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1
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Zhang Y, Li J. Recent advancements in understanding of biological role of homeobox C9 in human cancers. World J Clin Oncol 2024; 15:1168-1176. [PMID: 39351453 PMCID: PMC11438841 DOI: 10.5306/wjco.v15.i9.1168] [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: 05/16/2024] [Revised: 07/14/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
Homeobox (HOX) C9, a member of the HOX family, is an important transcription factor, and it plays a significant role in various biological processes. This family of genes is highly valued for their essential roles in establishing and maintaining the body axis during embryonic development and adult tissues. Further, HOXC9 plays a central role in neuronal differentiation, angiogenesis, and adipose distribution, which are essential for the development of the nervous system, maturation of tissues and organs, and maintenance of energy balance and metabolic health. Recent research has found that abnormal HOXC9 expression is closely associated with the development and progression of various tumor types. The HOXC9 expression level can be an indicator of tumor prognosis. Therefore, elucidating the association between HOXC9 expression and its regulatory mechanisms and tumorigenesis can provide novel insights on the diagnosis and treatment of patients with cancer.
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Affiliation(s)
- Yong Zhang
- Department of Clinical Laboratory, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang 222042, Jiangsu Province, China
| | - Jing Li
- Department of Respiratory and Critical Care Medicine, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang 222042, Jiangsu Province, China
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2
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Ahmadpour Youshanlui M, Yari A, Bahojb Mahdavi SZ, Amini M, Baradaran B, Ahangar R, Pourbagherian O, Mokhtarzadeh AA. BRD4 expression and its regulatory interaction with miR-26a-3p, DLG5-AS1, and JMJD1C-AS1 lncRNAs in gastric cancer progression. Discov Oncol 2024; 15:356. [PMID: 39152304 PMCID: PMC11329449 DOI: 10.1007/s12672-024-01230-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 08/12/2024] [Indexed: 08/19/2024] Open
Abstract
Gastric cancer remains a significant health challenge despite advancements in diagnosis and treatment. Early detection is critical to reducing mortality, necessitating the investigation of molecular mechanisms underlying gastric cancer progression. This study focuses on BRD4 expression and its correlation with miR-26a-3p, DLG5-AS1, and JMJD1C-AS1 lncRNAs in gastric cancer. Analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed significant upregulation of BRD4 in gastric cancer tissues compared to normal tissues, correlating negatively with miR-26a-3p and positively with DLG5-AS1 and JMJD1C-AS1 lncRNAs. Quantitative RT-PCR confirmed these findings in 25 gastric cancer tissue samples and 25 normal samples. BRD4's overexpression was associated with reduced survival rates and older patient age. MiR-26a-3p, a known tumor suppressor, showed decreased expression in gastric cancer tissues, with ROC analysis suggesting it, alongside BRD4, as a potential diagnostic biomarker. Additionally, bioinformatics predicted miR-26a-3p's interaction with BRD4 mRNA. Upregulated lncRNAs DLG5-AS1 and JMJD1C-AS1 likely act as competing endogenous RNAs, sponging miR-26a-3p, thus promoting BRD4 dysregulation. These lncRNAs have not been previously studied in gastric cancer. The findings propose a novel BRD4/lncRNA/miRNA regulatory axis in gastric cancer, highlighting the potential of BRD4, DLG5-AS1, and JMJD1C-AS1 as biomarkers for early diagnosis. Further studies with larger sample sizes and in vivo and in vitro experiments are needed to elucidate this regulatory mechanism's role in gastric cancer progression.
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Affiliation(s)
| | - Amirhossein Yari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Ahangar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Omid Pourbagherian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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3
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Li Z, Zhang C, Zhang Q, Dong Y, Sha X, Jiang M, Yan J, Wang W, Li H, Zhang Y, Zhou YL. Identification of a potential bioinformatics-based biomarker in keloids and its correlation with immune infiltration. Eur J Med Res 2023; 28:476. [PMID: 37915086 PMCID: PMC10621210 DOI: 10.1186/s40001-023-01421-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 10/01/2023] [Indexed: 11/03/2023] Open
Abstract
Keloid formation is a pathological consequence resulting from cutaneous irritation and injury, primarily attributed to excessive collagen matrix deposition and fibrous tissue proliferation. Chronic inflammation, left uncontrolled over an extended period, also stands as a substantial contributing factor. The precise mechanisms underlying keloid formation remain unclear. Therefore, this study aimed to identify key genes for diagnostic purposes. To achieve this, we used two Gene Expression Omnibus (GEO) data sets to identify differentially expressed genes. We identified one particular gene, homeobox C9 (HOXC9), using a thorough strategy involving two algorithms (least absolute shrinkage and selection operator and support vector machine-recursive feature elimination) and weighted gene co-expression network analysis. We then assessed its expression in normal and keloid tissues. In addition, we explored its temporal expression patterns via Mfuzz time clustering analysis. In our comprehensive analysis, we observed that immune infiltration, as well as cell proliferation, are crucial to keloid formation. Thus, we investigated immune cell infiltration in the keloid and normal groups, as well as the correlation between HOXC9 and these immune cells. It was found that HOXC9 was closely associated with the immune microenvironment of keloids. This shows that HOXC9 can serve as a potential biomarker and therapeutic target for keloids.
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Affiliation(s)
- Zihan Li
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
- The Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Chuwei Zhang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Qingrong Zhang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Institute of Burn Research, Southwest Hospital, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yipeng Dong
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Xinyu Sha
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Ming Jiang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Jun Yan
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Wenmiao Wang
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Houqiang Li
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yi Zhang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China.
| | - You Lang Zhou
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China.
- The Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, China.
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4
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Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS. An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 2023; 322:121667. [PMID: 37023952 DOI: 10.1016/j.lfs.2023.121667] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/07/2023]
Abstract
Gastric cancer (GC) is 4th in incidence and mortality rates globally. Several genetic and epigenetic factors, including microRNAs (miRNAs), affect its initiation and progression. miRNAs are short chains of nucleic acids that can regulate several cellular processes by controlling their gene expression. So, dysregulation of miRNAs expressions is associated with GC initiation, progression, invasion capacity, apoptosis evasions, angiogenesis, promotion and EMT enhancement. Of important pathways in GC and controlled by miRNAs are Wnt/β-catenin signaling, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR and TGFb signaling. Hence, this review was conducted to review an updated view of the role of miRNAs in GC pathogenesis and their modulatory effects on responses to different GC treatment modalities.
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Feng L, Li Z, Xiong Y, Yan T, Fu C, Zeng Q, Wang H. HtrA2 Independently Predicts Poor Prognosis and Correlates with Immune Cell Infiltration in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2023; 2023:4067418. [PMID: 36704205 PMCID: PMC9873461 DOI: 10.1155/2023/4067418] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/28/2022] [Accepted: 01/07/2023] [Indexed: 01/19/2023]
Abstract
High-temperature requirement protein A2 (HtrA2), a mitochondrial protein, is related to apoptosis regulation. However, the role of HtrA2 in hepatocellular carcinoma (HCC) remains unclear. In the present study, we explored the prognostic value and expression pattern of HtrA2 in HCC and confirmed its independent value for predicting outcomes via Cox analyses. LinkedOmics and GEPIA2 were used to construct the coexpression and functional networks of HtrA2. Additionally, the data obtained from TCGA was analyzed to investigate the relationship between the infiltration of immune cells and HtrA2 mRNA expression. Finally, the expression pattern of HtrA2 in HCC was confirmed by wet-lab experiments. The results showed high HtrA2 expression (P < 0.001) presented in tumor tissues in TCGA-HCC. Moreover, high HtrA2 expression was confirmed to be associated with poor HCC patient survival (P < 0.05). HtrA2 has also been recognized as an essential risk factor for overall survival (P=0.01, HR = 1.654, 95% CI 1.128-2.425), disease-specific survival (P=0.004, HR = 2.204, 95% CI 1.294-3.753), and progression-free interval (P=0.007, HR = 1.637, 95% CI 1.145-2.341) of HCC. HCC patients with low HtrA2 methylation had worse overall survival than patients with high methylation (P=0.0019). Functional network analysis suggests that HtrA2 regulates mitochondrial homeostasis through pathways involving multiple microRNAs and transcription factors in HCC. In addition, HtrA2 expression correlated with infiltrating levels of multiple immune cell populations. At last, increased expression of HtrA2 in HCC was confirmed using wet-lab experiments. Our study provides evidence that the upregulation of HtrA2 in HCC is an independent predictor of prognosis. Our results provide the foundation for further study on the roles of HtrA2 in HCC tumorigenesis.
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Affiliation(s)
- Lei Feng
- The Division of Gastroenterology and Hepatology, Suining Central Hospital, Suining, Sichuan, China
- North Sichuan Medical College, Nanchong, Sichuan, China
| | - Zhen Li
- Sichuan Vocational and Technical College, Suining, Sichuan, China
| | - Yao Xiong
- North Sichuan Medical College, Nanchong, Sichuan, China
| | - Ting Yan
- Zunyi Medical University, Zunyi, Guizhou, China
| | - Changmin Fu
- Zunyi Medical University, Zunyi, Guizhou, China
| | - Qiuyue Zeng
- North Sichuan Medical College, Nanchong, Sichuan, China
| | - Huamin Wang
- North Sichuan Medical College, Nanchong, Sichuan, China
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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7
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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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8
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Tang Y, Wang T, Yu Y, Yan Y, Wu C. Upregulation of HOXC9 generates interferon-gamma resistance in gastric cancer by inhibiting the DAPK1/RIG1/STAT1 axis. Cancer Sci 2021; 112:3455-3468. [PMID: 34159686 PMCID: PMC8409412 DOI: 10.1111/cas.15043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/28/2021] [Accepted: 06/19/2021] [Indexed: 12/14/2022] Open
Abstract
Clinical reports indicate that gastric cancer (GC) has a high mortality rate, but its pathological mechanism remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene coexpression network analysis was applied to screen significant genes correlated with GC development. Gene set enrichment analysis was also used to unearth the most relevant biological functions of significant genes. As a result, we discovered homeobox C9 (HOXC9) as a novel oncogene in GC, primarily through negatively regulating immune response. High expression of HOXC9 predicted a poor prognosis in GC patients, and knocking down HOXC9 efficiently enhanced the interferon‐gamma (IFNγ)‐dependent apoptosis in two GC cell lines as well as organoids from patients. Furthermore, cleaved caspase‐3/7 and phosphorylated signal transducer and activator of transcription 1 (p‐STAT1) were also significantly enhanced in HOXC9 knockdown cells and organoids treated with IFNγ. Mechanistically, we found that HOXC9 inhibited the death‐associated protein kinase 1 (DAPK1) and its downstream retinoic acid‐inducible gene‐I (RIG1) to generate GC IFNγ resistance. In summary, we identified and confirmed that HOXC9 generates IFNγ resistance in GC by inhibiting the DAPK1/RIG1/p‐STAT1 axis.
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Affiliation(s)
- Yuanxin Tang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Taifang Wang
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yue Yu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuhao Yan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Chunli Wu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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9
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Abstract
Gastric cancer (GC) is one of the most common malignant tumors. The mechanism of how GC develops is vague, and therapies are inefficient. The function of microRNAs (miRNAs) in tumorigenesis has attracted the attention from many scientists. During the development of GC, miRNAs function in the regulation of different phenotypes, such as proliferation, apoptosis, invasion and metastasis, drug sensitivity and resistance, and stem-cell-like properties. MiRNAs were evaluated for use in diagnostic and prognostic predictions and exhibited considerable accuracy. Although many problems exist for the application of therapy, current studies showed the antitumor effects of miRNAs. This paper reviews recent advances in miRNA mechanisms in the development of GC and the potential use of miRNAs in the diagnosis and treatment of GC.
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Hwang GR, Yuen JG, Ju J. Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development. Int J Mol Sci 2021; 22:ijms22041624. [PMID: 33562727 PMCID: PMC7915611 DOI: 10.3390/ijms22041624] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.
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Azimi M, Totonchi M, Rahimi M, Firouzi J, Sahranavard P, Emami Razavi A, Memari F, Kamali F, Ebrahimi M. An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in human gastric cancer. J Gastroenterol Hepatol 2021; 36:436-445. [PMID: 32633423 DOI: 10.1111/jgh.15176] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/06/2020] [Accepted: 07/01/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Cancer stem cells (CSCs), a subpopulation of tumor cells, assess the capacity of self-renewal, metastasis, and therapeutic resistance. Regulation of CSCs and their epithelial to mesenchymal transition (EMT) potential is one of the promising strategies to eliminate cancer or to inhibit metastasis. Micro-RNAs (miRNAs) as regulators of several cell properties, such as self-renewal, metastasis, and resistance to the drug, could be proper targets in cancer diagnosis and therapy. The aim of the present study is to select common miRNAs targeting both self-renewal and metastasis in gastric cancer. METHODS Stemness-related and EMT-related genes were selected by literature mining. The common miRNAs targeting genes were chosen using different databases and r programming language. The expression pattern of selected miRNAs and genes was evaluated in gastrospheres-as a gastric CSC model-and gastric tumor biopsies. RESULTS Based on the integrated analysis, six miRNAs common to both stemness and metastasis were identified. miR-200c-3p and miR-520c-3p overexpressed in MKN-45 gastrospheres and grade III tumors. In AGS spheres, however, miR-520c-3p and miR-200c-3p upregulation and miR-34a-5p downregulation were similar to grade II tumors. Interestingly, miR-200c-3p and miR-520c-3p indicated a positive correlation with OCT4 and NOTCH1 expression in grade III tumors and MKN-45 spheres. Protein-protein network revealed that the EMT acquisition can be induced by stemness activation through intermediated core-regulatory genes, including CTNNB1, CTNND1, MAML1, KAT2A, and MAML3. CONCLUSION The upregulation of mir-200c-3p and mir-520c-3p could effect on stemness and metastasis in gastric cancer as well as gastric CSCs. Therefore, they can be used as diagnosis and prognostic factors.
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Affiliation(s)
- Mahnaz Azimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mehdi Totonchi
- Department of Genetics, Reproductive Biomedical Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Mahsa Rahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Javad Firouzi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Parisa Sahranavard
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amirnader Emami Razavi
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Fereidoon Memari
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Kamali
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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12
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Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, Salehi R, Sadeghi B, Manian M. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int 2021; 21:62. [PMID: 33472628 PMCID: PMC7816485 DOI: 10.1186/s12935-020-01719-5] [Citation(s) in RCA: 372] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.
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Affiliation(s)
- Asieh Emami Nejad
- Department of Biology, Payame Noor University (PNU), P.O.Box 19395-3697, Tehran, Iran
| | - Simin Najafgholian
- Department of Emergency Medicine, School of Medicine , Arak University of Medical Sciences, Arak, Iran
| | - Alireza Rostami
- Department of Surgery, School of Medicine Amiralmomenin Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Alireza Sistani
- Department of Emergency Medicine, School of Medicine Valiasr Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Samaneh Shojaeifar
- Department of Midwifery, Faculty of Nursing and Midwifery , Arak University of Medical Sciences , Arak, Iran
| | - Mojgan Esparvarinha
- Department of Immunology, School of Medicine , Tabriz University of Medical Sciences , Tabriz, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences , Isfahan, Iran
| | - Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Ahmadlou
- Sciences Medical of University Arak, Hospital Amiralmomenin, Center Development Research Clinical, Arak, Iran
| | - Rasoul Salehi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Bahman Sadeghi
- Department of Health and Community Medicine, School of Medicine, Arak University of Medical Sciences, Arak, 3848176341, Iran.
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Department of Medical Laboratory Science, Faculty of Medical Science Kermanshah Branch, Islamic Azad University, Imam Khomeini Campus, Farhikhtegan Bld., Shahid J'afari St., Kermanshah, 3848176341, Iran.
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Fu T, Ji X, Bu Z, Zhang J, Wu X, Zong X, Fan B, Jia Z, Ji J. Identification of key long non-coding RNAs in gastric adenocarcinoma. Cancer Biomark 2020; 27:541-553. [PMID: 32176636 DOI: 10.3233/cbm-192389] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Gastric cancer is the third leading cause of cancer-related deaths worldwide. OBJECTIVE The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gastric adenocarcinoma. METHODS The lncRNA and mRNA expression profile between gastric adenocarcinoma and adjacent non-tumor tissues were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between gastric adenocarcinoma and adjacent non-tumor tissues were identified after bioinformatics analysis. DElncRNA-DEmRNA co-expression network and DElncRNA-nearby DEmRNA interaction network were constructed, respectively. Functional annotation for DEmRNAs interacted with DElncRNAs was performed. Receiver operating characteristic (ROC) analysis of selected DElncRNAs was conducted. RESULTS Based on TCGA, the mRNA and lncRNA expression profiles of 375 gastric adenocarcinoma and 32 adjacent non-tumor tissues were downloaded. A total of 1502 DEmRNAs and 928 DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues were identified. HOXC-AS3 might involve with gastric adenocarcinoma by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13) with cis-effect. AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations might play roles in gastric adenocarcinoma through regulating pathways of Fat digestion and absorption and Vitamin digestion and absorption. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) have excellent diagnostic value for gastric adenocarcinoma. CONCLUSIONS This study identifies key lncRNAs in gastric adenocarcinoma which provides clues for exploring the pathogenesis and developing potential biomarkers for gastric adenocarcinoma.
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Sun B, Han Y, Cai H, Huang H, Xuan Y. Long non-coding RNA SNHG3, induced by IL-6/STAT3 transactivation, promotes stem cell-like properties of gastric cancer cells by regulating the miR-3619-5p/ARL2 axis. Cell Oncol (Dordr) 2020; 44:179-192. [PMID: 32930970 DOI: 10.1007/s13402-020-00560-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 08/31/2020] [Accepted: 09/04/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Chemotherapy is, next to surgery and radiotherapy, the mainstay regimen for the clinical management of gastric cancer. This therapy is, however, heavily compromised by the acquisition of resistance. Here, we aimed to clarify the potential involvement of long non-coding RNA SNGH3 in the acquisition of cisplatin resistance and stemness in gastric cancer. METHODS Cell viability and proliferation were measured using Cell Counting Kit-8 and colony formation assays, respectively. Stem cell-like cell growth was evaluated using a mammosphere formation assay. RNA levels of SNHG2, OCT-4, SOX-2, CD44, miR-3619-5p and ARL2 were determined using qRT-PCR, whereas protein levels of OCT-4, SOX-2, CD44, ARL2, STAT3 and pSTAT3 were determined using Western blotting. Dual luciferase reporter assays were employed to interrogate regulatory interactions between STAT3, SNHG3, miR-3619-5p and ARL2, respectively. Direct binding of STAT3 to the SNHG3 promoter was investigated using a chromatin immunoprecipitation assay. RESULTS We found that IL-6 triggered stem cell-like properties in cisplatin-treated gastric cancer cells and activated STAT3, which in turn transcriptionally regulated SNHG3 expression. SNHG3 expression up-regulation positively correlated with cisplatin resistance and stemness of gastric cancer cells, while SNHG3 down-regulation inhibited stem cell-like properties. In addition, we found that SNHG3 up-regulated ARL2 expression through sponging miR-3619-5p, which predominantly mediated the oncogenic properties of SNHG3 in this disease. CONCLUSIONS Our data indicate an involvement of aberrant SNHG3 over-expression in the acquisition of both cisplatin resistance and stemness of gastric cancer cells, and of the IL-6/STAT3/SNHG3/miR-3619-5p/ARL2 signaling cascade in the oncogenic properties of SNHG3.
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Affiliation(s)
- Bo Sun
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Yang Han
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Hong Cai
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, 200032, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
| | - Hua Huang
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, 200032, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
| | - Yi Xuan
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, 200032, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
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Jin X, Dai L, Ma Y, Wang J, Yan H, Jin Y, Zhu X, Liu Z. Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis. BMC Cancer 2020; 20:866. [PMID: 32907552 PMCID: PMC7487678 DOI: 10.1186/s12885-020-07346-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 08/26/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND An increasing number of studies have described the aberrant expression of homeobox (HOX) proteins in gastric cancer (GC), which is critically associated with the prognosis and clinicopathological characteristics of GC. This study was conducted to investigate the clinical value and action mechanisms of HOX proteins in GC. METHODS A comprehensive search of PubMed, Embase, Web of Science and Cochrane Library was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) and the pooled odds ratio (OR) with its 95% CI were used to assess the effect of HOX protein expression on the prognosis and clinicopathological features of GC, respectively. RESULTS Nineteen studies containing 3775 patients were selected for this study. Heterogeneity among HRs of overall survival (OS) was markedly high (I2 = 90.5%, p = 0.000). According to the subgroup analysis, increased expression of HOX protein in the downregulated subgroup was associated with a good prognosis for patients with GC (pooled HR: 0.46, 95% CI: 0.36-0.59, I2 = 3.1%, p = 0.377), while overexpression of HOX protein in the upregulated subgroup was correlated with a reduced OS (pooled HR: 2.59, 95% CI: 1.79-3.74, I2 = 73.5%, p = 0.000). The aberrant expression of HOX protein was crucially related to the TNM stage, depth of tumour invasion, tumour size, lymph node metastasis, distant metastasis, vascular invasion, histological differentiation and Lauren classification in patients with GC. In addition, the molecular mechanisms by which HOX proteins regulate tumorigenesis and development of GC were also explored. CONCLUSIONS HOX proteins play vital roles in GC progression, which might serve as prognostic markers and therapeutic targets for GC.
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Affiliation(s)
- Xiao Jin
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China
| | - Lu Dai
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China
| | - Yilan Ma
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China
| | - Jiayan Wang
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China
| | - Haihao Yan
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China
| | - Ye Jin
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China
| | - Xiaojuan Zhu
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China
| | - Zheng Liu
- Institute of Digestive Endoscopy and Medical Centre for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210011, People's Republic of China.
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16
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HOXC9 overexpression is associated with gastric cancer progression and a prognostic marker for poor survival in gastric cancer patients. Int J Clin Oncol 2020; 25:2044-2054. [PMID: 32816159 DOI: 10.1007/s10147-020-01772-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND As a member of the homeobox family, HOXC9 is overexpressed in several malignant tumors and may be regarded as a biomarker for prognostic evaluation. However, the expression pattern and prognostic significance of HOXC9 in gastric cancer have not been detailedly studied. METHODS HOXC9 mRNA expression difference in normal tissues and gastric cancer tissues were investigated using RT-PCR, and immunohistochemistry was used to analyze HOXC9 protein expression in precancerous lesions and gastric cancer at different stages, and its clinicopathological characteristics and survival were statistically tested. RESULTS Compared to the normal gastric mucosa tissues, the expression levels of HOXC9 mRNA in the human gastric cancer tissues were significantly higher. HOXC9 protein levels of gastric cancer were obviously higher than that in other noncancerous tissues (P < 0.001). Positive expression of HOXC9 was associated with tumor size (P = 0.036), lymphatic invasion (P = 0.001), depth of invasion (P < 0.001), lymph-node metastasis (P < 0.001), and higher stage disease (P < 0.001). Furthermore, Kaplan-Meier survival curves showed that HOXC9 expression is inversely correlated with both disease-specific and disease-free 5 year survival of patients with gastric cancer (P < 0.001 for both). Strikingly, our multivariate Cox regression analysis revealed that HOXC9 expression was an independent poor prognostic factor in gastric cancer (P < 0.05). CONCLUSIONS HOXC9 expression was observed in a subset of patients with gastric cancer and was associated with an unfavorable prognosis. As well as being a new prognostic indicator, HOXC9 protein could be a useful marker for early diagnosis.
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17
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Malinowski B, Musiała N, Wiciński M. Metformin's Modulatory Effects on miRNAs Function in Cancer Stem Cells-A Systematic Review. Cells 2020; 9:cells9061401. [PMID: 32512882 PMCID: PMC7348732 DOI: 10.3390/cells9061401] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/27/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin’s ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs’ major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.
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18
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Kim B, Jang J, Heo YJ, Kang SY, Yoo H, Sohn I, Min BH, Kim KM. Dysregulated miRNA in a cancer-prone environment: A study of gastric non-neoplastic mucosa. Sci Rep 2020; 10:6600. [PMID: 32313120 PMCID: PMC7171080 DOI: 10.1038/s41598-020-63230-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 03/16/2020] [Indexed: 11/09/2022] Open
Abstract
Understanding cancer-prone environments is important to efficiently detect and prevent cancers. The associations between miRNA and cancer-prone environments are still largely unknown in gastric cancer (GC). Six miRNAs that are differentially expressed during gastric carcinogenesis were selected, and quantitative real-time PCR was performed in an independent training set (fresh non-tumor and tumor samples from 18 GC patients) and validation sets (set 1 with formalin-fixed paraffin-embedded non-tumor and tumor samples from 19 solitary GC and set 2 with 37 multiple GC patients). The results were compared with those of 37 gastric mucosa from 20 healthy volunteers. The expression levels of miR-26a, miR-375, and miR-1260 in gastric mucosa from healthy volunteers were statistically higher than that of non-tumorous gastric mucosa located 3 cm apart from the GC in the training set (miR-26a, P < 0.0001; miR-375, P = 0.0049; miR-1260, P = 0.0172), validation set 1 (miR-26a and miR-375, P < 0.0001; miR-1260, P = 0.0008), and validation set 2 (miR-26a, miR-375, and miR-1260, P < 0.0001). And a combination of miR-26a and miR-1260 showed the highest area under the curve value of 0.89. miRNAs are differentially expressed in non-neoplastic gastric mucosa and can be used as a biomarker to predict cancer-prone environments.
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Affiliation(s)
- Binnari Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Jiryeon Jang
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - You Jeong Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Heejin Yoo
- Statistics and Data Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Insuk Sohn
- Statistics and Data Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. .,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea.
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19
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Khan AQ, Ahmed EI, Elareer NR, Junejo K, Steinhoff M, Uddin S. Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies. Cells 2019; 8:840. [PMID: 31530793 PMCID: PMC6721829 DOI: 10.3390/cells8080840] [Citation(s) in RCA: 207] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/28/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022] Open
Abstract
Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known to regulate expression of more than 60% of the human genes, and their aberrant expression has been associated with the pathogenesis of human cancers and the regulation of stemness features of CSCs. CSCs are the small population of cells present in human malignancies well-known for cancer resistance, relapse, tumorigenesis, and poor clinical outcome which compels the development of novel and effective therapeutic protocols for better clinical outcome. Interestingly, the role of miRNAs in maintaining and regulating the functioning of CSCs through targeting various oncogenic signaling pathways, such as Notch, wingless (WNT)/β-Catenin, janus kinases/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase/ protein kinase B (PI3/AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB), is critical and poses a huge challenge to cancer treatment. Based on recent findings, here, we have documented the regulatory action or the underlying mechanisms of how miRNAs affect the signaling pathways attributed to stemness features of CSCs, such as self-renewal, differentiation, epithelial to mesenchymal transition (EMT), metastasis, resistance and recurrence etc., associated with the pathogenesis of various types of human malignancies including colorectal cancer, lung cancer, breast cancer, head and neck cancer, prostate cancer, liver cancer, etc. We also shed light on the fact that the targeted attenuation of deregulated functioning of miRNA related to stemness in human carcinogenesis could be a viable approach for cancer treatment.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Eiman I Ahmed
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Noor R Elareer
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Kulsoom Junejo
- General Surgery Department, Hamad General Hospital, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
- Weill Cornell Medicine, Doha, P.O. Box 24811, Qatar
- Weill Cornell University, New York, NY 10065, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar.
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Su H, Ren F, Jiang H, Chen Y, Fan X. Upregulation of microRNA-520a-3p inhibits the proliferation, migration and invasion via spindle and kinetochore associated 2 in gastric cancer. Oncol Lett 2019; 18:3323-3330. [PMID: 31452811 DOI: 10.3892/ol.2019.10663] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 06/05/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miR) serve important roles in the development and progression of tumors by targeting different genes. miR-520a-3p reported in lung and breast cancers as a tumor suppressor gene. However, the expression and functional significance of miR-520a-3p is not completely understood in gastric cancer (GC). In the present study, it was demonstrated that the expression levels of miR-520a-3p were significantly downregulated in GC tissues and cells using RT-qPCR. In addition, downregulated expression of miR-520a-3p was associated with the clinical stage of the tumor and invasion in patients with GC. Furthermore, overexpression of miR-520a-3p significantly inhibited cell proliferation, invasion and migration in SGC-7901 and MGC-803 GC cell lines using proliferation, wound healing and cell invasion assays. Spindle and kinetochore associated 2 (SKA2) was upregulated in GC cells using western blot analysis and a target gene of miR-520a-3p; miR-520a-3p mimics significantly reduced SKA2 expression. In addition, upregulation of SKA2 protein expression SKA2 reversed the miR-520a-3p-mediated inhibition of SGC-7901 cell proliferation, migration and invasion. In conclusion, miR-520a-3p functioned as a tumor suppressor gene by targeting SKA2 in GC cell lines, and may serve as a novel prognostic and potential therapeutic marker.
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Affiliation(s)
- Hui Su
- Department of General Surgery, Ningbo No. 2 Hospital, Zhejiang 315010, P.R. China
| | - Feng Ren
- Department of General Surgery, Ningbo No. 2 Hospital, Zhejiang 315010, P.R. China
| | - Haitao Jiang
- Department of General Surgery, Ningbo No. 2 Hospital, Zhejiang 315010, P.R. China
| | - Yunjie Chen
- Department of General Surgery, Ningbo No. 2 Hospital, Zhejiang 315010, P.R. China
| | - Xiaoxiang Fan
- Department of Interventional Therapy, Ningbo No. 2 Hospital, Zhejiang 315010, P.R. China
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