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Ranapour S, Motamed N. Effect of Silibinin on the Expression of Mir-20b, Bcl2L11, and Erbb2 in Breast Cancer Cell Lines. Mol Biotechnol 2023; 65:1979-1990. [PMID: 36905464 DOI: 10.1007/s12033-023-00702-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/14/2023] [Indexed: 03/12/2023]
Abstract
This study aimed to evaluate the comparative effect of silibinin (SB) on the expression of MiR‑20b and BCL2L11 in T47D and MCF-7 cell lines. Molecular simulation studies were carried out to analyze Erbb2, as a potential target of SB, to direct the breast cancer cells toward apoptosis. At first, cell viability, apoptosis, and cell cycle arrest-inducing capacity of SB were examined using MTT and flow cytometry analysis, respectively. Real-time PCR (RT-PCR) was employed to assess the effect of SB on BCL2L11, Phosphatase and tensin homolog (PTEN), and Caspase 9 mRNarrest-indu. Moreover, alterations in Caspase 9 protein expression were determined using Western blot analysis. Finally, AutoDockVina software was used to dock the SB/ MiR‑20b and SB/ erb-b2 receptor tyrosine kinase 2 (Erbb2) interaction. The obtained data revealed the potent cytotoxicity of SB in both T47D and MCF-7 cells through apoptosis induction and cell cycle arrest. SB-treated cells also showed downregulation of MiR‑20b and high expression of BCL2L11, PTEN, and Caspase 9 mRNA compared to non-treated cancer cells. Computational docking showed a strong interaction between SB/ MiR‑20b and SB/Erbb2. It can be concluded that SB had a strong anti-tumorigenic activity through BCL2L11upregulation and MiR‑20b down expression, maybe through targeting the PTEN and interacting with Erbb2, which resulted in apoptotic induction and cell cycle arrest.
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Affiliation(s)
- Sanaz Ranapour
- Department of Cellular and Molecular Biology, Kish International Campus, University of Tehran, Kish, Iran
| | - Nasrin Motamed
- Department of Cellular and Molecular Biology, Kish International Campus, University of Tehran, Kish, Iran.
- Department of Cellular and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, 14155-6455, Iran.
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2
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Fadaka AO, Akinsoji T, Klein A, Madiehe AM, Meyer M, Keyster M, Sikhwivhilu LM, Sibuyi NRS. Stage-specific treatment of colorectal cancer: A microRNA-nanocomposite approach. J Pharm Anal 2023; 13:1235-1251. [PMID: 38174117 PMCID: PMC10759263 DOI: 10.1016/j.jpha.2023.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 01/05/2024] Open
Abstract
Colorectal cancer (CRC) is among the leading causes of cancer mortality. The lifetime risk of developing CRC is about 5% in adult males and females. CRC is usually diagnosed at an advanced stage, and at this point therapy has a limited impact on cure rates and long-term survival. Novel and/or improved CRC therapeutic options are needed. The involvement of microRNAs (miRNAs) in cancer development has been reported, and their regulation in many oncogenic pathways suggests their potent tumor suppressor action. Although miRNAs provide a promising therapeutic approach for cancer, challenges such as biodegradation, specificity, stability and toxicity, impede their progression into clinical trials. Nanotechnology strategies offer diverse advantages for the use of miRNAs for CRC-targeted delivery and therapy. The merits of using nanocarriers for targeted delivery of miRNA-formulations are presented herein to highlight the role they can play in miRNA-based CRC therapy by targeting different stages of the disease.
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Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Taiwo Akinsoji
- School of Medicine, Southern Illinois University, Springfield, IL, 62702, USA
| | - Ashwil Klein
- Plant Omics Laboratory, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Abram Madimabe Madiehe
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
- Nanobiotechnology Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Mervin Meyer
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Marshall Keyster
- Environmental Biotechnology Laboratory, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Lucky Mashudu Sikhwivhilu
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Advanced Materials Division, Mintek, Johannesburg, 2125, South Africa
- Department of Chemistry, Faculty of Science, Engineering and Agriculture, University of Venda, Thohoyandou, 0950, South Africa
| | - Nicole Remaliah Samantha Sibuyi
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Advanced Materials Division, Mintek, Johannesburg, 2125, South Africa
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Lu Y, Gu F, Ma Y, Li R, Luo Y, Da X, Jiang L, Li X, Liu Y. Simultaneous Delivery of Doxorubicin and EZH2-Targeting siRNA by Vortex Magnetic Nanorods Synergistically Improved Anti-Tumor Efficacy in Triple-Negative Breast Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2301307. [PMID: 37376877 DOI: 10.1002/smll.202301307] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/19/2023] [Indexed: 06/29/2023]
Abstract
Triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, currently lacks a targeted therapy and has a high clinical recurrence rate. The present study reports an engineered magnetic nanodrug based on Fe3 O4 vortex nanorods coated with a macrophage membrane loaded with doxorubicin (DOX) and Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) siRNA. This novel nanodrug displays excellent tissue penetration and preferential tumor accumulation. More importantly, it significantly increases tumor suppression compared to chemotherapy, suggesting the synergistic activity of the combination of doxorubicin and EZH2-inhibition. Importantly, owing to tumor-targeted delivery, nanomedicine shows an excellent safety profile after systemic delivery, unlike conventional chemotherapy. In summary, chemotherapy and gene therapy are combined into a novel magnetic nanodrug carrying doxorubicin and EZH2 siRNA, which shows promising clinical application potential in TNBC therapy.
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Affiliation(s)
- Yunshu Lu
- Department of Breast Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
| | - Fenfen Gu
- Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
| | - Yuwei Ma
- Department of Breast Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
| | - Ruonan Li
- Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai, 200093, P. R. China
| | - Yi Luo
- Biotheus Inc., Guangdong Province, Zhuhai, 519080, P. R. China
- Clinical Pharmacy Innovation Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
| | - Xianhong Da
- Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai, 200093, P. R. China
| | - Lan Jiang
- Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai, 200093, P. R. China
| | - Xiang Li
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai, 200093, P. R. China
| | - Yan Liu
- Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
- Clinical Pharmacy Innovation Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
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Tariq L, Arafah A, Sehar N, Ali A, Khan A, Rasool I, Rashid SM, Ahmad SB, Beigh S, Dar TUH, Rehman MU. Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression. Med Oncol 2023; 40:282. [PMID: 37639075 DOI: 10.1007/s12032-023-02099-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 08/29/2023]
Abstract
Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.
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Affiliation(s)
- Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aarif Ali
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, 45142, Jazan, Saudi Arabia
| | - Iyman Rasool
- Department of Pathology, Government Medical College (GMC-Srinagar), Karanagar, Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Saba Beigh
- Department of Public Health, Faculty of Applied Medical Science, Al Baha University, 65431, Al Baha, Saudi Arabia
| | - Tanveer Ul Hassan Dar
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia.
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Alshahrani SH, Rakhimov N, Gupta J, Hassan ZF, Alsalamy A, Saleh EAM, Alsaab HO, Al-Aboudy FK, Alawadi AR, Mustafa YF. The mechanisms, functions and clinical applications of miR-542-3p in human cancers. Pathol Res Pract 2023; 248:154724. [PMID: 37542861 DOI: 10.1016/j.prp.2023.154724] [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: 07/10/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/07/2023]
Abstract
MicroRNAs, as a major type of noncoding RNAs, have crucial roles in various functions during development. Available data have shown that miR-542-3p decreased in various types of cancers. MiR-542-3p is engaged in various cancer-related behaviors like glycolysis, metastasis, epithelial-to-mesenchymal transition (EMT), cell cycle, apoptosis, and proliferation via targeting at least 18 genes and some important signaling pathways like Wnt/β-catenin, Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Janus kinase 2 (JAK2) signaling, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling. Current studies have proposed that the level of miR-542-3p could be modulated by several upstream regulators like transcription factors, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). In addition, the level of miR-542-3p or its related lncRNAs/circRNAs are correlated with poor prognosis and clinicopathological features of cancer-affected patients. Here, we have discussed the biogenesis, function, and regulation of miR-542-3p as well as its aberrant expression in various types of neoplastic cells. Moreover, we have discussed the prognostic value of miR-542-3p in cancer. Finally, we have added the underlying molecular mechanism of miR-542-3p in cancer pathogenesis.
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Affiliation(s)
| | - Nodir Rakhimov
- Head of the Department of Oncology, Samarkand State Medical University, Amir Temur street 18, Samarkand, Uzbekistan; Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli 103, Tashkent, Uzbekistan
| | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura Pin Code 281406, U. P., India.
| | | | - Ali Alsalamy
- Department of Computer Technical engineering, College of Information Technology Imam Ja'afarAl-Sadiq University Al-Muthanna, Iraq
| | - Ebraheem Abdu Musad Saleh
- Department of Chemistry, Prince Sattam Bin Abdulaziz University, Wadi Al-Dawasir 11991, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | | | - Ahmed Radhi Alawadi
- Medical Analysis Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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6
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Liu J, Pan Y, Liu Y, Wei W, Hu X, Xin W, Chen N. The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets. J Cell Physiol 2023; 238:1693-1715. [PMID: 37334436 DOI: 10.1002/jcp.31053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023]
Abstract
This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3-kinases (PI3K)-protein kinase B-mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)-3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein-protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted.
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Affiliation(s)
- Jie Liu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yongli Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Yuheng Liu
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Xiaoping Hu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Nan Chen
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
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7
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Liu Y, Hong G, Mao L, Su Z, Liu T, Liu H. A Novel Paclitaxel Derivative for Triple-Negative Breast Cancer Chemotherapy. Molecules 2023; 28:molecules28093662. [PMID: 37175072 PMCID: PMC10180349 DOI: 10.3390/molecules28093662] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 05/15/2023] Open
Abstract
Paclitaxel-triethylenetetramine hexaacetic acid conjugate (PTX-TTHA), a novel semi-synthetic taxane, is designed to improve the water solubility and cosolvent toxicity of paclitaxel in several aminopolycarboxylic acid groups. In this study, the in vitro and in vivo antitumor effects and mechanisms of PTX-TTHA against triple-negative breast cancer (TNBC) and its intravenous toxicity were evaluated. Results showed the water solubility of PTX-TTHA was greater than 5 mg/mL, which was about 7140-fold higher than that of paclitaxel (<0.7 µg/mL). PTX-TTHA (10-105 nmol/L) could significantly inhibit breast cancer proliferation and induce apoptosis by stabilizing microtubules and arresting the cell cycle in the G2/M phase in vitro, with its therapeutic effect and mechanism similar to paclitaxel. However, when the MDA-MB-231 cell-derived xenograft (CDX) tumor model received PTX-TTHA (13.73 mg/kg) treatment once every 3 days for 21 days, the tumor inhibition rate was up to 77.32%. Furthermore, PTX-TTHA could inhibit tumor proliferation by downregulating Ki-67, and induce apoptosis by increasing pro-apoptotic proteins (Bax, cleaved caspase-3) and TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and reducing anti-apoptotic protein (Bcl-2). Moreover, PTX-TTHA demonstrated no sign of acute toxicity on vital organs, hematological, and biochemical parameters at the limit dose (138.6 mg/kg, i.v.). Our study indicated that PTX-TTHA showed better water solubility than paclitaxel, as well as comparable in vitro and in vivo antitumor activity in TNBC models. In addition, the antitumor mechanism of PTX-TTHA was related to microtubule regulation and apoptosis signaling pathway activation.
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Affiliation(s)
- Yuetong Liu
- The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Ge Hong
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Lina Mao
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Zhe Su
- Tianjin Institute for Drug Control, Tianjin 300070, China
| | - Tianjun Liu
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Hong Liu
- The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
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8
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Pang B, Gan Y, Wang J, Qu S. lncRNA ARAP1-AS1 enhances proliferation and impairs apoptosis of lymphoma cells by sponging miR-6867-5p. Cancer Biomark 2023; 38:333-342. [PMID: 37599524 DOI: 10.3233/cbm-230103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
BACKGROUND Numerous evidence have suggested the vital role of lncRNAs in human tumorigenesis. And lncRNA APAP1-AS1 has been proved to act as an oncogene. OBJECTIVE Nevertheless, the molecular process underlying ARAP1-AS1 for the lymphoma progression has not been well studied. METHODS RT-qPCR was used to ascertain the miR-6867-5p and ARAP1-AS1 in lymphoma cells and tissues. The localization of ARAP1-AS1 was determined via subcellular fractionation analysis. A xenograft model was used to investigate the influence of ARAP1-AS1 in formation of tumor in vivo. In addition, interactions between ARAP-AS1 and miR-6867-5p were tested by bioinformatics analysis, RIP assay, luciferase reporter and Pearson's correlation analysis. Combined with loss-of-function experiments, MTT assays and flow cytometry were performed to evaluate the function of miR-6867-5p and also ARAP-AS1 in proliferation and apoptosis of lymphoma cells, respectively. RESULTS ARAP1-AS1 was remarkably upregulated in lymphoma cells and tissues, while miR-6867-5p expression was downregulated. Furthermore, high ARAP1-AS1 expression suppressed miR-6867-5p expression in lymphoma cell lines (Raji and CA46), and Pearson's analysis showed negative correlation between ARAP1-AS1 expression and also miR-6867-5p expression. In addition, knockdown of ARAP1-AS1 resulted in weakened cell viability and uplifted apoptosis rate of lymphoma cells (Raji and CA46) as well as a delay in the tumor growth in vivo. Further investigations illustrated that miR-6867-5p inhibitor reversed all above biological activities. CONCLUSIONS LncRNA ARAP1-AS1 served as a tumor-promoter in lymphoma cells by sponging with miR-6867-5p, which may help to provide potential therapeutic target gene for lymphoma patients.
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Affiliation(s)
- Bo Pang
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
| | - Yanfang Gan
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
| | - Jing Wang
- Department of Cardiovascular Medicine, Wuhan Asia Heart Hospital, Wuhan, Hubei, China
| | - Shifang Qu
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
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Yin J, Yin Z, Lai P, Liu X, Ma J. Pyroptosis in Periprosthetic Osteolysis. Biomolecules 2022; 12:biom12121733. [PMID: 36551161 PMCID: PMC9775904 DOI: 10.3390/biom12121733] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/12/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022] Open
Abstract
Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting in the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts may be the decisive factor. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by gasdermins (GSDMs) family, among which GSDMD is the best characterized. Recent evidence indicates that activation of NLRP3 inflammasomes and pyroptosis play a pivotal role in the pathological process of PPO. Here, we review the pathological process of PPO, the molecular mechanism of pyroptosis and the interventions to inhibit the inflammation and pyroptosis of different cells during the PPO. Conclusively, this review provides theoretical support for the search for new strategies and new targets for the treatment of PPO by inhibiting pyroptosis and inflammation.
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Affiliation(s)
- Jian Yin
- Department of Orthopedics, Shanghai General Hospital of Nanjing Medical University, Shanghai 201600, China
- Department of Orthopedics, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing 211100, China
| | - Zhaoyang Yin
- Department of Orthopedics, The Affiliated Lianyungang Hospital of Xuzhou Medical University (The First People’s Hospital of Lianyungang), Lianyungang 222000, China
| | - Peng Lai
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Xinhui Liu
- Department of Orthopedics, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing 211100, China
- Correspondence: (J.M.); (X.L.)
| | - Jinzhong Ma
- Department of Orthopedics, Shanghai General Hospital of Nanjing Medical University, Shanghai 201600, China
- Department of Orthopedics, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing 211100, China
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
- Correspondence: (J.M.); (X.L.)
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10
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Wang Z, Wang MM, Geng Y, Ye CY, Zang YS. Membrane-associated RING-CH protein (MARCH8) is a novel glycolysis repressor targeted by miR-32 in colorectal cancer. J Transl Med 2022; 20:402. [PMID: 36064706 PMCID: PMC9446774 DOI: 10.1186/s12967-022-03608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 08/24/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer-related deaths worldwide. Aberrant cellular metabolism is a hallmark of cancer cells, and disturbed metabolism showed clinical significance in CRC. The membrane-associated RING-CH 8 (MARCH8) protein, the first MARCH E3 ligase, plays an oncogenic role and serves as a prognostic marker in multiple cancers, however, the role of MARCH8 in CRC is unclear. In the present study, we aimed to investigate the biomarkers and their underlying mechanism for CRC. METHOD In this study, we first examined the function of MARCH8 in CRC by analysing public database. Besides, we performing gene silencing studies and generating cellular overexpression and xenograft models. Then its protein substrate was identified and validated. In addition, the expression of MARCH8 was investigated in tissue samples from CRC patients, and the molecular basis for decreased expression was analysed. RESULTS Systematic analysis reveals that MARCH8 is a beneficial prognostic marker in CRC. In CRC, MARCH8 exhibited tumor-suppressive activity both in vivo and in vitro. Furthermore, we found that MARCH8 is negatively correlated with hexokinase 2 (HK2) protein in CRC patients. MARCH8 regulates glycolysis and promotes ubiquitination-mediated proteasome degradation to reduces HK2 protein levels. Then HK2 inhibitor partially rescues the effect of MARCH8 knockdown in CRC. Poised chromatin and elevated miR-32 repressed MARCH8 expression. CONCLUSION In summary, we propose that in CRC, poised chromatin and miR-32 decrease the expression of MARCH8, further bind and add ubiquitin, induce HK2 degradation, and finally repress glycolysis to promote tumor suppressors in CRC.
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Affiliation(s)
- Zhan Wang
- Department of Medical Oncology, Second Affiliated Hospital of Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Miao-Miao Wang
- Department of Medical Oncology, Second Affiliated Hospital of Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Yan Geng
- Department of Nursing, Zhabei Branch Hospital, Second Affiliated Hospital of Naval Medical University, No. 619, Zhonghuaxin Road, Shanghai, 200070, China
| | - Chen-Yang Ye
- Department of Medical Oncology, Second Affiliated Hospital of Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Yuan-Sheng Zang
- Department of Medical Oncology, Second Affiliated Hospital of Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, China.
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11
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Varvil MS, Bailey T, Dhawan D, Knapp DW, Ramos-Vara JA, dos Santos AP. The miRNome of canine invasive urothelial carcinoma. Front Vet Sci 2022; 9:945638. [PMID: 36072391 PMCID: PMC9443663 DOI: 10.3389/fvets.2022.945638] [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] [Received: 05/16/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Urothelial carcinoma (UC) comprises up to 2% of all naturally occurring neoplasia in dogs and can be challenging to diagnose. MicroRNAs (miRNAs) have been reported to be dysregulated in numerous diseases, including neoplasia. MiRNA expression has been evaluated in human UC, but there is limited information regarding the miRNA transcriptome of UC in dogs. Our study aimed to evaluate differential miRNA expression in bladder tissue collected from normal canine urothelium and canine invasive UC (iUC) to elucidate the dysregulated pathways in canine UC. Next-Generation RNA sequencing (RNA-Seq) was performed for dogs with UC (n = 29) and normal canine urothelium (n = 4). Raw RNA data were subjected to normalization, and pairwise comparison was performed using EdgeR with Benjamini-Hochberg FDR multiple testing correction (p < 0.05; >2-fold change) comparing tissue samples of normal urothelium to canine iUC samples. Principal component analysis and hierarchical cluster analysis were performed. MiRNA of FFPE tissue samples of separate iUC (n = 5) and normal urothelium (n = 5) were used to evaluate five miRNAs using RT-qPCR. Pathway analysis was performed utilizing miRWalk, STRING database, and Metascape utilizing KEGG pathways and GO terms databases. Twenty-eight miRNAs were differentially expressed (DE) by RNA-Seq. RT-qPCR confirmed that four miRNAs are significantly downregulated in UC compared to healthy urothelial samples (miR-105a, miR-143, miR-181a, and miR-214). Principal component analysis and hierarchical cluster analysis showed separation between miRNAs in iUC and the control group. The DE miRNAs are most often associated with gene silencing by miRNA, miRNAs in cancer, and miRNAs involved in DNA damage responses. Proteins involved include HRAS, KRAS, ARAF, RAF1, MAPK1, MAP2K1, MAPK3, FGFR3, EGFR, HBEGF, RASSF1, E2F2, E2F3, ERBB2, SRC, MMP1, and UP3KA. The differential expression of miRNAs in canine iUC compared to normal canine urothelial tissue indicates that these markers should be further evaluated for their potential role as diagnostic and therapeutic targets.
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Affiliation(s)
- Mara S. Varvil
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Taylor Bailey
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Deepika Dhawan
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Deborah W. Knapp
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
- Center for Cancer Research, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - José A. Ramos-Vara
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
- Center for Cancer Research, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - Andrea P. dos Santos
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
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12
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Wang X, Shang Y, Dai S, Wu W, Yi F, Cheng L. MicroRNA-16-5p Aggravates Myocardial Infarction Injury by Targeting the Expression of Insulin Receptor Substrates 1 and Mediating Myocardial Apoptosis and Angiogenesis. Curr Neurovasc Res 2021; 17:11-17. [PMID: 31870262 DOI: 10.2174/1567202617666191223142743] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/12/2019] [Accepted: 11/18/2019] [Indexed: 01/07/2023]
Abstract
PURPOSE Myocardial infarction is a common cardiovascular disease. MicroRNA-16-5p (miR-16-5p) was upregulated in heart and kidney hypoxia/reoxygenation (H/R) injury. However, the role of miR-16-5p in myocardial infarction injury is still unclear. METHODS Human adult ventricular cardiomyocytes (AC16) were treated with ischemia/reperfusion (H/R). The miR-16-5p level was evaluated through real-time PCR. The activity of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was detected via LDH and CK-MB monitoring kits. Cell viability was examined with 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetra-zolium bromide (MTT) assay. Western blotting was used to analyze the protein levels. The luci-ferase report assay confirmed the relative luciferase activity. RESULTS miR-16-5p was elevated in H/R-treated AC16 cells. miR-16-5p overexpression and knockdown were carried out. miR-16-5p knockdown repressed cell apoptosis, attenuated LDH and CK-MB activities, and enhanced cell viability in H/R-treated AC16 cells. Moreover, miR-16-5p knockdown promoted angiogenesis in human microvascular endothelial cells (HMVEC), causing elevation of vascular endothelial growth factor (VEGF), insulin receptor substrates 1 (IRS1), minichromosome maintenance complex component 2 (MCM2) and proliferating cell nuclear antigen (PCNA) protein levels. Moreover, miR-16-5p was testified to target IRS1. IRS1 silencing alleviated miR-16-5p knockdown-mediated inhibition of apoptosis in AC16 cells. CONCLUSION miR-16-5p knockdown increased cell viability and angiogenesis, as well as inhibited cell apoptosis by increasing IRS1. These findings indicated that miR-16-5p knockdown may be a new therapeutic target for myocardial infarction.
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Affiliation(s)
- Xiancan Wang
- Department of Cardiovascular Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430014, China
| | - Yuqiang Shang
- Department of Cardiovascular Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430014, China
| | - Shilin Dai
- Department of Cardiovascular Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430014, China
| | - Wei Wu
- Department of Cardiovascular Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430014, China
| | - Fan Yi
- Department of Cardiovascular Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430014, China
| | - Long Cheng
- Department of Cardiovascular Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430014, China
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13
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Chen X, Ding Z, Li T, Jiang W, Zhang J, Deng X. MicroR-26b Targets High Mobility Group, AT-hook 2 to Ameliorate Myocardial Infarction-induced Fibrosis by Suppression of Cardiac Fibroblasts Activation. Curr Neurovasc Res 2021; 17:204-213. [PMID: 32370714 DOI: 10.2174/1567202617666200506101258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Myocardial Fibrosis (MF) is an important physiological change after myocardial infarction (MI). MicroRNA-26b (MiR-26b) has a certain inhibitory effect on pulmonary fibrosis. However, the role of miR-26b in MI-induced MF rats and underlying molecular mechanisms remain unknown. METHODS Forty male Sprague Dawley (SD) rats weighing 200-250 g were divided into four groups (n=10): Sham group, MF group, MF + negative control (NC) agomir group and MF + miR-26b agomir group. Cardiac fibroblasts were isolated from cardiac tissue. Fibrosis levels were detected by MASSON staining, while the expression of related genes was detected by RT-qPCR, Western blotting and Immunohistochemistry, respectively. TargetScan and dual-luciferase reporter assay were utilized to predict the relationship between miR-26b and high mobility group, AT-hook 2 (HMGA2). RESULTS The study found the expression of miR-26b to be down-regulated in the myocardium of MF rats (P<0.01). miR-26b overexpression in vitro significantly reduced the survival rate of cardiac fibroblasts and inhibited the expression of the fibrillar-associated protein (α-SMA alphasmooth muscle actin (α-SMA) and collagen I) (P<0.01). TargetScan indicated that HMGA2 was one of the target genes of miR-26b; dual-luciferase reporter assay further confirmed the targeted regulatory relationship (P<0.01). Moreover, miR-26b overexpression significantly reduced the expression of HMGA2 (P<0.01). Notably, HMGA2 overexpression reversed the inhibitory effect of miR-26b overexpression on cardiac fibroblast viability and the expression of α-SMA and collagen I (P<0.01). Animal experiments further indicated that miR-26b overexpression inhibited MIinduced rat MF by inhibiting the expression of HMGA2 (P<0.05, P<0.01). CONCLUSION In short, these findings indicate that miR-26b targets HMGA2 to ameliorate MI-induced fibrosis by suppression of cardiac fibroblasts activation.
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Affiliation(s)
- Xiao Chen
- Department of Cardiopulmonary Rehabilitation, Jiangsu Rongjun Hospital, Wuxi City, Jiangsu Province, 214000, China
| | - Zhaosheng Ding
- Department of Cardiopulmonary Rehabilitation, Jiangsu Rongjun Hospital, Wuxi City, Jiangsu Province, 214000, China
| | - Tong Li
- Department of Cardiopulmonary Rehabilitation, Jiangsu Rongjun Hospital, Wuxi City, Jiangsu Province, 214000, China
| | - Wei Jiang
- Department of Cardiopulmonary Rehabilitation, Jiangsu Rongjun Hospital, Wuxi City, Jiangsu Province, 214000, China
| | - Jiawei Zhang
- Department of Cardiopulmonary Rehabilitation, Jiangsu Rongjun Hospital, Wuxi City, Jiangsu Province, 214000, China
| | - Xuejun Deng
- Department of Pathology, The First Affiliated Hospital of University of South China, Hengyang City, Hunan Province, 421001, China
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Liu QF, Zhang Y, Deng L, Zhang T, Xiao JP, Zhou ZM, Bi N. MiR-32 Suppresses the Development of Lung Cancer via Modulating PI3K/Akt. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Our team utilized qRT-PCR for prospecting miR-32 expression level in primary lung carcinoma tissues and cell lines, as well as Kaplan–Meier method for dissecting the relation of miR-32 expression with the prognosis of lung carcinoma. We transfected lung cancer A549 cells with
miR-32 mimic/inhibitor and mimic/inhibitor NC, and appraised the influences of miR-32 on the phenotype changes of lung carcinoma cells via MTT assay, wound healing assay and cell apoptosis assay, separately. Then the target gene of miR-32 was predicted via bioinformatics. Finally, Western
blotting was adopted for analyzing the impact of alteration of miR-32 expression on the PI3K/Akt axis in A549 cells. In lung carcinoma tissues as well as cells, miR-32 expression is down-regulated, and miR-32 partakes in the progress of lung carcinoma via PI3K/Akt pathway.
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Affiliation(s)
- Qing-Feng Liu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Ye Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Lei Deng
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Tao Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Jian-Ping Xiao
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Zong-Mei Zhou
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Nan Bi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, China
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15
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López de Las Hazas MC, Gil-Zamorano J, Cofán M, Mantilla-Escalante DC, Garcia-Ruiz A, Del Pozo-Acebo L, Pastor O, Yañez-Mo M, Mazzeo C, Serra-Mir M, Doménech M, Valls-Pedret C, Rajaram S, Sabaté J, Ros E, Sala-Vila A, Dávalos A. One-year dietary supplementation with walnuts modifies exosomal miRNA in elderly subjects. Eur J Nutr 2021; 60:1999-2011. [PMID: 32979076 DOI: 10.1007/s00394-020-02390-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 09/14/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE Epidemiological studies and clinical trials support the association of nut consumption with a lower risk of prevalent non-communicable diseases, particularly cardiovascular disease. However, the molecular mechanisms underlying nut benefits remain to be fully described. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and play a pivotal role in health and disease. Exosomes are extracellular vesicles released from cells and mediate intercellular communication. Whether nut consumption modulates circulating miRNAs (c-miRNAs) transported in exosomes is poorly described. METHODS Cognitively healthy elderly subjects were randomized to either control (n = 110, abstaining from walnuts) or daily supplementation with walnuts (15% of their total energy, ≈30-60 g/day, n = 101) for 1-year. C-miRNAs were screened in exosomes isolated from 10 samples, before and after supplementation, and identified c-miRNA candidates were validated in the whole cohort. In addition, nanoparticle tracking analysis and lipidomics were assessed in pooled exosomes from the whole cohort. RESULTS Exosomal hsa-miR-32-5p and hsa-miR-29b-3p were consistently induced by walnut consumption. No major changes in exosomal lipids, nanoparticle concentration or size were found. CONCLUSION Our results provide novel evidence that certain c-miRNAs transported in exosomes are modulated by walnut consumption. The extent to which this finding contributes to the benefits of walnuts deserves further research.
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Affiliation(s)
- María-Carmen López de Las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, IMDEA Food Institute, CEI UAM+CSIC, Ctra. De Cantoblanco 8, 28049, Madrid, Spain
| | - Judit Gil-Zamorano
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, IMDEA Food Institute, CEI UAM+CSIC, Ctra. De Cantoblanco 8, 28049, Madrid, Spain
| | - Montserrat Cofán
- Lipid Clinic, Endocrinology and Nutrition Service, Institut d´Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Diana C Mantilla-Escalante
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, IMDEA Food Institute, CEI UAM+CSIC, Ctra. De Cantoblanco 8, 28049, Madrid, Spain
| | - Almudena Garcia-Ruiz
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, IMDEA Food Institute, CEI UAM+CSIC, Ctra. De Cantoblanco 8, 28049, Madrid, Spain
| | - Lorena Del Pozo-Acebo
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, IMDEA Food Institute, CEI UAM+CSIC, Ctra. De Cantoblanco 8, 28049, Madrid, Spain
| | - Oscar Pastor
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
- Servicio de Bioquímica Clínica (UCA-CCM), Hospital Ramón y Cajal-IRYCIS, 28034, Madrid, Spain
| | - María Yañez-Mo
- Department of Molecular Biology, UAM, 28049, Madrid, Spain
- Centro de Biología Molecular Severo Ochoa (CBM-SO), Instituto de Investigación Sanitaria Princesa (IIS-IP), 28049, Madrid, Spain
| | - Carla Mazzeo
- Department of Molecular Biology, UAM, 28049, Madrid, Spain
- Centro de Biología Molecular Severo Ochoa (CBM-SO), Instituto de Investigación Sanitaria Princesa (IIS-IP), 28049, Madrid, Spain
| | - Mercè Serra-Mir
- Lipid Clinic, Endocrinology and Nutrition Service, Institut d´Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain
| | - Monica Doménech
- Lipid Clinic, Endocrinology and Nutrition Service, Institut d´Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain
| | - Cinta Valls-Pedret
- Lipid Clinic, Endocrinology and Nutrition Service, Institut d´Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain
| | - Sujatha Rajaram
- Center for Nutrition, Healthy Lifestyle and Disease Prevention, School of Public Health, Loma Linda University, Loma Linda, CA, 92350, USA
| | - Joan Sabaté
- Center for Nutrition, Healthy Lifestyle and Disease Prevention, School of Public Health, Loma Linda University, Loma Linda, CA, 92350, USA
| | - Emilio Ros
- Lipid Clinic, Endocrinology and Nutrition Service, Institut d´Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Aleix Sala-Vila
- Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, 08003, Spain.
- Hospital del Mar Medical Research Institute, IMIM, Dr. Aiguader 88, 08003, Barcelona, Spain.
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, IMDEA Food Institute, CEI UAM+CSIC, Ctra. De Cantoblanco 8, 28049, Madrid, Spain.
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16
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He T, Zhang X, Hao J, Ding S. Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor. Front Physiol 2021; 12:684529. [PMID: 34140896 PMCID: PMC8204087 DOI: 10.3389/fphys.2021.684529] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/28/2021] [Indexed: 12/13/2022] Open
Abstract
The Phosphatase and tensin homolog (PTEN) gene is one of the most important tumor suppressor genes, which acts through its unique protein phosphatase and lipid phosphatase activity. PTEN protein is widely distributed and exhibits complex biological functions and regulatory modes. It is involved in the regulation of cell morphology, proliferation, differentiation, adhesion, and migration through a variety of signaling pathways. The role of PTEN in malignant tumors of the digestive system is well documented. Recent studies have indicated that PTEN may be closely related to many other benign processes in digestive organs. Emerging evidence suggests that PTEN is a potential therapeutic target in the context of several non-neoplastic diseases of the digestive tract. The recent discovery of PTEN isoforms is expected to help unravel more biological effects of PTEN in non-neoplastic digestive diseases.
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Affiliation(s)
- Tianyu He
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Xiaoyun Zhang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
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17
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Chen R, Yang M, Huang W, Wang B. Cascades between miRNAs, lncRNAs and the NF-κB signaling pathway in gastric cancer (Review). Exp Ther Med 2021; 22:769. [PMID: 34055068 PMCID: PMC8145527 DOI: 10.3892/etm.2021.10201] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/28/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is a common digestive tract malignancy that is mainly treated with surgery combined with perioperative adjuvant chemoradiotherapy and biological targeted therapy. However, the diagnosis rate of early gastric cancer is low and both postoperative recurrence and distant metastasis are thorny problems. Therefore, it is essential to study the pathogenesis of gastric cancer and search for more effective means of treatment. The nuclear factor-κB (NF-κB) signaling pathway has an important role in the occurrence and development of gastric cancer and recent studies have revealed that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are able to regulate this pathway through a variety of mechanisms. Understanding these interrelated molecular mechanisms is helpful in guiding improvements in gastric cancer treatment. In the present review, the functional associations between miRNAs, lncRNAs and the NF-κB signaling pathway in the occurrence, development and prognosis of gastric cancer were discussed. It was concluded that miRNAs and lncRNAs have complex relations with the NF-κB signaling pathway in gastric cancer. miRNAs/target genes/NF-κB/target proteins, signaling molecules/NF-κB/miRNAs/target genes, lncRNAs/miRNAs/NF-κB/genes or mRNAs, lncRNAs/target genes/NF-Κb/target proteins, and lncRNAs/NF-κB/target proteins cascades are all important factors in the occurrence and development of gastric cancer.
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Affiliation(s)
- Risheng Chen
- Department of Anesthesiology, Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Mingxiu Yang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology (2016TP1015), Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Weiguo Huang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology (2016TP1015), Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Baiyun Wang
- Department of Anesthesiology, Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
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18
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Zhan D, Lin M, Chen J, Cai W, Liu J, Fang Y, Li Y, Wu B, Wang G. Hypoxia-inducible factor-1α regulates PI3K/AKT signaling through microRNA-32-5p/PTEN and affects nucleus pulposus cell proliferation and apoptosis. Exp Ther Med 2021; 21:646. [PMID: 33968177 PMCID: PMC8097185 DOI: 10.3892/etm.2021.10078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 03/01/2021] [Indexed: 01/07/2023] Open
Abstract
Intervertebral disc degeneration and resulting low back pain arises from the programmed apoptosis of nucleus pulposus cells (NPCs). Recent studies show that hypoxia-inducible factor-1α plays a vital role in the etiology and pathogenesis of disc degeneration. However, the underlying mechanism of HIF-1α in NPCs is unclear. The present study identified 994 significant differentially expressed miRNAs by analyzing microarray data downloaded from the Gene Expression Omnibus database. MicroRNA(miR)-32-5p expression was 2.81-fold upregulated in NPCs compared with that of the healthy control tissues (P<0.05). A total of 331 significant differentially expressed mRNAs were identified, and PTEN was downregulated in NPCs of non-degenerative disc tissues from young patients. miR-32-5p was predicted to target the PTEN 3'-untranslated region (UTR). To confirm these results, in-vitro experiments investigating the molecular function of miR-32-5p and PTEN were performed. Furthermore, hypoxia induced miR-32-5p and PTEN expression. HIF-1α inhibited NPC proliferation and promoted cell apoptosis by regulating miR-32-5p and PTEN. miR-32-5p promoted NPC proliferation and decreased cell apoptosis. Next, it was verified whether miR-32-5p targeted the PTEN 3'-UTR using dual-luciferase reporter assays. Finally, it was observed that PI3K/AKT/mTOR signaling pathway was upregulated by a miR-32-5p mimic, which improved cell proliferation and decreased apoptosis. Importantly, PTEN was downregulated in these experiments; and inhibition of miR-32-5p had the opposite effect. Overall, these results demonstrate that HIF-1α regulates cell proliferation and apoptosis by controlling the miR-32-5p/PTEN/PI3K/AKT/mTOR axis in NPCs.
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Affiliation(s)
- Daolu Zhan
- Department of Spine Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Mingxia Lin
- Department of Spine Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Jian Chen
- Department of Spine Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Wentao Cai
- Department of Spine Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Jian Liu
- Department of Spine Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Yehan Fang
- Department of Sports Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Yibo Li
- Department of Spine Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Bin Wu
- Department of Spine Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
| | - Guangji Wang
- Department of Sports Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Xiuying, Haikou, Hainan 570311, P.R. China
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19
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Wu W, Chen Y, Ye S, Yang H, Yang J, Quan J. Transcription factor forkhead box K1 regulates miR-32 expression and enhances cell proliferation in colorectal cancer. Oncol Lett 2021; 21:407. [PMID: 33841568 PMCID: PMC8020380 DOI: 10.3892/ol.2021.12668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/16/2021] [Indexed: 12/13/2022] Open
Abstract
Increased microRNA (miR)-32 expression in colorectal cancer (CRC) tissues enhances CRC cell proliferation, migration, invasion and attenuates CRC cell apoptosis by repressing the expression of phosphatase and tensin homolog (PTEN). Forkhead box K1 (FOXK1) was identified as a potential interacting transcription factor using DNA pull-down assays and mass spectrometry. The present study aimed to elucidate the role of FOXK1 in regulating miR-32 expression in CRC. The expressions of FOXK1, miR-32, transmembrane protein 245 gene (TMEM245) and PTEN were compared between CRC and normal colonic tissues. Levels of miR-32, TMEM245, PTEN and the proliferation and apoptosis of CRC cells were studied using FOXK1-overexpression or knockdown, or by simultaneously interfering with FOXK1 and miR-32 expression. Direct FOXK1 binding to the miR-32 promoter was verified using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The results showed elevated FOXK1, miR-32 and TMEM245 expression, and significantly decreased PTEN expression in CRC, compared with normal colonic tissues. Correlations between the expressions of TMEM245 and miR-32, FOXK1 and miR-32, and FOXK1 and TMEM245 were positive and significant. FOXK1-knockdown led to decreased miR-32 and TMEM245 expression and increased PTEN expression, whereas FOXK1-overexpression had the opposite effect. Overexpressed FOXK1 promoted the malignancy of CRC cells in vitro by stimulating proliferation and reducing apoptosis; whereas FOXK1-depletion suppressed such malignancy and a miR-32 inhibitor partially reversed the effects of FOXK1. The results of ChIP and dual-luciferase reporter assays indicated that FOXK1 directly binds to the promoter of TMEM245/miR-32. Thus, the FOXK1-miR-32-PTEN signaling axis may play a crucial role in the pathogenesis and development of CRC.
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Affiliation(s)
- Weiyun Wu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Yongze Chen
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Shicai Ye
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Hui Yang
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Jianyun Yang
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Juanhua Quan
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
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20
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Liu X, Wang X, Zhang L, Zhou Y, Yang L, Yang M. By targeting apoptosis facilitator BCL2L13, microRNA miR-484 alleviates cerebral ischemia/reperfusion injury-induced neuronal apoptosis in mice. Bioengineered 2021; 12:948-959. [PMID: 33724167 PMCID: PMC8806345 DOI: 10.1080/21655979.2021.1898134] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Neuronal apoptosis was considered as one of the main factors of cerebral ischemia/reperfusion injury. Understanding the molecular regulatory mechanism of neuronal apoptosis under the cerebral ischemia/reperfusion injury may provide the novel therapeutic targets for cerebral ischemia/reperfusion injury. However, the molecular regulatory mechanism of neurons fate determination under the cerebral ischemia/reperfusion injury remains poorly understood. This study was aimed to delve into the related molecular mechanism of miR-484 on the regulation of cerebral ischemia/reperfusion injury-induced neuronal apoptosis in mice. In this study, quantitative real-time polymerase chain reaction assays revealed that the expression level of miR-484 was down-regulated in neurons following OGD. Then, CCK8 assay western blot assay, and flow cytometry assay verified that upregulation of miR-484 increased viability and inhibited apoptosis of neurons following OGD. Further bioinformatics methods and dual-luciferase reporter assay were applied together to anticipate and certify the interaction between miR-484 and BCL2L13. Finally, cerebral infarct size assessment and TUNEL staining confirmed that overexpression of miR-484 alleviated cerebral ischemia/reperfusion injury in mice, and overexpression of BCL2L13 could abolish the effect of miR-484-suppressed cell apoptosis. All these results suggested that miR-484 alleviates cerebral ischemia/reperfusion injury-induced neuronal apoptosis in mice by targeting apoptosis facilitator BCL2L13.
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Affiliation(s)
- Xindong Liu
- Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu City, Sichuan Province, China
| | - Xin Wang
- Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu City, Sichuan Province, China
| | - Lijuan Zhang
- Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu City, Sichuan Province, China
| | - Yi Zhou
- Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu City, Sichuan Province, China
| | - Le Yang
- Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu City, Sichuan Province, China
| | - Minghao Yang
- Department of Cerebrovascular Disease, The Second Affiliated Hospital of Guilin Medical University, Guilin City, Guangxi Zhuang Autonomous Region, China
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21
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Wu Q, Zhao J, Zheng Y, Xie X, He Q, Zhu Y, Wang N, Huang L, Lu L, Hu T, Zeng J, Xia H, Zhang Y, Zhong W. Associations between common genetic variants in microRNAs and Hirschsprung disease susceptibility in Southern Chinese children. J Gene Med 2021; 23:e3301. [PMID: 33294994 PMCID: PMC7900950 DOI: 10.1002/jgm.3301] [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: 08/08/2020] [Revised: 11/16/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022] Open
Abstract
Introduction Hirschsprung disease (HSCR), characterized by the defective migration of enteric neural crest cells, is a severe congenital tract disease in infants. Its etiology is not clear at present, although a genetic component plays an important role in its etiology. Many studies focused on the polymorphisms of microRNA (miRNA) in several disease progressions have been reported, including HSCR. However, the findings remain inconclusive. The present study aimed to explore the association of genetic variants in miRNAs and HSCR susceptibility in Southern Chinese children. Methods Five single nucleotide polymorphisms (SNPs) (miR‐146A rs2910164, miR‐4318 rs8096901, miR‐3142 rs2431697, miR‐3142 rs2431097 and miR‐3142 rs5705329) were included to be genotyped in the stratified analysis through the Mass ARRAY iPLEX Gold system (Sequenom, San Diego, CA, USA) conducted on all the samples, comprising 1470 cases and 1473 controls. After quality control, the minor allele frequency was compared in cases and controls to analyze the association between SNPs and HSCR using PLINK 1.9 (https://www.cog‐genomics.org/plink) and multiple heritability models were tested (additive, recessive and dominant models). Results Our results indicated that miR‐4318 rs8096901 polymorphisms were associated with HSCR susceptibility in Southern Chinese children, especially in short‐segment HSCR (S‐HSCR) patients after stratified analysis. Conclusions In summary, we report that miR‐4318 rs8096901 was associated with HSCR, especially in SHSCR patients.
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Affiliation(s)
- Qi Wu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jinglu Zhao
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yi Zheng
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiaoli Xie
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Qiuming He
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yun Zhu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ning Wang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lihua Huang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lifeng Lu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Tuqun Hu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jixiao Zeng
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Huimin Xia
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yan Zhang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wei Zhong
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
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22
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Peng B, Theng PY, Le MTN. Essential functions of miR-125b in cancer. Cell Prolif 2020; 54:e12913. [PMID: 33332677 PMCID: PMC7848968 DOI: 10.1111/cpr.12913] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/20/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are small and highly conserved non-coding RNAs that silence target mRNAs, and compelling evidence suggests that they play an essential role in the pathogenesis of human diseases, especially cancer. miR-125b, which is the mammalian orthologue of the first discovered miRNA lin-4 in Caenorhabditis elegans, is one of the most important miRNAs that regulate various physiological and pathological processes. The role of miR-125b in many types of cancer has been well established, and so here we review the current knowledge of how miR-125b is deregulated in different types of cancer; its oncogenic and/or tumour-suppressive roles in tumourigenesis and cancer progression; and its regulation with regard to treatment response, all of which are underlined in multiple studies. The emerging information that elucidates the essential functions of miR-125b might help support its potentiality as a diagnostic and prognostic biomarker as well as an effective therapeutic tool against cancer.
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Affiliation(s)
- Boya Peng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biomedical Sciences, School of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong.,N.1 Institute for Health, National University of Singapore, Singapore, Singapore
| | - Poh Ying Theng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Minh T N Le
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biomedical Sciences, School of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong.,N.1 Institute for Health, National University of Singapore, Singapore, Singapore.,City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
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23
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Viscardi G, Di Natale D, Fasano M, Brambilla M, Lobefaro R, De Toma A, Galli G. Circulating biomarkers in malignant pleural mesothelioma. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:434-451. [PMID: 36046389 PMCID: PMC9400735 DOI: 10.37349/etat.2020.00028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 12/09/2020] [Indexed: 12/14/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor strictly connected to asbestos exposure. Prognosis is dismal as diagnosis commonly occurs in advanced stage. Radiological screenings have not proven to be effective and also pathological diagnosis may be challenging. In the era of precision oncology, validation of robust non-invasive biomarkers for screening of asbestos-exposed individuals, assessment of prognosis and prediction of response to treatments remains an important unmet clinical need. This review provides an overview on current understanding and possible applications of liquid biopsy in MPM, mostly focused on the utility as diagnostic and prognostic test.
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Affiliation(s)
- Giuseppe Viscardi
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80131 Naples, Italy 2Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Davide Di Natale
- Department of Translational Medical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, 80131 Naples, Italy
| | - Morena Fasano
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80131 Naples, Italy
| | - Marta Brambilla
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Riccardo Lobefaro
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Alessandro De Toma
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Giulia Galli
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
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24
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Fadaka AO, Sibuyi NRS, Madiehe AM, Meyer M. MicroRNA-based regulation of Aurora A kinase in breast cancer. Oncotarget 2020; 11:4306-4324. [PMID: 33245732 PMCID: PMC7679040 DOI: 10.18632/oncotarget.27811] [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: 08/18/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
The involvement of non-coding RNAs (ncRNAs) in cellular physiology and disease pathogenesis is becoming increasingly relevant in recent years specifically in cancer research. Breast cancer (BC) has become a health concern and accounts for most of the cancer-related incidences and mortalities reported amongst females. In spite of the presence of promising tools for BC therapy, the mortality rate of metastatic BC cases is still high. Therefore, the genomic exploration of the BC subtype and the use of ncRNAs for possible regulation is pivotal. The expression and prognostic values of AURKA gene were assessed by Oncomine, GEPIA, KM-plotter, and bc-GenExMiner v4.4, respectively. Associated proteins and functional enrichment were evaluated by Cytoscape and DAVID databases. Additionally, molecular docking approach was employed to investigate the regulatory role of hsa-miR-32-3p assisted argonaute (AGO) protein of AURKA gene in BC. AURKA gene was highly expressed in patients with BC relative to normal counterpart and significantly correlated with poor survival. The docking result suggested that AURKA could be regulated by hsa-miR-32-3p as confirmed by the reported binding energy and specific interactions. The study gives some insights into role of AURKA and its regulation by microRNAs through AGO protein. It also provides exciting opportunities for cancer therapeutic intervention.
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Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Nicole Remaliah Samantha Sibuyi
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Abram Madimabe Madiehe
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa.,Nanobiotechnology Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Mervin Meyer
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
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25
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Propofol ameliorated diabetic peripheral neuropathic pain via modulating miR-150/EPHB2 axis. Mol Cell Toxicol 2020. [DOI: 10.1007/s13273-020-00103-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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26
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Wu HK, Liu C, Li XX, Ji W, Xin CD, Hu ZQ, Zhou L. PHLPP2 is regulated by competing endogenous RNA network in pathogenesis of colon cancer. Aging (Albany NY) 2020; 12:12812-12840. [PMID: 32633726 PMCID: PMC7377866 DOI: 10.18632/aging.103246] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 04/18/2020] [Indexed: 12/16/2022]
Abstract
Recently, homologous pleckstrin-homology (PH)-domain leucine-rich-repeat protein phosphatases (PHLPP2) has been reported as a tumor suppressor in colon cancer. This study aimed to unravel the possible involvement of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) regulating PHLPP2 in colon cancer. Expressions of candidate lncRNAs and miRNAs were verified by the RT-qPCR and Western blot analyses in colon cancer. The roles of candidate genes in colon cancer were investigated in HT-29 cells in vitro and in mouse tumor xenograft model in vivo. PHLPP2, a target of miR-141 and miR-424, was downregulated in colon cancer. PHLPP2 upregulation and miR-141 and miR-424 downregulation suppressed the colon cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition, and promote cell apoptosis, which also resulted in suppression of tumor metastasis and formation. Furthermore, LINC00402, LINC00461, and SFTA1P were identified as the targets of miR-141 and miR-424 and acted as competitive endogenous RNAs (ceRNAs) of PHLPP2. The upregulation of LINC00402, LINC00461, and SFTA1P was verified to enhance the suppressive effects of PHLPP2 in the pathogenesis of colon cancer. Conjointly, our results demonstrated the suppressive effects of PHLPP2 in colon cancer and proved that LINC00402, LINC00461, and SFTA1P acted as ceRNAs of PHLPP2 by competitive binding to miR-141 and miR-424.
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Affiliation(s)
- Hong-Kun Wu
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China
| | - Chang Liu
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China
| | - Xin-Xing Li
- Department of General Surgery, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China
| | - Wei Ji
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China
| | - Chen-De Xin
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China
| | - Zhi-Qian Hu
- Department of General Surgery, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China
| | - Lin Zhou
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, P.R. China
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27
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Zeng S, Liu S, Feng J, Gao J, Xue F. MicroRNA-32 promotes ovarian cancer cell proliferation and motility by targeting SMG1. Oncol Lett 2020; 20:733-741. [PMID: 32565999 PMCID: PMC7285996 DOI: 10.3892/ol.2020.11624] [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: 01/01/2019] [Accepted: 11/22/2019] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy and one of the leading causes of cancer-related deaths among women. Metastasis is the main cause of poor prognosis in OC. MicroRNA (miRNA/miR) has been shown to play an important role in tumorigenesis and metastasis in various cancer types by affecting the expression of its targets. In the present study, the role of miR-32 (miR-32-5p) in OC was explored. Reverse transcription-quantitative PCR results showed that miR-32 expression was significantly upregulated in both OC tissues and cell lines. Inhibition of miR-32 by transfection with miR-32 inhibitor in OC cells markedly suppressed cell proliferation, migration and invasion. In addition, a luciferase assay showed that suppressor of morphogenesis in genitalia 1 (SMG1) is a direct target of miR-32, and interference in SMG1 expression with transfection of SMG1 small hairpin RNA restored miR-32-mediated OC cell proliferation, migration and invasion. Taken together, these results indicate that miR-32 may promote OC cell growth and motility by targeting SMG1. The data of the present study suggest that miR-32 may serve as a potential therapeutic target for OC treatment in the future.
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Affiliation(s)
- Saitian Zeng
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.,Department of Gynecology and Obstetrics, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Shikai Liu
- Department of Gynecology and Obstetrics, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Jing Feng
- Department of Gynecology and Obstetrics, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Jiefan Gao
- Department of Gynecology and Obstetrics, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Fengxia Xue
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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28
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Xu F, Liu G, Wang L, Wang X, Jin X, Bo W. miR-494 promotes progression of retinoblastoma via PTEN through PI3K/AKT signaling pathway. Oncol Lett 2020; 20:1952-1960. [PMID: 32724440 PMCID: PMC7377044 DOI: 10.3892/ol.2020.11749] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence has indicated that the dysregulation of microRNA (miRNA) occur in the pathogenesis of retinoblastoma (RB). Aim of the present study was to investigate the possible role of miR-494 (miR-494-3p) in RB. It was demonstrated that miR-494 expression was increased in RB tissue samples and cell lines. Also, it was prominently associated with clinicopathological features. Functional assays showed that RB cell proliferation, invasion and migration can be promoted by miR-494 overexpression. Besides, phosphatase and tensin homolog (PTEN) was verified as a possible target of miR-494 by a luciferase assay, western blot and qRT-PCR assay in RB. miR-494 and PTEN expression was negatively related in a correlation analysis on tumor tissues of 66 patients. In addition, PTEN was proved to reverse miR-494 effect on RB cell progression. Moreover, PI3K/AKT signaling pathway was validated to take part in RB progression. Taken together, the current study proposes that miR-494 might function as a tumor promoter and regulates RB progression through targeting PTEN.
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Affiliation(s)
- Fen Xu
- Department of Clinical Laboratory, Jinan Zhangqiu District Hospital of TCM, Jinan, Shandong 250200, P.R. China
| | - Guiqin Liu
- Department of Ophthalmology, Jinan Zhangqiu District Hospital of TCM, Jinan, Shandong 250200, P.R. China
| | - Lijuan Wang
- Department of Paediatrics, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China
| | - Xiyan Wang
- Department of Anesthesiology, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China
| | - Xiao Jin
- Department of Rehabilitation Medicine, The People's Hospital of Zhangqiu Area, Jinan, Shandong 250200, P.R. China
| | - Wen Bo
- Department of Ophthalmology, Maternity and Child Health Care of Zaozhuang, Zaozhuang Ophthalmological Hospital, Zaozhuang, Shandong 277100, P.R. China
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29
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Esmaeili M, Keshani M, Vakilian M, Esmaeili M, Peymani M, Seyed Forootan F, Chau TL, Göktuna SI, Zaker SR, Nasr Esfahani MH, Ghaedi K. Role of non-coding RNAs as novel biomarkers for detection of colorectal cancer progression through interaction with the cell signaling pathways. Gene 2020; 753:144796. [PMID: 32450203 DOI: 10.1016/j.gene.2020.144796] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/06/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common types of cancer which affects the colon and the rectum. Approximately one third of annual CRC mortality occurs due to the late detection of this type of cancer. Therefore, there is an urgent need for more powerful diagnostic and prognostic tools for identification and treatment of colorectal tumorigenesis. Non-coding RNAs (ncRNAs) have been implicated in the pathology of CRC and also linked to metastasis, proliferation, differentiation, migration, angiogenesis and apoptosis in numerous cancers. Recently, attention has turned towards ncRNAs as specific targets for diagnosis, prognosis and treatment of various types of cancers, including CRC. In this review, we have tried to outline the roles of ncRNAs, and their involvement in signaling pathways responsible for the progression of CRC.
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Affiliation(s)
- Mohadeseh Esmaeili
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran.
| | - Maryam Keshani
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran.
| | - Mehrdad Vakilian
- Department of Cell Regeneration and Advanced Therapies, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, Sevilla, Spain; Department of Cellular Biology, Genetics and Physiology, Faculty of Science, University of Malaga (UMA), Málaga, Spain.
| | - Maryam Esmaeili
- Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran; Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Farzad Seyed Forootan
- Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran; Legal Medicine Research Centre, Legal Medicine Organization, Tehran, Iran.
| | - Tieu Lan Chau
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
| | - Serkan Ismail Göktuna
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey; National Nanotechnology Research Institute (UNAM), Bilkent University, Ankara, Turkey.
| | - Sayed Rasoul Zaker
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Mohammad Hossein Nasr Esfahani
- Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
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Danbaran GR, Aslani S, Sharafkandi N, Hemmatzadeh M, Hosseinzadeh R, Azizi G, Jadidi-Niaragh F, Babaie F, Mohammadi H. How microRNAs affect the PD-L1 and its synthetic pathway in cancer. Int Immunopharmacol 2020; 84:106594. [PMID: 32416456 DOI: 10.1016/j.intimp.2020.106594] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/27/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022]
Abstract
Programmed cell death-ligand 1 (PD-L1) is a glycoprotein that is expressed on the cell surface of both hematopoietic and nonhematopoietic cells. PD-L1 play a role in the immune tolerance and protect self-tissues from immune system attack. Dysfunction of this molecule has been highlighted in the pathogenesis of tumors, autoimmunity, and infectious disorders. MicroRNAs (miRNAs) are endogenous molecules that are classified as small non-coding RNA with approximately 20-22 nucleotides (nt) length. The function of miRNAs is based on complementary interactions with target mRNA via matching completely or incompletely. The result of this function is decay of the target mRNA or preventing mRNA translation. In the past decades, several miRNAs have been discovered which play an important role in the regulation of PD-L1 in various malignancies. In this review, we discuss the effect of miRNAs on PD-L1 expression and consider the effect of miRNAs on the synthetic pathway of PD-L1, especially during cancers.
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Affiliation(s)
| | - Saeed Aslani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nadia Sharafkandi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Hosseinzadeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Babaie
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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Challenges in Cancer Biomarker Discovery Exemplified by the Identification of Diagnostic MicroRNAs in Prostate Tissues. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9086829. [PMID: 32462034 PMCID: PMC7225851 DOI: 10.1155/2020/9086829] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/20/2020] [Accepted: 04/25/2020] [Indexed: 12/23/2022]
Abstract
Identification and clinical translation of routinely tested biomarkers require a complex and multistep workflow. Here, we described a confirmatory process estimating the utility of previously identified candidate tissue miRNAs for diagnosis of prostate cancer (PCa). RNA was isolated from formalin-fixed paraffin-embedded (FFPE) prostate tissue surgically resected from 44 patients with PCa and 24 patients with benign prostate hyperplasia (BPH). Of the 92 RNA samples obtained, 68 represented 42 malignant (PCa) areas and 26 represented nonmalignant (PCa 0%) areas of the prostate tissue sections. The levels of miR-32-5p, miR-183-5p, miR-141-5p, miR-187-3p, miR-375, miR-663b, miR-615-3p, miR-205-5p, miR-221-3p, and miR-222-3p were evaluated using Exiqon chemistry. Five (miR-32-5p, miR-141-5p, miR-187-3p, miR-375, and miR-615-3p), one (miR-32-5p), and two (miR-32-5p and miR-141-5p) miRNAs discriminated between BPH and areas of cancer-bearing prostate tissue harboring different numbers of cancer cells (PCa 15–70%, PCa 2–10%, and PCA 0%, respectively), with an area under the receiver operating characteristics curve (AUC-ROC) > 0.9. Only miRNA 32-5p discriminated BPH specimens from sections of cancer-bearing prostate tissue with a low percentage, a high percentage, or no dysplastic cells. miR-32-5p could be considered as potential diagnostic biomarker discriminating BPH from noncancerous areas within cancer-bearing prostate tissue. However, further clinical studies are warranted to confirm its diagnostic utility.
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The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective. Int J Mol Sci 2020; 21:ijms21030980. [PMID: 32024140 PMCID: PMC7037112 DOI: 10.3390/ijms21030980] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/14/2020] [Accepted: 01/15/2020] [Indexed: 12/26/2022] Open
Abstract
Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. Epigenetic alterations have been shown to participate in this complex environment, through mechanisms including DNA methylation, non-coding RNAs, histone modifications, and chromatin changes. Despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in VC, and cross-talk between different epigenetic machineries is rarely examined. We conducted a systematic review based on PUBMED and MEDLINE databases up to 30 September 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in VC; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding RNA, followed by DNA methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). Nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without VC, supporting their applicability as biomarkers. Assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between microRNAs, DNA methylation, and histone modification regarding potential influences on VC risk.
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Streleckiene G, Inciuraite R, Juzenas S, Salteniene V, Steponaitiene R, Gyvyte U, Kiudelis G, Leja M, Ruzgys P, Satkauskas S, Kupcinskiene E, Franke S, Thon C, Link A, Kupcinskas J, Skieceviciene J. miR-20b and miR-451a Are Involved in Gastric Carcinogenesis through the PI3K/AKT/mTOR Signaling Pathway: Data from Gastric Cancer Patients, Cell Lines and Ins-Gas Mouse Model. Int J Mol Sci 2020; 21:877. [PMID: 32013265 PMCID: PMC7038213 DOI: 10.3390/ijms21030877] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 01/22/2020] [Accepted: 01/28/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common and lethal gastrointestinal malignancies worldwide. Many studies have shown that development of GC and other malignancies is mainly driven by alterations of cellular signaling pathways. MicroRNAs (miRNAs) are small noncoding molecules that function as tumor-suppressors or oncogenes, playing an essential role in a variety of fundamental biological processes. In order to understand the functional relevance of miRNA dysregulation, studies analyzing their target genes are of major importance. Here, we chose to analyze two miRNAs, miR-20b and miR-451a, shown to be deregulated in many different malignancies, including GC. Deregulated expression of miR-20b and miR-451a was determined in GC cell lines and the INS-GAS mouse model. Using Western Blot and luciferase reporter assay we determined that miR-20b directly regulates expression of PTEN and TXNIP, and miR-451a: CAV1 and TSC1. Loss-of-function experiments revealed that down-regulation of miR-20b and up-regulation of miR-451a expression exhibits an anti-tumor effect in vitro (miR-20b: reduced viability, colony formation, increased apoptosis rate, and miR-451a: reduced colony forming ability). To summarize, the present study identified that expression of miR-20b and miR-451a are deregulated in vitro and in vivo and have a tumor suppressive role in GC through regulation of the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Greta Streleckiene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
| | - Ruta Inciuraite
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
| | - Simonas Juzenas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany
| | - Violeta Salteniene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
| | - Ruta Steponaitiene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
| | - Ugne Gyvyte
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
| | - Gediminas Kiudelis
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
| | - Marcis Leja
- Institute for Clinical and Preventive Medicine, University of Latvia, Riga LV-1586, Latvia;
- Faculty of Medicine, University of Latvia, Riga LV-1586, Latvia
- Department of Research, Riga East University Hospital, Riga LV-1038, Latvia
- Digestive Diseases Centre GASTRO, Riga LV-1079, Latvia
| | - Paulius Ruzgys
- Biophysical Research Group, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas LT-44404, Lithuania; (P.R.); (S.S.)
| | - Saulius Satkauskas
- Biophysical Research Group, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas LT-44404, Lithuania; (P.R.); (S.S.)
| | - Eugenija Kupcinskiene
- Department of Biology, Faculty of Nature Sciences, Vytautas Magnus University, Kaunas LT-44404, Lithuania;
| | - Sabine Franke
- Institute of Pathology, Otto-von-Guericke University, 39120 Magdeburg, Germany;
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany; (C.T.); (A.L.)
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany; (C.T.); (A.L.)
| | - Juozas Kupcinskas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; (G.S.); (R.I.); (S.J.); (V.S.); (R.S.); (U.G.); (G.K.); (J.K.)
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Zhang Y, Wang J, An W, Chen C, Wang W, Zhu C, Chen F, Chen H, Zheng W, Gong J. MiR-32 Inhibits Proliferation and Metastasis by Targeting EZH2 in Glioma. Technol Cancer Res Treat 2019; 18:1533033819854132. [PMID: 31138033 PMCID: PMC6542126 DOI: 10.1177/1533033819854132] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Purpose: Glioma is identified as a broad category of brain and spinal cord tumors. MiR-32 is important in regulating the genesis of different cancers; however, the underlying mechanisms of miR-32 in glioma still largely unknown. This study aimed to elucidate pathobiological functions of miR-32 in glioma and verify its effect on the regulation of enhancer of zeste homolog 2. Methods: The expression of miR-32 and enhancer of zeste homolog 2 was detected by quantitative real-time polymerase chain reaction and Western blot in glioma tissues and cells. Cell Counting Kit-8 (CCK-8) assay was used to examine the effects of miR-32 on human glioma cells proliferation. Transwell assay was used to examine cell metastasis, respectively. Two bioinformatics analysis software and luciferase reporter assay were chosen to confirm targeting association between miR-32 and enhancer of zeste homolog 2. Results: MiR-32 was downregulated in glioma tissues and cells. Furthermore, enhancer of zeste homolog 2 expression was upregulated and negatively correlated with miR-32 in clinical tissues. Ectopic expression of miR-32 inhibited glioma cell proliferation, migration, and invasion. Enhancer of zeste homolog 2 was identified as direct target gene of miR-32 in glioma. Overexpression of enhancer of zeste homolog 2 ablated the inhibitory effects of miR-32. Conclusion: In summary, our finding suggests that miR-32 acts an important role in inhibiting glioma cell proliferation and metastasis and suppresses the expression of ABCC4 by directly targeting its 3′-untranslated region. The miR-32/enhancer of zeste homolog 2 axis may provide new insights to the treatment for glioma.
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Affiliation(s)
- Yuan Zhang
- 1 Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan City, Shandong Province, People's Republic of China.,2 Shandong Key Laboratory of Brain Function Remodeling, Jinan City, Shandong Province, People's Republic of China
| | - Jiangang Wang
- 1 Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan City, Shandong Province, People's Republic of China.,2 Shandong Key Laboratory of Brain Function Remodeling, Jinan City, Shandong Province, People's Republic of China
| | - Wenzhi An
- 3 Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou City, Hebei Province, People's Republic of China
| | - Chen Chen
- 4 Taishan Medical University, Taian City, Shandong Province, People's Republic of China
| | - Wencheng Wang
- 4 Taishan Medical University, Taian City, Shandong Province, People's Republic of China
| | - Chao Zhu
- 5 Department of Neurosurgery, Affiliated Hospital of Taishan Medical University, Taian City, Shandong Province, People's Republic of China
| | - Fangzhou Chen
- 5 Department of Neurosurgery, Affiliated Hospital of Taishan Medical University, Taian City, Shandong Province, People's Republic of China
| | - Huizhao Chen
- 5 Department of Neurosurgery, Affiliated Hospital of Taishan Medical University, Taian City, Shandong Province, People's Republic of China
| | - Wei Zheng
- 5 Department of Neurosurgery, Affiliated Hospital of Taishan Medical University, Taian City, Shandong Province, People's Republic of China
| | - Jie Gong
- 1 Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan City, Shandong Province, People's Republic of China.,2 Shandong Key Laboratory of Brain Function Remodeling, Jinan City, Shandong Province, People's Republic of China
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35
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Soleimani A, Rahmani F, Saeedi N, Ghaffarian R, Khazaei M, Ferns GA, Avan A, Hassanian SM. The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer. J Cell Biochem 2019; 120:19245-19253. [PMID: 31512778 DOI: 10.1002/jcb.29268] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 06/11/2019] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.
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Affiliation(s)
- Atena Soleimani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nikoo Saeedi
- Student Research Committee, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Rana Ghaffarian
- Student Research Committee, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, Sussex, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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36
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Soleimani A, Rahmani F, Ferns GA, Ryzhikov M, Avan A, Hassanian SM. Role of Regulatory Oncogenic or Tumor Suppressor miRNAs of PI3K/AKT Signaling Axis in the Pathogenesis of Colorectal Cancer. Curr Pharm Des 2019; 24:4605-4610. [PMID: 30636581 DOI: 10.2174/1381612825666190110151957] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the leading cause of cancer death worldwide and its incidence is increasing. In most patients with CRC, the PI3K/AKT signaling axis is over-activated. Regulatory oncogenic or tumor suppressor microRNAs (miRNAs) for PI3K/AKT signaling regulate cell proliferation, migration, invasion, angiogenesis, as well as resistance to chemo-/radio-therapy in colorectal cancer tumor tissues. Thus, regulatory miRNAs of PI3K/AKT/mTOR signaling represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies. This review summarizes the current knowledge of miRNAs' regulatory roles of PI3K/AKT signaling in CRC pathogenesis.
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Affiliation(s)
- Atena Soleimani
- Department of Medical Biochemistry, faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Medical Biochemistry, faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Mikhail Ryzhikov
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO, United States
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of M edical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Medical Biochemistry, faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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37
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Yu Y, Dong JT, He B, Zou YF, Li XS, Xi CH, Yu Y. LncRNA SNHG16 induces the SREBP2 to promote lipogenesis and enhance the progression of pancreatic cancer. Future Oncol 2019; 15:3831-3844. [PMID: 31664866 DOI: 10.2217/fon-2019-0321] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: Blocking lipogenesis could significantly inhibit the progression of pancreatic cancer. Exploring the regulatory mechanisms of lipogenesis by lncRNA SNHG16 might be of great significance to control the development of pancreatic cancer. Methods: The proliferation, migration, invasion and lipogenesis were determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, transwell and Oil Red O staining assays, respectively. The interactions among lncRNA SNHG16, miR-195 and SREBP2 were analyzed by dual luciferase reporter assays. Results: Both the knock down of lncRNA SNHG16 and SREBP2 and overexpression of miR-195 suppressed the proliferation, migration, invasion and lipogenesis in pancreatic cancer cells. LncRNA SNHG16 directly sponged miR-195 to modulate the lipogenesis via regulating the expression of SREBP2. Conclusion: LncRNA SNHG16 accelerated the development of pancreatic cancer and promoted lipogenesis via directly regulating miR-195/SREBP2 axis.
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Affiliation(s)
- Yi Yu
- Department of Pediatrics, Ruijin Hospital North, Shanghai Jiaotong University, School of Medicine, Shanghai 201801, PR China
| | - Jia-Tian Dong
- Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, PR China
| | - Bing He
- Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, PR China
| | - Yu-Feng Zou
- Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, PR China
| | - Xue-Song Li
- Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, PR China
| | - Chen-Hui Xi
- Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, PR China
| | - Yuan Yu
- Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, PR China
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38
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Razdan A, de Souza P, Roberts TL. Role of MicroRNAs in Treatment Response in Prostate Cancer. Curr Cancer Drug Targets 2019; 18:929-944. [PMID: 29644941 PMCID: PMC6463399 DOI: 10.2174/1568009618666180315160125] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/14/2017] [Accepted: 06/15/2017] [Indexed: 12/16/2022]
Abstract
Prostate cancer (PCa) is the most common non-skin cancer in men worldwide, resulting in significant mortality and morbidity. Depending on the grade and stage of the cancer, patients may be given radiation therapy, hormonal therapy, or chemotherapy. However, more than half of these patients develop resistance to treatment, leading to disease progression and metastases, often with lethal consequences. MicroRNAs (miRNAs) are short, non-coding RNAs, which regulate numerous physiological as well as pathological processes, including cancer. miRNAs mediate their regulatory effect predominately by binding to the 3'-untranslated region (UTR) of their target mRNAs. In this review, we will describe the mechanisms by which miRNAs mediate resistance to radiation and drug therapy (i.e. hormone therapy and chemotherapy) in PCa, including control of apoptosis, cell growth and proliferation, autophagy, epithelial-to-mesenchymal transition (EMT), invasion and metastasis, and cancer stem cells (CSCs). Furthermore, we will discuss the utility of circulating miRNAs isolated from different body fluids of prostate cancer patients as non-invasive biomarkers of cancer detection, disease progression, and therapy response. Finally, we will shortlist the candidate miRNAs, which may have a role in drug and radioresistance, that could potentially be used as predictive biomarkers of treatment response.
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Affiliation(s)
- Anshuli Razdan
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia
| | - Paul de Souza
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.,School of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.,Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Tara Laurine Roberts
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.,School of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.,The University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia
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39
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Arabsorkhi Z, Gharib E, Yaghmoorian Khojini J, Farhadieh M, Nazemalhosseini‐Mojarad E, Zali MR. miR‐298 plays a pivotal role in colon cancer invasiveness by targeting PTEN. J Cell Physiol 2019; 235:4335-4350. [DOI: 10.1002/jcp.29310] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 09/30/2019] [Indexed: 01/07/2023]
Affiliation(s)
- Zahra Arabsorkhi
- Department of Molecular Biology, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Ehsan Gharib
- Department of Molecular Biology, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences Tehran Iran
| | | | | | - Ehsan Nazemalhosseini‐Mojarad
- Department of Gastrointestinal Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Mohammad Reza Zali
- Department of Gastrointestinal Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences Tehran Iran
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40
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Kumar N, Dougherty JA, Manring HR, Elmadbouh I, Mergaye M, Czirok A, Greta Isai D, Belevych AE, Yu L, Janssen PML, Fadda P, Gyorke S, Ackermann MA, Angelos MG, Khan M. Assessment of temporal functional changes and miRNA profiling of human iPSC-derived cardiomyocytes. Sci Rep 2019; 9:13188. [PMID: 31515494 PMCID: PMC6742647 DOI: 10.1038/s41598-019-49653-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 07/31/2019] [Indexed: 12/22/2022] Open
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been developed for cardiac cell transplantation studies more than a decade ago. In order to establish the hiPSC-CM-based platform as an autologous source for cardiac repair and drug toxicity, it is vital to understand the functionality of cardiomyocytes. Therefore, the goal of this study was to assess functional physiology, ultrastructural morphology, gene expression, and microRNA (miRNA) profiling at Wk-1, Wk-2 & Wk-4 in hiPSC-CMs in vitro. Functional assessment of hiPSC-CMs was determined by multielectrode array (MEA), Ca2+ cycling and particle image velocimetry (PIV). Results demonstrated that Wk-4 cardiomyocytes showed enhanced synchronization and maturation as compared to Wk-1 & Wk-2. Furthermore, ultrastructural morphology of Wk-4 cardiomyocytes closely mimicked the non-failing (NF) adult human heart. Additionally, modulation of cardiac genes, cell cycle genes, and pluripotency markers were analyzed by real-time PCR and compared with NF human heart. Increasing expression of fatty acid oxidation enzymes at Wk-4 supported the switching to lipid metabolism. Differential regulation of 12 miRNAs was observed in Wk-1 vs Wk-4 cardiomyocytes. Overall, this study demonstrated that Wk-4 hiPSC-CMs showed improved functional, metabolic and ultrastructural maturation, which could play a crucial role in optimizing timing for cell transplantation studies and drug screening.
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Affiliation(s)
- Naresh Kumar
- Department of Emergency Medicine, Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Julie A Dougherty
- Department of Emergency Medicine, Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Heather R Manring
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ibrahim Elmadbouh
- Department of Emergency Medicine, Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Muhamad Mergaye
- Department of Emergency Medicine, Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Andras Czirok
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Dona Greta Isai
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Andriy E Belevych
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Lianbo Yu
- Center for Biostatistics, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Paul M L Janssen
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Paolo Fadda
- Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sandor Gyorke
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Maegen A Ackermann
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Mark G Angelos
- Department of Emergency Medicine, Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Mahmood Khan
- Department of Emergency Medicine, Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA. .,Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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Wang Q, He Y, Kan W, Li F, Ji X, Wu X, Wang X, Zhang Y, Chen J. microRNA-32-5p targets KLF2 to promote gastric cancer by activating PI3K/AKT signaling pathway. Am J Transl Res 2019; 11:4895-4908. [PMID: 31497207 PMCID: PMC6731418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 07/06/2019] [Indexed: 06/10/2023]
Abstract
Krüppel-like factor 2 (KLF2) is a member of the zinc finger family, which is considered a potential tumor suppressor gene due to its reduced expression in gastric cancer. MicroRNAs (miRNAs) are a class of short non-coding single-stranded RNAs that are closely related to the development of gastric cancer. The purpose of this study was to investigate the miRNAs that regulate KLF2 and explore its specific mechanism in gastric cancer. Bioinformatics software Targetscan identified that microRNA-32-5p (miRNA-32-5p) may bind to KLF2 mRNA to regulate its expression. In order to verify the regulatory effect of miRNA-32-5p on KLF2, the proliferation and migration assays were performed in both KLF2 overexpression and KLF2 knockdown gastric cancer cells. Dual-Luciferase reporter assay proved that KLF2 could bind to the PTEN promoter to induce its expression. Moreover, research on molecular mechanisms indicated that both miRNA-32-5p and shKLF2 downregulated the expression of PTEN and activated the PI3K/AKT signaling to promote the development of gastric cancer. Targeting miRNA-32-5p and KLF2 is expected to provide new sign and target for gastric cancer treatment.
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Affiliation(s)
- Qingqing Wang
- Department of Gastroenterology, Fengxian Hospital, Anhui University of Science and TechnologyShanghai 201499, P. R. China
- Department of Gastroenterology, Fengxian Hospital, Southern Medical UniversityShanghai 201499, P. R. China
| | - Yuan He
- Joint Center for Translational Medicine, Fengxian District Central Hospital6600th Nanfeng Road, Fengxian District, Shanghai 201499, P. R. China
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University500 Dongchuan Road, Shanghai 200241, P. R. China
| | - Weiqiong Kan
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University500 Dongchuan Road, Shanghai 200241, P. R. China
| | - Fucai Li
- School of Chemistry & Chemical Engineering, Shanghai Jiao Tong University800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Xiangjun Ji
- Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical UniversityGuangzhou, P. R. China
| | - Xuewen Wu
- Department of Gastroenterology, Fengxian Hospital, Anhui University of Science and TechnologyShanghai 201499, P. R. China
- Department of Gastroenterology, Fengxian Hospital, Southern Medical UniversityShanghai 201499, P. R. China
| | - Xinyue Wang
- Department of Gastroenterology, Fengxian Hospital, Anhui University of Science and TechnologyShanghai 201499, P. R. China
- Department of Gastroenterology, Fengxian Hospital, Southern Medical UniversityShanghai 201499, P. R. China
| | - Yue Zhang
- Department of Gastroenterology, Fengxian Hospital, Anhui University of Science and TechnologyShanghai 201499, P. R. China
| | - Jinlian Chen
- Department of Gastroenterology, Fengxian Hospital, Southern Medical UniversityShanghai 201499, P. R. China
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Jin Y, Cheng H, Cao J, Shen W. MicroRNA 32 promotes cell proliferation, migration, and suppresses apoptosis in colon cancer cells by targeting OTU domain containing 3. J Cell Biochem 2019; 120:18629-18639. [PMID: 31338872 DOI: 10.1002/jcb.28874] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 03/01/2019] [Accepted: 03/15/2019] [Indexed: 12/14/2022]
Abstract
Colorectal cancer is considered as the fourth leading reason of cancer-linked deaths worldwide. However, our knowledge about its pathogenic mechanism remains inadequate. MicroRNA 32 (miR-32), a member of small noncoding RNAs, has been found vital roles in tumorigenesis. This study studied its functions and underlying mechanism in colorectal cancer. The experiment revealed the obvious upregulation of miR-32 in colorectal cancer tissues and six cancer cell lines, compared with normal tissues and cells. Moreover, miR-32 upregulation reduced cell apoptosis and promoted cell proliferation and migration, while its downregulation displayed opposite effects. Dual luciferase reporter assays proved that miR-32 bound to the 3'-untranslated region (3'-UTR) of OTU domain containing 3 (OTUD3), suggesting that miR-32 directly targeted OTUD3. Further experiments demonstrated that overexpression of miR-32 could reduce the expression level of OTUD3. Furthermore, OTUD3 silence promoted proliferation and motility and decreased apoptosis for HCT116 cells and restored partly miR-32-mediated cell proliferation, migration, and antiapoptosis for colon cancer. Therefore, our study indicated that miR-32 enhanced cell proliferation and motility abilities, and inhibited apoptosis by directly targeting OTUD3 in colon cancer cells, which implied that miR-32 was hopeful to be a biomarker or target used for diagnosis and therapy of colon cancer.
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Affiliation(s)
- Yanzhao Jin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
| | - Hua Cheng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
| | - Jiaqing Cao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
| | - Wei Shen
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
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43
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Shirmohamadi M, Eghbali E, Najjary S, Mokhtarzadeh A, Kojabad AB, Hajiasgharzadeh K, Lotfinezhad P, Baradaran B. Regulatory mechanisms of microRNAs in colorectal cancer and colorectal cancer stem cells. J Cell Physiol 2019; 235:776-789. [PMID: 31264216 DOI: 10.1002/jcp.29042] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 06/13/2019] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) is one of the most lethal and hard-to-treat cancers in the world, which in its advanced stages, surgery and chemotherapy are the main common treatment approaches. The microRNAs (miRNAs), as novel markers for CRC detection, promote their regulatory effects via the 3'-untranslated binding region (3'-UTR) of target messenger RNA in posttranscriptional regulation of genes and also play a pivotal role in modulating resistance to chemotherapeutic agents. These small noncoding RNAs have also a critical role in CRC stem cells (CRCSCs) regulation, comprising self-renewal, differentiation, and tumorigenesis. Cancer stem cells (CSCs) are distinctive cell types inside a tumor tissue that are believed to derive from normal somatic stem cells. The CSCs have self-renewal abilities, angiogenesis, as well as specific surface markers expression characteristics. Furthermore, they are frequently criticized for tumor maintenance, treatment resistance, tumor development, and distant metastasis. In this review, we discuss the current understandings of CRCSCs and their environment with a focus on the role of miRNAs on the regulation of CSCs and their targeting application in CRC treatment.
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Affiliation(s)
- Masoud Shirmohamadi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Eghbali
- Medical Radiation Sciences Research Group, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shiva Najjary
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Parisa Lotfinezhad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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MicroRNA-32 targeting PTEN enhances M2 macrophage polarization in the glioma microenvironment and further promotes the progression of glioma. Mol Cell Biochem 2019; 460:67-79. [PMID: 31218569 DOI: 10.1007/s11010-019-03571-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/04/2019] [Indexed: 12/25/2022]
Abstract
This study was aimed to explore the molecular mechanism of macrophage polarization and its effect on glioma progression. THP1 cells were cocultured in conditioned medium from U87 human glioblastoma cells to simulate the glioma microenvironment. The expression of miR-32 and PTEN in THP1 cells was detected by real-time PCR. A luciferase reporter assay was conducted to confirm the target relation between miR-32 and PTEN. Western blot assays and ELISA were performed to detect PTEN, M2 macrophage-specific markers, PI3K/AKT signaling proteins, and apoptosis-related proteins. U87 cell proliferation was evaluated by CCK-8 and colony forming assays, and the migration ability of the cells was evaluated by Transwell and wound healing assays. The U87 culture supernatant promoted the M2 phenotype of THP1 cells. miR-32 was upregulated and PTEN was downregulated in THP1 cells with the M2 phenotype in the glioma microenvironment. Luciferase assays confirmed that PTEN expression was suppressed by miR-32 through interaction with the 3'UTR of PTEN. Overexpression of miR-32 suppressed PTEN expression in THP1 cells. Overexpression of miR-32 or downregulation of PTEN promoted the expression of M2 macrophage-specific markers, thereby enhancing M2 macrophage polarization. Additionally, miR-32 inhibited THP1 cell apoptosis via suppressing the PI3K/AKT signaling pathway. Most importantly, the proliferation and migration capacities of U87 cells treated with the THP1 culture supernatant after miR-32 overexpression were enhanced, and these effects could be reversed by cotransfection with pcDNA3.1-PTEN. miR-32 negatively modulates PTEN, thereby promoting M2 macrophage transformation through PI3K/AKT signaling, enhancing glioma proliferation and migration abilities.
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45
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Siveen KS, Raza A, Ahmed EI, Khan AQ, Prabhu KS, Kuttikrishnan S, Mateo JM, Zayed H, Rasul K, Azizi F, Dermime S, Steinhoff M, Uddin S. The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment, Metastasis and Drug Resistance in Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11060746. [PMID: 31146452 PMCID: PMC6628238 DOI: 10.3390/cancers11060746] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 05/22/2019] [Accepted: 05/24/2019] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, with high morbidity and mortality rates. A number of factors including modulation of the tumor microenvironment, high metastatic capability, and resistance to treatment have been associated with CRC disease progression. Recent studies have documented that tumor-derived extracellular vesicles (EVs) play a significant role in intercellular communication in CRC via transfer of cargo lipids, proteins, DNA and RNAs to the recipient tumor cells. This transfer influences a number of immune-related pathways leading to activation/differentiation/expression of immune cells and modulation of the tumor microenvironment that plays a significant role in CRC progression, metastasis, and drug resistance. Furthermore, tumor-derived EVs are secreted in large amounts in biological fluids of CRC patients and as such the expression analysis of EV cargoes have been associated with prognosis or response to therapy and may be a source of therapeutic targets. This review aims to provide a comprehensive insight into the role of EVs in the modulation of the tumor microenvironment and its effects on CRC progression, metastasis, and drug resistance. On the other hand, the potential role of CRC derived EVs as a source of biomarkers of response and therapeutic targets will be discussed in detail to understand the dynamic role of EVs in CRC diagnosis, treatment, and management.
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Affiliation(s)
- Kodappully S Siveen
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Afsheen Raza
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Eiman I Ahmed
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Abdul Q Khan
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Kirti S Prabhu
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Shilpa Kuttikrishnan
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Jericha M Mateo
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Hatem Zayed
- College of Health Sciences, Department of Biomedical Sciences, Qatar University, Doha P.O. Box 2713, Qatar.
| | - Kakil Rasul
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Fouad Azizi
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Said Dermime
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
| | - Martin Steinhoff
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
- Department of Dermatology 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
- Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
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Coronel-Hernández J, López-Urrutia E, Contreras-Romero C, Delgado-Waldo I, Figueroa-González G, Campos-Parra AD, Salgado-García R, Martínez-Gutierrez A, Rodríguez-Morales M, Jacobo-Herrera N, Terrazas LI, Silva-Carmona A, López-Camarillo C, Pérez-Plasencia C. Cell migration and proliferation are regulated by miR-26a in colorectal cancer via the PTEN-AKT axis. Cancer Cell Int 2019; 19:80. [PMID: 30983885 PMCID: PMC6444875 DOI: 10.1186/s12935-019-0802-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/23/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Invasion and metastasis are determinant events in the prognosis of Colorectal cancer (CRC), a common neoplasm worldwide. An important factor for metastasis is the acquired capacity of the cell to proliferate and invade adjacent tissues. In this paper, we explored the role of micro-RNA-26a in the regulation of proliferation and migration in CRC-derived cells through the negative regulation of PTEN, a key negative regulator of the AKT pathway. METHODS Expression levels of PTEN and mir-26a were surveyed in normal and CRC-derived cell lines; paraffin embedded human tissues, TCGA CRC expression data and a Balb/c mice orthotopic induced CRC model. CRC was induced by an initial intraperitoneal dose of the colonic carcinogen Azoxymethane followed by inflammatory promoter Dextran Sulfate Sodium Salt. Luciferase assays provide information about miR-26a-PTEN 3'UTR interaction. Proliferation and migration by real time cell analysis and wound-healing functional analyses were performed to assess the participation of mir-26a on important hallmarks of CRC and its regulation on the PTEN gene. RESULTS We observed a negative correlation between PTEN and mir-26a expression in cell lines, human tissues, TCGA data, and tissues derived from the CRC mouse model. Moreover, we showed that negative regulation of PTEN exerted by miR-26a affected AKT phosphorylation levels directly. Functional assays showed that mir-26a directly down-regulates PTEN, and that mir-26a over-expressing cells had higher proliferation and migration rates. CONCLUSIONS All this data proposes an important role of mir-26a as an oncomir in the progression and invasion of CRC. Our data suggested that mir-26a could be used as a biomarker of tumor development in CRC patients, however more studies must be conducted to establish its clinical role.
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Affiliation(s)
- Jossimar Coronel-Hernández
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, Mexico
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Eduardo López-Urrutia
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, Mexico
| | - Carlos Contreras-Romero
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, Mexico
| | - Izamary Delgado-Waldo
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, Mexico
| | - Gabriela Figueroa-González
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando No 22, Col. Sección XVI, Tlalpan, Zip code 14080 Mexico City, DF Mexico
| | - Alma D. Campos-Parra
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando No 22, Col. Sección XVI, Tlalpan, Zip code 14080 Mexico City, DF Mexico
| | - Rebeca Salgado-García
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando No 22, Col. Sección XVI, Tlalpan, Zip code 14080 Mexico City, DF Mexico
| | - Antonio Martínez-Gutierrez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando No 22, Col. Sección XVI, Tlalpan, Zip code 14080 Mexico City, DF Mexico
| | - Miguel Rodríguez-Morales
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando No 22, Col. Sección XVI, Tlalpan, Zip code 14080 Mexico City, DF Mexico
| | - Nadia Jacobo-Herrera
- Unidad de Bioquímica, Instituto de Ciencias Médicas y Nutrición, Salvador Zubirán, Tlalpan, Mexico City, DF Mexico
| | - Luis Ignacio Terrazas
- Laboratorio de Inmunología de Parásitos, Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, Mexico
| | - Abraham Silva-Carmona
- Laboratorio de Genética, Genómica y Bioinformática, Hospital Infantil de México, Mexico City, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, Mexico
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando No 22, Col. Sección XVI, Tlalpan, Zip code 14080 Mexico City, DF Mexico
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Li Q, Li Z, Lin Y, Che H, Hu Y, Kang X, Zhang Y, Wang L, Zhang Y. High glucose promotes hepatic fibrosis via miR‑32/MTA3‑mediated epithelial‑to‑mesenchymal transition. Mol Med Rep 2019; 19:3190-3200. [PMID: 30816482 PMCID: PMC6423609 DOI: 10.3892/mmr.2019.9986] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 02/12/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatic fibrosis is characterized by the aberrant production and deposition of extracellular matrix (ECM) proteins. Growing evidence indicates that the epithelial‑mesenchymal transition serves a crucial role in the progression of liver fibrogenesis. Although a subset of microRNAs (miRNAs or miRs) has recently been identified as essential regulators of the EMT gene expression, studies of the EMT in hyperglycemic‑induced liver fibrosis are limited. In the current study, it was observed that high glucose‑treated AML12 cells occurred EMT process, and miR‑32 expression was markedly increased in the liver tissue of streptozotocin‑induced diabetic rats and in high glucose‑treated AML12 cells. Additionally, the contribution of the EMT to liver fibrosis by targeting metastasis‑associated gene 3 (MTA3) under hyperglycemic conditions was suppressed by AMO‑32. The results indicated that miR‑32 and MTA3 may be considered as novel drug targets in the prevention and treatment of liver fibrosis under hyperglycemic conditions. These finding improves the understanding of the progression of liver fibrogenesis.
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Affiliation(s)
- Qiang Li
- Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
- Department of Gastroenterology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150030, P.R. China
| | - Zhange Li
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yuan Lin
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Hui Che
- Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yingying Hu
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xujuan Kang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Ying Zhang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Lihong Wang
- Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yong Zhang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
- Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, Heilongjiang 150086, P.R. China
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Wu W, Ye S, Tan W, Zhou Y, Quan J. Analysis of promoter methylation and epigenetic regulation of miR-32 in colorectal cancer cells. Exp Ther Med 2019; 17:3209-3214. [PMID: 30936995 DOI: 10.3892/etm.2019.7328] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 02/11/2019] [Indexed: 11/05/2022] Open
Abstract
MicroRNA-32 (miR-32) is upregulated in colorectal cancer (CRC) tissues; its overexpression leads to increased cell proliferation, migration and invasion, as well as reduced apoptosis of CRC cells, at least partly by inhibiting the target gene phosphatase and tensin homolog. However, the mechanisms of its upregulation have remained elusive. In the present study, the effects of methylation and acetylation on the expression of miR-32 were investigated. The promoter methylation status of miR-32 in the CRC cell lines HT-29 and HCT-116 and the normal colonic epithelial cell line NCM460 was investigated by bisulfate sequencing polymerase chain reaction (BSP). The potential role of methylation and histone acetylation in the regulation of miR-32 expression in CRC cells was investigated using the demethylation reagent 5-aza-2'-deoxycytidine (5-Aza-dC), the histone deacetylase inhibitor trichostatin A (TSA) and transfection of DNA methyltransferase 1 (DNMT1) overexpression plasmid. BSP revealed that CpG sites in the miR-32 promoter region of CRC and normal colonic epithelial cells were all hypomethylated, with methylation rates of 0.12, 1.14 and 0.64% in HCT-116, HT-29 and NCM460 cells, respectively. Treatment with 5-Aza-dC and/or TSA and transfection with DNMT1 plasmid did not significantly alter the expression of miR-32. Therefore, the present results suggest that methylation and histone acetylation do not affect miR-32 expression in CRC cells.
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Affiliation(s)
- Weiyun Wu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Shicai Ye
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Wenkai Tan
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Yu Zhou
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Juanhua Quan
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
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Wu W, Tan W, Ye S, Zhou Y, Quan J. Analysis of the promoter region of the human miR-32 gene in colorectal cancer. Oncol Lett 2019; 17:3743-3750. [PMID: 30881496 PMCID: PMC6403515 DOI: 10.3892/ol.2019.10042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 02/01/2019] [Indexed: 12/13/2022] Open
Abstract
The pathogenesis of colorectal cancer (CRC) is poorly understood. MicroRNA (miR)-32 upregulation in CRC tissues was previously reported, where it increased the proliferation, migration and invasion, and reduced apoptosis of CRC cells by inhibiting the expression of phosphatase and tensin homolog (PTEN). However, the mechanism underlying miR-32 upregulation remains unknown. miR-32 is an intronic miRNA located within intron 14 of the transmembrane protein 245 gene (TMEM245). The present study aimed to elucidate the biological pathways underlying miR-32 regulation in CRC. A truncated promoter containing the 5′-flanking region of TMEM245/miR-32 gene was constructed. The promoter region was analyzed by dual luciferase reporter assay in CRC cells. DNA pull-down assay and mass spectrometry (MS) were used to identify proteins binding to the core promoter. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and transcription factor (TF) analyses were used to identify the binding proteins. The −320 to −1 bp fragment of the 5′-flanking region exhibited the highest luciferase activity. The regions spanning −606 to −320 bp exhibited a significant decrease in luciferase activity, compared with the −320 to −1 bp fragment. DNA pull-down assay and MS revealed 403 potential miR-32 promoter binding proteins. GO and KEGG pathway analysis indicated that these proteins were involved in numerous physiological and biochemical processes, including ‘structural molecule activity’, ‘RNA binding’, ‘small molecule metabolic process’ and ‘biogenesis’. Furthermore, TF analysis revealed 10 potential interacting TFs, including SMAD family member 1 (SMAD1), signal transducer and activator of transcription 1 (STAT1) and forkhead box K1 (Foxk1). These results suggested that the core promoter region may be located within-320 to −1 bp of the 5′-flanking region of TMEM245/miR-32 gene, while the region from −606 to −320 bp may harbor repressive regulatory elements. The TFs SMAD1, STAT1 and Foxk1 may be involved in the transcriptional regulation of miR-32.
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Affiliation(s)
- Weiyun Wu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Wenkai Tan
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Shicai Ye
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Yu Zhou
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Juanhua Quan
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
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50
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Yan H, Jiang L, Zou H, Chen T, Liang H, Tang L. PTEN suppresses the inflammation, viability, and motility of AP-AR42J cells by activating the Wnt/β-catenin pathway. RSC Adv 2019; 9:5460-5469. [PMID: 35515912 PMCID: PMC9060792 DOI: 10.1039/c8ra08998a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/14/2019] [Indexed: 11/23/2022] Open
Abstract
Acute pancreatitis (AP), a kind of common acute abdominal disease and typical chemical inflammation, is commonly caused by pancreatin digestion of the pancreas and surrounding tissues. The gene for phosphate and tension homology deleted on chromosome ten (PTEN) is a tumor suppressor that regulates numerous cellular processes. In the present study, we have elaborately investigated the effect of PTEN on the alleviating of AP and its underlying mechanisms. Firstly, we demonstrated an up-regulation of PTEN in the pancreatic tissues from AP rats by immunochemistry, qRT-PCR and western-blot assays. Subsequently, cellular experiments exhibited that PTEN has a significant inhibition effect on the proliferation, invasion and migration of AP cells. Further underlying mechanism studies showed that the growth of AP cells was mainly restrained by PTEN in the G1 phase through activation of the Wnt/β-catenin pathway, which can be demonstrated by the down-regulation of various pro-inflammatory cytokines such as IL-6, IL-10, TNF and IL-1β. Taking these results together, we can draw the conclusion that PTEN plays a significant role in suppressing the inflammation, viability and motility of acute pancreatitis and could be a potential target for AP therapies. Acute pancreatitis (AP), a kind of common acute abdominal disease and typical chemical inflammation, is commonly caused by pancreatin digestion of the pancreas and surrounding tissues.![]()
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Affiliation(s)
- Hongtao Yan
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Li Jiang
- Cardiac Care Unit of Cardiothoracic Surgery, General Hospital of Western Theater Command Chengdu Sichuan 610083 P. R. China
| | - Hong Zou
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Tao Chen
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Hongyin Liang
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Lijun Tang
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
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