c-Src, and CSL. Immunofluorescence showed that endothelial cells in hypoxic culture began to express the α-SMA, and the expression of vWF increased with hypoxia. Cell viability, scratch, and transwell results showed that endothelial cells in the hypoxic group were more capable of viability and migration than those in the normoxic group. The induction of EnMT by hypoxia can be inhibited by using notch3-specific inhibitor DAPT and Jagged-1. This study also found that miR-7-5p can regulate endothelial NOTCH3, indicating that miRNA is also involved in the process of endothelial-mesenchymal transformation. CONCLUSION Hypoxia promotes the transformation of endothelial cells into mesenchymal cells by opening the NOTCH3 pathway, which lays the foundation for disease progression or clinical prognosis, and is of great significance in the treatment of diseases.
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Affiliation(s)
- Li-Le Wang
- Department of Respiratory Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Xiao-Li Zhu
- Department of Respiratory Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Shu-Hua Han
- Department of Respiratory Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Lu Xu
- Department of Respiratory Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- School of Medicine, Southeast University, Nanjing 210009, China
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Ghafouri-Fard S, Hajiesmaeili M, Shoorei H, Bahroudi Z, Taheri M, Sharifi G. The Impact of lncRNAs and miRNAs in Regulation of Function of Cancer Stem Cells and Progression of Cancer. Front Cell Dev Biol 2021; 9:696820. [PMID: 34368145 PMCID: PMC8339916 DOI: 10.3389/fcell.2021.696820] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
Stem cells have two important features, namely the ability for self-renewal and the capacity to differentiate into some cell kinds with specialized functions. These two features are also present in cancer stem cells (CSCs). These cells have been detected in almost all kinds of cancers facilitating their tumorigenicity. Molecular cascades that control self-renewal of stem cells, namely the Wnt, Notch, and Hedgehog pathways have been suggested to influence CSCs functions as well. Moreover, non-coding RNAs can regulate function of CSCs. Function of miRNAs in the regulation of CSCs has been mostly assessed in breast cancer and hepatocellular carcinoma. miR-130a-3p, miR-600, miR-590-5p, miR-142-3p, miR-221, miR-222, miR-638, miR-375, miR-31, and miR-210 are among those regulating this feature in breast cancer. Moreover, miR-206, miR-192-5p, miR-500a-3p, miR-125, miR-125b, miR-613, miR-217, miR-194, and miR-494 regulate function of CSCs in hepatocellular carcinoma. DILC, lncTCF7, MUF, HAND2-AS1, MALAT1, DLX6-AS1, HOTAIR, and XIST are among lncRNAs that regulate function of CSCs. In the present paper, we explain the effects of these two classes of non-coding RNAs in the regulation of activity of CSCs.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Hajiesmaeili
- Critical Care Quality Improvement Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Zahra Bahroudi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Guive Sharifi
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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He J, Fu Y, Hu J, Chen J, Lou G. Hypomethylation-Mediated AGR2 Overexpression Facilitates Cell Proliferation, Migration, and Invasion of Lung Adenocarcinoma. Cancer Manag Res 2021; 13:5177-5185. [PMID: 34234561 PMCID: PMC8255649 DOI: 10.2147/cmar.s304869] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/04/2021] [Indexed: 12/25/2022] Open
Abstract
Objective Studies have indicated that AGR2 is crucial in many cancers. However, its methylation level in lung adenocarcinoma (LUAD) is rarely known. Hence, the effect of AGR2 methylation on LUAD was explored in the study. Methods qRT-PCR was adopted to detect the expression of AGR2 in LUAD cells and normal lung cells. Methylation-specific PCR (MSP) was used to detect the methylation of AGR2 promoter region in different cell lines. MTT, Transwell and wound healing assays were used to verify the progression of cells in each transfection group. Results The expression of AGR2 was significantly up-regulated in LUAD cells relative to that in normal cells. Moreover, the expression of AGR2 was inversely modulated by DNA methylation, and the hypomethylation of CpG islands would lead to the increased expression of AGR2. Finally, overexpression and hypomethylation of AGR2 facilitated the proliferation, invasion and migration of LUAD cells. Conclusion These results demonstrated that hypomethylation of AGR2 promoter region promoted the expression of AGR2 in LUAD cells, thus promoting the progression of LUAD cells.
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Affiliation(s)
- Junming He
- Department of Cardiothoracic Surgery, Yiwu Central Hospital, Yiwu, 322000, People's Republic of China
| | - Yin Fu
- Department of Cardiothoracic Surgery, Yiwu Central Hospital, Yiwu, 322000, People's Republic of China
| | - Jiangwei Hu
- Department of Cardiothoracic Surgery, Yiwu Central Hospital, Yiwu, 322000, People's Republic of China
| | - Jian Chen
- Department of Cardiothoracic Surgery, Yiwu Central Hospital, Yiwu, 322000, People's Republic of China
| | - Guoliang Lou
- Department of Cardiothoracic Surgery, Yiwu Central Hospital, Yiwu, 322000, People's Republic of China
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Weidle UH, Birzele F, Brinkmann U, Auslaender S. Gastric Cancer: Identification of microRNAs Inhibiting Druggable Targets and Mediating Efficacy in Preclinical In Vivo Models. Cancer Genomics Proteomics 2021; 18:497-514. [PMID: 34183383 DOI: 10.21873/cgp.20275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 01/06/2023] Open
Abstract
In addition to chemotherapy, targeted therapies have been approved for treatment of locally advanced and metastatic gastric cancer. The therapeutic benefit is significant but more durable responses and improvement of survival should be achieved. Therefore, the identification of new targets and new approaches for clinical treatment are of paramount importance. In this review, we searched the literature for down-regulated microRNAs which interfere with druggable targets and exhibit efficacy in preclinical in vivo efficacy models. As druggable targets, we selected transmembrane receptors, secreted factors and enzymes. We identified 38 microRNAs corresponding to the criteria as outlined. A total of 13 miRs target transmembrane receptors, nine inhibit secreted proteins and 16 attenuate enzymes. These microRNAs are targets for reconstitution therapy of gastric cancer. Further target validation experiments are mandatory for all of the identified microRNAs.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRed), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Simon Auslaender
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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Yoshida K, Yamamoto Y, Ochiya T. miRNA signaling networks in cancer stem cells. Regen Ther 2021; 17:1-7. [PMID: 33598508 PMCID: PMC7848775 DOI: 10.1016/j.reth.2021.01.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/06/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) are a small cell subpopulation in many cancer types and are involved in various processes of tumor progression, such as initiation, metastasis and recurrence. The distinguished features of CSCs include a variety of biological properties, including self-renewal, multidifferentiation, stemness marker expression, and resistance to chemotherapy and radiotherapy. Despite their great potential of clinical importance, the CSC signaling pathways are not well understood at the molecular level. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs that play an important role in the regulation of several cellular, physiological, and developmental processes. Aberrant miRNA expression is associated with many human diseases, including cancer. miRNAs have been implicated in the regulation of CSC properties; therefore, a better understanding of miRNA-induced modulation of CSC gene expression could aid in the identification of promising biomarkers and therapeutic targets. In the present review, we summarize the major findings of the impacts of miRNAs on CSC signaling networks; we then discuss the recent advances that have improved our understanding of CSC regulation by miRNA-mediated signaling networks and that may lead to the development of miRNA therapeutics specifically targeting CSCs.
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Affiliation(s)
- Kosuke Yoshida
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Yamamoto
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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Jiang X, Cheng Y, He Y, Cong S, Sun L, Wu D, Wu H, Zhang G. LNC00115 Mediates Cisplatin Resistance by Regulating the miR-7/ERK Signalling Pathway in Ovarian Cancer. Cancer Manag Res 2021; 13:3817-3826. [PMID: 34007214 PMCID: PMC8123956 DOI: 10.2147/cmar.s295097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Background Ovarian cancer has one of the highest mortality rates among all gynaecological malignancies, and increasing evidence suggests that lncRNAs are widely involved in the development of ovarian tumours. This study aimed to investigate the mechanism of the LNC00115/miR-7/ERK axis in the cisplatin resistance of ovarian cancer cells. Methods The expression of miR-7 and LNC00115 in ovarian cancer cell lines and tissues was detected by qRT-PCR. The ovarian cancer cell lines were constructed by overexpressing or knocking down the expression of LNC00115 or miR-7. CCK-8, transwell invasion, Western blot, immunohistochemistry, and luciferase reporter assays were carried out to identify the targets of LNC00115 and explore its roles and mechanisms in ovarian cancer. A nude mouse model was established, and the expression of LNC00115, miR-7 and ERK was detected. The changes in the tumours and body weights of the nude mice were measured. Results LNC00115 was upregulated in ovarian cancer tissues and cisplatin-resistant ovarian cancer cells. Moreover, LNC00115 promoted the cisplatin resistance, invasion and migration of ovarian cancer cells. LNC00115 was shown to directly target miR-7, and miR-7 was downregulated in ovarian cancer tissues and cisplatin-resistant ovarian cancer cells. miR-7 inhibited the cisplatin resistance, invasion and migration of ovarian cancer cells and directly targeted ERK. ERK was overexpressed in cisplatin-resistant ovarian cancer cells and ovarian cancer tissues. In animal experiments, overexpression of LNC00115 enhanced the cisplatin resistance of ovarian cancer cells, while miR-7 had the opposite effect. Mechanistically, LNC00115 sponged miR-7 to increase the expression of ERK, which in turn enhanced the cisplatin resistance of ovarian cancer. Conclusion Our data clarify the mechanism by which the LNC00115/miR-7/ERK axis promotes cisplatin resistance and provide a new clinical strategy for combating cisplatin resistance in ovarian cancer.
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Affiliation(s)
- Xinyan Jiang
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Yan Cheng
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Yanan He
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Shanshan Cong
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Liyuan Sun
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Di Wu
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Han Wu
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Guangmei Zhang
- The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
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Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies. Int J Mol Sci 2021; 22:ijms22073418. [PMID: 33810350 PMCID: PMC8037554 DOI: 10.3390/ijms22073418] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer’s bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients’ management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including, Helicobacter pylori cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent experimental models to study this highly complex disease were discussed, highlighting the importance of gastric cancer understanding in the hard-fought struggle against cancer relapse, metastasis and bad prognosis.
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Korać P, Antica M, Matulić M. MiR-7 in Cancer Development. Biomedicines 2021; 9:325. [PMID: 33806891 PMCID: PMC8004586 DOI: 10.3390/biomedicines9030325] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNA involved in the regulation of specific mRNA translation. They participate in cellular signaling circuits and can act as oncogenes in tumor development, so-called oncomirs, as well as tumor suppressors. miR-7 is an ancient miRNA involved in the fine-tuning of several signaling pathways, acting mainly as tumor suppressor. Through downregulation of PI3K and MAPK pathways, its dominant role is the suppression of proliferation and survival, stimulation of apoptosis and inhibition of migration. Besides these functions, it has numerous additional roles in the differentiation process of different cell types, protection from stress and chromatin remodulation. One of the most investigated tissues is the brain, where its downregulation is linked with glioblastoma cell proliferation. Its deregulation is found also in other tumor types, such as in liver, lung and pancreas. In some types of lung and oral carcinoma, it can act as oncomir. miR-7 roles in cell fate determination and maintenance of cell homeostasis are still to be discovered, as well as the possibilities of its use as a specific biotherapeutic.
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Affiliation(s)
- Petra Korać
- Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000 Zagreb, Croatia;
| | - Mariastefania Antica
- Division of Molecular Biology, Rudjer Bosković Institute, Bijenička 54, 10000 Zagreb, Croatia;
| | - Maja Matulić
- Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000 Zagreb, Croatia;
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Heydarzadeh S, Ranjbar M, Karimi F, Seif F, Alivand MR. Overview of host miRNA properties and their association with epigenetics, long non-coding RNAs, and Xeno-infectious factors. Cell Biosci 2021; 11:43. [PMID: 33632341 PMCID: PMC7905430 DOI: 10.1186/s13578-021-00552-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 02/06/2021] [Indexed: 12/19/2022] Open
Abstract
MicroRNA-derived structures play impressive roles in various biological processes. So dysregulation of miRNAs can lead to different human diseases. Recent studies have extended our comprehension of the control of miRNA function and features. Here, we overview some remarkable miRNA properties that have potential implications for the miRNA functions, including different variants of a miRNA called isomiRs, miRNA arm selection/arm switching, and the effect of these factors on miRNA target selection. Besides, we review some aspects of miRNA interactions such as the interaction between epigenetics and miRNA (different miRNAs and their related processing enzymes are epigenetically regulated by multiple DNA methylation enzymes. moreover, DNA methylation could be controlled by diverse mechanisms related to miRNAs), direct and indirect crosstalk between miRNA and lnc (Long Non-Coding) RNAs as a further approach to conduct intercellular regulation called "competing endogenous RNA" (ceRNA) that is involved in the pathogenesis of different diseases, and the interaction of miRNA activities and some Xeno-infectious (virus/bacteria/parasite) factors, which result in modulation of the pathogenesis of infections. This review provides some related studies to a better understanding of miRNA involvement mechanisms and overcoming the complexity of related diseases that may be applicable and useful to prognostic, diagnostic, therapeutic purposes and personalized medicine in the future.
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Affiliation(s)
- Samaneh Heydarzadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Ranjbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farokh Karimi
- Department of Biotechnology, Faculty of Science, University of Maragheh, Maragheh, Iran
| | - Farhad Seif
- Department of Immunology and Allergy, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran
- Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wu M, Lan H, Ye Z, Wang Y. Hypermethylation of the PZP gene is associated with hepatocellular carcinoma cell proliferation, invasion and migration. FEBS Open Bio 2021; 11:826-832. [PMID: 33471436 PMCID: PMC7931217 DOI: 10.1002/2211-5463.13093] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 12/03/2020] [Accepted: 01/18/2021] [Indexed: 01/11/2023] Open
Abstract
Pregnancy zone protein (PZP), a member of the proteinase inhibitor I39 (‐2‐macroglobulin) family of proteins, is involved in the initiation and development of various tumors. The gene encoding PZP is hypermethylated and expressed at low levels in hepatocellular carcinoma (HCC) tissue and cells, but the function of PZP in HCC cells remains unclear. Here, we analyzed DNA methylation and mRNA expression of HCC in The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset. We identified 10 methylation‐driven genes, of which PZP was significantly hypermethylated and poorly expressed in tumor tissue. We confirmed that PZP is highly methylated and poorly expressed in HCC cell lines via quantitative real‐time PCR experiment and methylation‐specific PCR. Furthermore, PZP markedly inhibited the proliferation, invasion and migration of HCC cells. These findings may provide a basis for exploring novel therapeutic targets for HCC.
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Affiliation(s)
- Minhua Wu
- Department of Medical Oncology, Lishui Municipal Central Hospital, Zhejiang Province, China
| | - Hui Lan
- Department of Medical Oncology, Lishui Municipal Central Hospital, Zhejiang Province, China
| | - Zhongwei Ye
- Department of Medical Oncology, Lishui Municipal Central Hospital, Zhejiang Province, China
| | - Yonghui Wang
- Department of Medical Oncology, Lishui Municipal Central Hospital, Zhejiang Province, China
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The role of microRNA-338-3p in cancer: growth, invasion, chemoresistance, and mediators. Life Sci 2021; 268:119005. [PMID: 33421526 DOI: 10.1016/j.lfs.2020.119005] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 12/14/2022]
Abstract
Cancer still remains as one of the leading causes of death worldwide. Metastasis and proliferation are abnormally increased in cancer cells that subsequently, mediate resistance of cancer cells to different therapies such as radio-, chemo- and immune-therapy. MicroRNAs (miRNAs) are endogenous short non-coding RNAs that can regulate expression of target genes at post-transcriptional level and capable of interaction with mRNA-coding genes. Vital biological mechanisms including apoptosis, migration and differentiation are modulated by these small molecules. MiRNAs are key players in regulating cancer proliferation and metastasis as well as cancer therapy response. MiRNAs can function as both tumor-suppressing and tumor-promoting factors. In the present review, regulatory impact of miRNA-338-3p on cancer growth and migration is discussed. This new emerging miRNA can regulate response of cancer cells to chemotherapy and radiotherapy. It seems that miRNA-338-3p has dual role in cancer chemotherapy, acting as tumor-promoting or tumor-suppressor factor. Experiments reveal anti-tumor activity of miRNA-338-3p in cancer. Hence, increasing miRNA-338-3p expression is of importance in effective cancer therapy. Long non-coding RNAs, circular RNAs and hypoxia are potential upstream mediators of miRNA-338-3p in cancer. Anti-tumor agents including baicalin and arbutin can promote expression of miRNA-338-3p in suppressing cancer progression. These topics are discussed to shed some light on function of miRNA-338-3p in cancer cells.
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Zhang X, Ma L, Zhai L, Chen D, Li Y, Shang Z, Zhang Z, Gao Y, Yang W, Li Y, Pan Y. Construction and validation of a three-microRNA signature as prognostic biomarker in patients with hepatocellular carcinoma. Int J Med Sci 2021; 18:984-999. [PMID: 33456356 PMCID: PMC7807177 DOI: 10.7150/ijms.49126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC), a common type of primary liver cancer, is one of the most aggressive malignant tumors worldwide. Although overall survival (OS) rates for HCC has significantly improved in recent years, however, the exact predictive value of microRNA (miRNA) for the prognosis of HCC has not yet been recognized. Here, we aimed to identify potential prognostic miRNAs involved in HCC by bioinformatics analysis and validated expression levels through quantitative polymerase chain reaction (qPCR) and GEO database. The RNA expression profiles and corresponding clinical information of HCC were available from The Cancer Genome Atlas (TCGA) datasets. Differentially expression and standardization analysis of miRNAs, Kaplan-Meier curve and time dependent ROC curve were performed by using R tools. Differentially expressed miRNAs (DEmiRNAs) and clinical parameters involved in the OS of HCC were confirmed by Cox regression models. And functional enrichment analysis was used to establish functions of the targeted genes of DEmiRNAs. A total of 300 DEmiRNAs were significantly related with HCC, of which 40 were down-regulated and 260 were up-regulated. A total of 344 patients with DEmiRNAs, status, overall survival (OS) time were randomized into training group (172) and test group (172). Multivariate Cox regression analyses revealed that 3 miRNA (hsa-miR-139-3p, hsa-miR-760, hsa-miR-7-5p) had independent prognostic significance for the OS of HCC in both training and test group. Moreover, according to Kaplan Meier analysis, the OS of HCC patients with high-risk score was shorter in validation and entire series. The time dependent ROC curve demonstrated high accuracy of the signature for OS. Besides, target genes of three miRNAs were analyzed by functional enrichment analysis and 20 genes associated with OS were verified by using Kaplan-Meier method. Compared with normal and benign group, the relative expression level of hsa-miR-139-3p was significantly decreased, while hsa-miR-7-5p and hsa-miR-760 were distinctly increased in the plasma of HCC patients. The same results were observed in the independent cohort. Collectively, our research suggested that three-miRNA signature could serve as an independent prognostic indicator for HCC patients.
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Affiliation(s)
- Xi Zhang
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Li Ma
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Li Zhai
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Dong Chen
- Department of Ultrasound, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Yong Li
- Department of Abdominal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Zhongjun Shang
- Department of Hospital Affairs, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Zongmei Zhang
- Department of Pathology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Yanzhang Gao
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Wei Yang
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Yixun Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Experimental Diagnosis, Yunnan Key Laboratory of Laboratory Medicine, Kunming, Yunnan, P.R. China
| | - Yuqing Pan
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Experimental Diagnosis, Yunnan Key Laboratory of Laboratory Medicine, Kunming, Yunnan, P.R. China
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Peng J, Liu F, Zheng H, Wu Q, Liu S. IncRNA ZFAS1 contributes to the radioresistance of nasopharyngeal carcinoma cells by sponging hsa-miR-7-5p to upregulate ENO2. Cell Cycle 2020; 20:126-141. [PMID: 33342344 DOI: 10.1080/15384101.2020.1864128] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Previous research revealed that lncRNA ZFAS1 could promote nasopharyngeal carcinoma (NPC) by inhibiting its downstream target axis. However, the association between ZFAS1 and radioresistant NPC cells is unclear. This study aimed to explore the roles of ZFAS1 in the radioresistance of NPC. Bioinformatics analysis was conducted to identify the significant factors (ENO2 and miR-7-5p) that contributed to the radioresistance of NPC cells. After performing qRT-PCR analysis, we found that the expression of ZFAS1 and ENO2 was upregulated in NPC cells but that the miR-7-5p expression was downregulated in the same samples. Apart from that, we noticed that ZFAS1 inhibition enhanced the sensitivity of NPC cells to radiation therapy by repressing cell proliferation and promoting cell apoptosis. Subsequently, we found that ZFAS1 could sponge miR-7-5p to upregulate ENO2, which was the target of miR-7-5p. Experimental results also indicated that the suppression of miR-7-5p inhibited the sensitivity of NPC cells to radiation therapy, thereby suppressing ENO2 expression. Overall, our findings suggested that ZFAS1 contributed to the radioresistance of NPC cells by regulating the miR-7-5p/ENO2 axis and that ZFAS1 might be a potential therapeutic target for addressing the radioresistance of NPC cells.
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Affiliation(s)
- Jiaojiao Peng
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Feng Liu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Hong Zheng
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Qi Wu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Shixi Liu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
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Lin J, Liu Z, Liao S, Li E, Wu X, Zeng W. Elevated microRNA-7 inhibits proliferation and tumor angiogenesis and promotes apoptosis of gastric cancer cells via repression of Raf-1. Cell Cycle 2020; 19:2496-2508. [PMID: 32931357 PMCID: PMC7553585 DOI: 10.1080/15384101.2020.1807670] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 07/01/2020] [Accepted: 08/01/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Since the essential involvement of microRNAs (miRNAs) in the development and progression of GC, the study was for the exploration of the value of microRNA-7 (miR-7) in the evaluation of neoadjuvant chemotherapy for gastric cancer (GC) and its effects on apoptosis, proliferation and angiogenesis of GC. METHODS miR-7 expression in serum of GC patients before and after neoadjuvant chemotherapy were detected to explore its role in neoadjuvant chemotherapy of GC. The GC cells were transfected with miR-7 mimics/inhibitors, or siRNA-Raf-1 to figure out their roles in proliferation, migration, invasion, cycle distribution and apoptosis. Tumor xenograft was conducted to test tumor growth. Microvessel density (MVD) in tumors was tested by immunohistochemical staining. RESULTS miR-7 expression in serum of GC patients was lower than that of healthy controls while it was elevated after neoadjuvant chemotherapy. Moreover, higher miR-7 expression was exhibited in chemotherapy-effective patients rather than chemotherapy-ineffective patients (P < 0.01). miR-7 expression in serum was connected with tumor size, degree of differentiation, TNM stage and lymphatic metastasis.miR-7 was decreased and Raf-1 was elevated in GC cells (both P < 0.05). Elevated miR-7 or declined Raf-1 inhibited GC cell migration, proliferation and invasion, cell cycle entry, xenografted tumor growth and MVD and stimulated apoptosis (all P < 0.05). Down-regulated Raf-1 reversed the impacts of miR-7 knockdown on GC cells (all P < 0.05). CONCLUSION Our study highlights that elevated miR-27a indicates the good efficacy of neoadjuvant chemotherapy in GC and miR-7 targets Raf-1 to suppress tumor development and angiogenesis of GC cells.
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Affiliation(s)
- Jing Lin
- Oncology Department, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- CONTACT Jing Lin
| | - Zewa Liu
- Oncology Department, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Shasha Liao
- Oncology Department, Shantou Longhu People’s Hospital, Shantou, Guangdong, China
| | - E Li
- Oncology Department, Shantou Longhu People’s Hospital, Shantou, Guangdong, China
| | - Xiaohua Wu
- Oncology Department, Shantou Longhu People’s Hospital, Shantou, Guangdong, China
| | - Wanting Zeng
- MSci Applied Medical Science, Division of Medicine, University College London, London, WC1E 6BT, United Kingdom
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Jin HF, Wang JF, Shao M, Zhou K, Ma X, Lv XP. Down-Regulation of miR-7 in Gastric Cancer Is Associated With Elevated LDH-A Expression and Chemoresistance to Cisplatin. Front Cell Dev Biol 2020; 8:555937. [PMID: 33072745 PMCID: PMC7536350 DOI: 10.3389/fcell.2020.555937] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 08/14/2020] [Indexed: 01/03/2023] Open
Abstract
MicroRNAs (miRNAs) are dysregulated in the context of many cancer types, making them potentially ideal diagnostic or therapeutic targets in patients in which they are aberrantly expressed. In the present study, we found miR-7 to be downregulated in gastric cancer (GC), and we further determined its expression to be closely linked to GC sensitivity to the chemotherapeutic compound cisplatin. This effect appears to be at least partially attributable to the regulation of LDH-A, which is a miR-7 target gene and expression of LDH-A is negatively correlated with miR-7 expression in primary GC tumor samples. When upregulated, we also determined that miR-7 was able to inhibit the proliferation, colony formation, and glycolysis of GC cells owing to its regulation of LDH-A. Moreover, overexpression of miR-7 render cells more sensitive to cisplatin. Our results thus provide novel evidence that miR-7 is a key mediator of GC growth and chemosensitivity through its regulation of LDH-A, thus potentially highlighting this pathway as a therapeutic target for treating affected patients.
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Affiliation(s)
- Hui-Fang Jin
- Department of Bloood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ju-Feng Wang
- Department of Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Ming Shao
- Department of Bloood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kailu Zhou
- Medical College of Zhengzhou University, Zhengzhou, China
| | - Xiao Ma
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xian-Ping Lv
- Department of Bloood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Xin L, Li SH, Liu C, Zeng F, Cao JQ, Zhou LQ, Zhou Q, Yuan YW. Methionine represses the autophagy of gastric cancer stem cells via promoting the methylation and phosphorylation of RAB37. Cell Cycle 2020; 19:2644-2652. [PMID: 32926650 DOI: 10.1080/15384101.2020.1814044] [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] [Indexed: 12/31/2022] Open
Abstract
This study focused on the role of methionine (MET) in the autophagy of gastric cancer stem cells (GCSCs) and aims to elaborate its regulatory mechanism. In the present study, the GCSCs were isolated from human gastric cancer cell lines using an anti-CD44 antibody, and then cultured in MET+ homocysteine (HCY)- or MET-HCY+ medium. In MET+HCY-treated GCSCs, autophagy was suppressed, the methylation and phosphorylation of RAB37 were elevated, and miR-200b expression was down-regulated. Lentiviral vector (LV-) carrying methionine-γ lyase (an enzyme that could specifically lyse MET; Metase) promoted autophagy, reduced the methylation and phosphorylation of RAB37, and up-regulated miR-200b expression in MET+HCY--treated GCSCs. Then, we found that miR-200b suppressed the expression of protein kinase C α (PKCα), a protein that could inactivate RAB37 through promoting its phosphorylation. LV-Metase down-regulated RAB37 phosphorylation via miR-200b/PKCα, thus promoting the RAB37-mediated autophagy and suppressing cell viability in MET+HCY-treated GCSCs. Finally, the in vivo study proved that LV-Metase treatment inhibited tumor growth through up-regulating RAB37 expression. In conclusion, MET suppressed RAB37 expression via enhancing its methylation and suppressed RAB37 activity via miR-200b/PKCα axis, thus repressing RAB37-mediated autophagy in GCSCs. The supplementation of Metase lysed MET, thus inducing the autophagy of GCSCs and inhibiting tumor growth.
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Affiliation(s)
- Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
| | - Shi-Hao Li
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
| | - Chuan Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
| | - Fei Zeng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
| | - Jia-Qing Cao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
| | - Li-Qiang Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
| | - Qi Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
| | - Yi-Wu Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi, China
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Nei Endonuclease VIII-Like1 (NEIL1) Inhibits Apoptosis of Human Colorectal Cancer Cells. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5053975. [PMID: 32685496 PMCID: PMC7336199 DOI: 10.1155/2020/5053975] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/13/2020] [Indexed: 12/25/2022]
Abstract
The study is aimed at investigating the role of Nei endonuclease VIII-like1 (NEIL1) in the pathogenesis of colorectal cancer (CRC). The human CRC (HCT116 and SW480) cells were subjected to the siRNA silencing and recombinant plasmid overexpression of NEIL1. Transfection of siNEIL1 significantly inhibited the cell growth. It also increased the Bax expression levels, while it decreased the Bcl-2 expression levels in human CRC cells, leading the Bax/Bcl-2 balance toward apoptosis. Moreover, the apoptosis was promoted through the caspase-9 signaling pathway. One the other hand, high expression of NEIL1 promoted the cell viability and reduced the apoptosis, inducing the balance of Bax/Bcl-2 in the human colon cancer cells to be antiapoptotic. In addition, the caspase-9 signaling pathway inhibited apoptosis, contrary to the results obtained by downregulating NEIL1 expression. Furthermore, NEIL1 was negatively regulated by miR-7-5p, indicating that miR-7-5p inhibited the NEIL1 expression after transcription. Overexpression of miR-7-5p reversed the effects of NEIL1 on these CRC cells. In conclusion, NEIL1 promotes the proliferation of CRC cells, which is regulated negatively by miR-7-5p. These findings suggest that NEIL1 is a potential therapeutic target for CRC.
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Zhao D, Shun E, Ling F, Liu Q, Warsi A, Wang B, Zhou Q, Zhu C, Zheng H, Liu K, Zheng X. Plk2 Regulated by miR-128 Induces Ischemia-Reperfusion Injury in Cardiac Cells. MOLECULAR THERAPY-NUCLEIC ACIDS 2019; 19:458-467. [PMID: 31902745 PMCID: PMC6948232 DOI: 10.1016/j.omtn.2019.11.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/11/2019] [Accepted: 11/24/2019] [Indexed: 12/19/2022]
Abstract
Ischemia-reperfusion (I/R) injury occurs during cardiac surgery and is the major factor leading to heart dysfunction and heart failure. Our previous study showed that gene and microRNA expression profiles are altered in heart grafts with extended I/R injury. In this study, we, for the first time, demonstrated that I/R injury upregulates the expression of Polo-like kinase 2 (Plk2) but decreases miR-128 expression in heart cells both in vitro and in vivo. Silencing Plk2 using small interfering RNA (siRNA) protects cells from Antimycin A-induced cell apoptosis/death. Silencing Plk2 also decreases phosphorylated p65 expression but increases Angiopoietin 1 expression. In addition, Plk2 is negatively regulated by miR-128. miR-128 exerts a protective effect on cell apoptosis similar to Plk2 siRNA in response to I/R stress. Methylation inhibitor 5-azacytidine (5-AZ) increases the expression of miR-128 and subsequently reduces Plk2 expression and cell apoptosis. In conclusion, this study demonstrated that Plk2 regulated by miR-128 induces cell apoptosis/death in response to I/R stress through activation of the nuclear factor κB (NF-κB) signal pathway. miR-128 and Plk2 are new targets for preventing cardiac I/R injury or oxidative stress-mediated injury.
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Affiliation(s)
- Duo Zhao
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Department of Cardiovascular Surgery, The First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Edward Shun
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Fengjun Ling
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Qing Liu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ayesha Warsi
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Bowen Wang
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Qinfeng Zhou
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Cuilin Zhu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Hao Zheng
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Kexiang Liu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China.
| | - Xiufen Zheng
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Department of Surgery, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada.
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