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1
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Kandettu A, Kuthethur R, Chakrabarty S. A detailed review on the role of miRNAs in mitochondrial-nuclear cross talk during cancer progression. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167731. [PMID: 39978440 DOI: 10.1016/j.bbadis.2025.167731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 01/11/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs that are associated with biochemical pathways through the post-transcriptional regulation of gene expression in different cell types. Based on their expression pattern and function, miRNAs can have oncogenic and tumor suppressor activities in different cancer cells. Altered mitochondrial function and bioenergetics are known hallmarks of cancer cells. Mitochondria play a central role in metabolic reprogramming during cancer progression. Cancer cells exploit mitochondrial function for cell proliferation, invasion, migration and metastasis. Genetic and epigenetic changes in nuclear genome contribute to altered mitochondrial function and metabolic reprogramming in cancer cells. Recent studies have identified the role of miRNAs as major facilitators of anterograde and retrograde signaling between the nucleus and mitochondria in cancer cells. Detailed analysis of the miRNA-mediated regulation of mitochondrial function in cancer cells may provide new avenues for the diagnosis, prognosis, and therapeutic management of the disease. Our review aims to discuss the role of miRNAs in nuclear-mitochondrial crosstalk regulating mitochondrial functions in different cancer types. We further discussed the potential application of mitochondrial miRNAs (mitomiRs) targeting mitochondrial biogenesis and metabolism in developing novel cancer therapy.
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Affiliation(s)
- Amoolya Kandettu
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS) Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Raviprasad Kuthethur
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS) Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS) Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
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2
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Hamdy NM, Zaki MB, Abdelmaksoud NM, Ismail RA, Abd-Elmawla MA, Rizk NI, Fathi D, Abulsoud AI. Insights into the genetic and epigenetic mechanisms governing X-chromosome-linked-miRNAs expression in cancer; a step-toward ncRNA precision. Int J Biol Macromol 2025; 289:138773. [PMID: 39675615 DOI: 10.1016/j.ijbiomac.2024.138773] [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: 12/04/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
Sex chromosomes play a significant role in establishing sex-specific differences in gene expression, thereby contributing to phenotypic diversity and susceptibility to various diseases. MicroRNAs (miRNAs), which are small non-coding RNAs encoded by both the X and Y chromosomes, exhibit sex-specific regulatory characteristics. Computational analysis has identified several X-linked miRNAs differentially expressed in sex-specific cancers. This review aims to elucidate the genetic and epigenetic mechanisms that govern the sex-specific expression of X- and Y-linked miRNAs, with particular attention to their functional role in regulating diverse cellular processes in different cancer pathways. In addition, this review provides a comprehensive understanding of the targeted therapeutic interventions and critical insights into the potential clinical implications of targeting sex-specific miRNAs. In conclusion, this review opens new horizons for further research to effectively translate these findings into viable treatment options.
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Affiliation(s)
- Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | | | - Rehab A Ismail
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mai A Abd-Elmawla
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Kasr Al-Ainy, Cairo 11562, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt
| | - Doaa Fathi
- Department of Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21526, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al Azhar University, Nasr City, Cairo 11231, Egypt
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3
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Nasimi Shad A, Akhlaghipour I, Alshakarchi HI, Saburi E, Moghbeli M. Role of microRNA-363 during tumor progression and invasion. J Physiol Biochem 2024; 80:481-499. [PMID: 38691273 DOI: 10.1007/s13105-024-01022-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/05/2024] [Indexed: 05/03/2024]
Abstract
Recent progresses in diagnostic and therapeutic methods have significantly improved prognosis in cancer patients. However, cancer is still considered as one of the main causes of human deaths in the world. Late diagnosis in advanced tumor stages can reduce the effectiveness of treatment methods and increase mortality rate of cancer patients. Therefore, investigating the molecular mechanisms of tumor progression can help to introduce the early diagnostic markers in these patients. MicroRNA (miRNAs) has an important role in regulation of pathophysiological cellular processes. Due to their high stability in body fluids, they are always used as the non-invasive markers in cancer patients. Since, miR-363 deregulation has been reported in a wide range of cancers, we discussed the role of miR-363 during tumor progression and metastasis. It has been reported that miR-363 has mainly a tumor suppressor function through the regulation of transcription factors, apoptosis, cell cycle, and structural proteins. MiR-363 also affected the tumor progression via regulation of various signaling pathways such as WNT, MAPK, TGF-β, NOTCH, and PI3K/AKT. Therefore, miR-363 can be introduced as a probable therapeutic target as well as a non-invasive diagnostic marker in cancer patients.
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Affiliation(s)
- Arya Nasimi Shad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hawraa Ibrahim Alshakarchi
- Al-Zahra Center for Medical and Pharmaceutical Research Sciences (ZCMRS), Al-Zahraa University for Women, Karbala, Iraq
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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4
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Zhang M, Zhang X, Huang S, Cao Y, Guo Y, Xu L. Programmed nanocarrier loaded with paclitaxel and dual-siRNA to reverse chemoresistance by synergistic therapy. Int J Biol Macromol 2024; 261:129726. [PMID: 38290632 DOI: 10.1016/j.ijbiomac.2024.129726] [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: 10/31/2023] [Revised: 01/13/2024] [Accepted: 01/22/2024] [Indexed: 02/01/2024]
Abstract
Paclitaxel (PTX) is commonly used in clinical tumor therapy. However, chemoresistance and the inducement of tumor metastasis severely affect the efficacy of PTX. To develop a treatment strategy to reverse chemoresistance, the co-delivery of PTX and small interfering RNA with nanocarriers were programmed in this study. The carrier we have programmed exhibits excellent safety, stability, and delivery efficiency for co-delivery of siRNA and PTX. After rapid release of siRNA, PTX could be released within 72 h. The siBcl-xL and siMcl-1 inhibited cell migration decreased the mitochondrial membrane potential, and induced the release of reactive oxygen species while synergistically functioning with the antineoplastic effects of PTX. Our strategy reduced IC50 values by 2-5-fold in different cell lines, and the results of flow cytometry confirmed increased apoptosis rates and effectively inhibited cell migration. Synergistic therapy effectively reversed chemoresistance in PTX-resistant breast cancer cells. Similarly, the synergistic administration strategy showed significant sensitizing effects in vivo. Our study demonstrates the combined application of multiple synergistic antitumor administration strategies.
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Affiliation(s)
- Mingming Zhang
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, PR China
| | - Xi Zhang
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, PR China
| | - Sijun Huang
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, PR China
| | - Yueming Cao
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, PR China
| | - Yi Guo
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, PR China.
| | - Li Xu
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, PR China.
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5
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Ruiz-Pozo VA, Cadena-Ullauri S, Guevara-Ramírez P, Paz-Cruz E, Tamayo-Trujillo R, Zambrano AK. Differential microRNA expression for diagnosis and prognosis of papillary thyroid cancer. Front Med (Lausanne) 2023; 10:1139362. [PMID: 37089590 PMCID: PMC10113479 DOI: 10.3389/fmed.2023.1139362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/16/2023] [Indexed: 04/08/2023] Open
Abstract
Papillary thyroid cancer accounts for 85% of thyroid cancer. The diagnosis is based on ultrasound methods and tumor biopsies (FNA). In recent years, research has revealed the importance of miRNAs, non-coding RNA molecules that regulate gene expression and are involved in many diseases. The present mini review describes upregulated and downregulated miRNAs expression in papillary thyroid cancer patient samples (tissue, serum, plasma) and the genes regulated by these non-coding molecules. In addition, a bibliographic search was performed to identify the expression of miRNAs that are common in tumor tissue and blood. The miRNAs miR-146b, miR-221-3p, miRNA 222, miR-21, miR-296-5p, and miR-145 are common in both tissue and bloodstream of PTC patient samples. Furthermore, these miRNAs regulate genes involved in biological processes such as cell differentiation, proliferation, migration, invasion, and apoptosis. In conclusion, miRNAs could potentially become valuable biomarkers, which could help in the early diagnosis and prognosis of papillary thyroid cancer.
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Pourgholamali B, Sohrabi B, Salbi M, Akbari S, Rastan I, Sayaf M, Jalil AT, Kadhim MM, Sheervalilou R, Mehrzad N. Bioinformatic Analysis Divulged Novel Prognostic Circulating MicroRNAs and Their Potential Target Genes in Breast Cancer. Appl Biochem Biotechnol 2023; 195:283-297. [PMID: 36074234 DOI: 10.1007/s12010-022-04151-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2022] [Indexed: 01/13/2023]
Abstract
Breast cancer (BC) is both an inherited and environmental-based disease which is the leading cause of death among women. Early detection of BC can prevent invasion and metastasis in patients. Currently, researchers endeavor to find non-invasive biological markers from body fluids. Circulating non-coding RNAs such as microRNAs (miRNAs) can potentially be valuable prognostic and detective biomarkers. To identify novel miRNA-based biomarkers, we utilized bioinformatic tools. To reach this goal, the miRNA expression profiles of GSE31309, GSE 44,281, GSE98181, and GSE118782 were analyzed through a limma package of R. Target gene prediction of differentially expressed miRNAs, called differentially expressed miRNAs (DEMs), between samples of healthy individuals and BC patients was implemented through Multimir package of R. Functional enrichment analysis of predicted target genes through Enrich R (online database) revealed that most of the genes are enriched in the mitochondrial outer membrane for cellular component, intrinsic apoptotic signaling regulations for biological processes, transcription co-receptor activity for molecular functions, and dopaminergic synapse pathway. Furthermore, our survival analysis results revealed that miR-29c and mir-361 have the potential to serve as prognostic biomarkers.
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Affiliation(s)
- Babak Pourgholamali
- Cellular and Molecular Research Center, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Behnoush Sohrabi
- Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
| | - Mandana Salbi
- Department of Microbiology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran
| | | | - Iman Rastan
- Department of Electronic and Electrical Engineering, Shiraz Azad University, Shiraz, Iran
| | - Masoud Sayaf
- Azad University Central Tehran Branch Faculty of Basic Sciences, Department of Cellular and Molecular Biology, Tehran, Iran
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Mustafa M Kadhim
- Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad, Iraq.,Department of Dentistry, Kut University College, Kut, Wasit, Iraq
| | - Roghayeh Sheervalilou
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Nazanin Mehrzad
- Department of Biology, Science and Research Branch Islamic Azad university, Tehran, Iran.
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7
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Ren L, Zhou H, Lei L, Zhang Y, Cai H, Wang X. Long non-coding RNA FOXD3 antisense RNA 1 augments anti-estrogen resistance in breast cancer cells through the microRNA-363/ trefoil factor 1/ phosphatidylinositol 3-kinase/protein kinase B axis. Bioengineered 2021; 12:5266-5278. [PMID: 34424807 PMCID: PMC8806484 DOI: 10.1080/21655979.2021.1962694] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Long non-coding RNA (lncRNA) FOXD3 antisense RNA 1 (FOXD3-AS1) has been reported to participate in multiple processes that contribute toward the development of cancer. The present study aimed to explore the effect of lncRNA FOXD3-AS1 on anti-estrogen resistance in breast cancer (BC) cells. FOXD3-AS1 was found to be highly expressed in BC cell lines. Moreover, FOXD3-AS1 was highly expressed in estrogen receptor-negative (ER-) cells compared to the ER-positive (ER+) cells. FOXD3-AS1 overexpression in T47D and MCF-7 (ER+) cells enhanced the resistance of cells to tamoxifen (TMX), whereas FOX3-AS1 downregulation reduced the TMX resistance in MDA-MB-231 (ER-) cells. Similar results were reproduced in vivo that FOXD3-AS1 inhibition reduced the growth of xenograft tumors formed by MDA-MB-231 cells following TMX treatment whereas FOXD3-AS1 overexpression in T47D cells facilitated tumor growth. The bioinformatic analysis and luciferase assays indicated that FOXD3-AS1 sponged microRNA-363 (miR-363) to restore expression of trefoil factor 1 (TFF1) mRNA. Overexpression of miR-363 reduced T47D cell proliferation induced by FOXD3-AS1, whereas overexpression of TFF1 restored growth of MDA-MB-231 cells reduced after FOXD3-AS1 silencing. The phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) was increased by FOXD3-AS1 but attenuated by miR-363. Inhibition of PI3K/Akt blocked the role of FOXD3-AS1 and reduced the TMX resistance in T47D and MCF-7 cells. Taken together, the present study suggested that FOXD3-AS1 sponges miR-363 to upregulate TFF1 expression, leading to PI3K/Akt signaling activation and anti-estrogen resistance in BC cells.
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Affiliation(s)
- Lili Ren
- Department of Integration of Traditional Chinese and Western Medicine, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, P.R. China
| | - Huanhuan Zhou
- Department of Medical Oncology, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, P.R. China
| | - Lei Lei
- Department of Medical Oncology, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, P.R. China
| | - Yongjun Zhang
- Department of Integration of Traditional Chinese and Western Medicine, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, P.R. China
| | - Hu Cai
- Department of Integration of Traditional Chinese and Western Medicine, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, P.R. China
| | - Xiaojia Wang
- Department of Medical Oncology, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, P.R. China
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8
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Li Y, Liu L, Lv Y, Zhang Y, Zhang L, Yu H, Tian W, Zhang Z, Cui S. Silencing long non-coding RNA HNF1A-AS1 inhibits growth and resistance to TAM of breast cancer cells via the microRNA-363/SERTAD3 axis. J Drug Target 2021; 29:742-753. [PMID: 33472456 DOI: 10.1080/1061186x.2021.1878362] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Long non-coding RNAs (lncRNAs) can exert effects on drug resistance of cancer cells. This study investigated the role of lncRNA HNF1A-antisense 1 (HNF1A-AS1) in growth and Tamoxifen (TAM) sensitivity of breast cancer (BC) cells. HNF1A-AS1 expression was promoted in BC cells and tissues. BC cells with HNF1A-AS1 silencing were constructed to detect cell proliferation. TAM resistant cell line with HNF1A-AS1 silencing and parent cell line with overexpressed HNF1A-AS1 were constructed to measure drug resistance. Silencing HNF1A-AS1 reduced proliferation and TAM resistance of BC cells. The downstream microRNAs (miRs) of HNF1A-AS1 and its targets were figured out and their functions in TAM resistance of BC cells were identified. HNF1A-AS1 sponged miR-363 to promote SERTAD3 expression. Downregulation of miR-363 or upregulation of SERTAD3 stimulated TAM resistance of BC cells. The findings in vitro were reproduced in in vivo experiments. It could be concluded that silencing HNF1A-AS1 inhibited growth and drug resistance to TAM of BC cells through the miR-363/SERTAD3 axis and the inactivation of the TGF-β/Smad pathway.
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Affiliation(s)
- Ying Li
- Prenatal Diagnosis Center, Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Ling Liu
- Prenatal Diagnosis Center, Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Yidong Lv
- Department of Galactophore, Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Yanwu Zhang
- Department of Galactophore, Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Linlin Zhang
- Department of Laboratory Medicine, Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Haiyang Yu
- Department of Laboratory Medicine, Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Weifang Tian
- Prenatal Diagnosis Center, Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Zhan Zhang
- Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
| | - Shihong Cui
- Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China
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9
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Safi A, Bastami M, Delghir S, Ilkhani K, Seif F, Alivand MR. miRNAs Modulate the Dichotomy of Cisplatin Resistance or Sensitivity in Breast Cancer: An Update of Therapeutic Implications. Anticancer Agents Med Chem 2021; 21:1069-1081. [PMID: 32885760 DOI: 10.2174/1871520620666200903145939] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/02/2020] [Accepted: 08/08/2020] [Indexed: 11/22/2022]
Abstract
Cisplatin has a broad-spectrum antitumor activity and is widely used for the treatment of various malignant tumors. However, acquired or intrinsic resistance of cisplatin is a major problem for patients during the therapy. Recently, it has been reported Cancer Stem Cell (CSC)-derived drug resistance is a great challenge of tumor development and recurrence; therefore, the sensitivity of Breast Cancer Stem Cells (BCSCs) to cisplatin is of particular importance. Increasing evidence has shown that there is a relationship between cisplatin resistance/sensitivity genes and related miRNAs. It is known that dysregulation of relevant miRNAs plays a critical role in regulating target genes of cisplatin resistance/sensitivity in various pathways such as cellular uptake/efflux, Epithelial-Mesenchymal Transition (EMT), hypoxia, and apoptosis. Furthermore, the efficacy of the current chemotherapeutic drugs, including cisplatin, for providing personalized medicine, can be improved by controlling the expression of miRNAs. Thus, potential targeting of miRNAs can lead to miRNA-based therapies, which will help overcome drug resistance and develop more effective personalized anti-cancer and cotreatment strategies in breast cancer. In this review, we summarized the general understandings of miRNAregulated biological processes in breast cancer, particularly focused on the role of miRNA in cisplatin resistance/ sensitivity.
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Affiliation(s)
- Asma Safi
- Clinical Research Development Unit, Shohada Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Bastami
- Clinical Research Development Unit, Shohada Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Delghir
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khandan Ilkhani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Seif
- Department of Immunology & Allergy, Academic Center for Education, Culture, and Research, Tehran, Iran
| | - Mohammad R Alivand
- Clinical Research Development Unit, Shohada Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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10
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Dong X, Li Y, Cao R, Xu H. MicroRNA-363-3p Inhibits the Expression of Renal Fibrosis Markers in TGF-β1-Treated HK-2 Cells by Targeting TGF-β2. Biochem Genet 2021; 59:1033-1048. [PMID: 33630202 DOI: 10.1007/s10528-021-10044-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/29/2021] [Indexed: 11/30/2022]
Abstract
This study aimed to explore the role of miR-363-3p in renal fibrosis (RF) in vitro. HK-2 cells were treated with transforming growth factor (TGF)-β1 for 72 h to establish an in vitro model of RF. Subsequently, western blot analysis and reverse transcription-quantitative PCR were used to detect the protein and mRNA expression levels of RF markers in TGF-β1-treated HK-2 cells, respectively. The results showed that the protein and mRNA expression levels of TGF-β2, α-smooth muscle actin (SMA), fibronectin, vimentin, collagen II and N-cadherin were increased, while the protein and mRNA expression levels of E-cadherin were decreased in TGF-β1-treated HK-2 cells. The level of miR-363-3p was significantly decreased in TGF-β1-treated HK-2 cells. TargetScan indicated that TGF-β2 was a direct target gene for miR-363-3p, which was further verified using dual luciferase reporter gene assays. Further analyses revealed that the increased protein and mRNA expression levels of TGF-β2, α-SMA, fibronectin, vimentin, collagen II, N-cadherin, increased phosphorylated-Smad3 protein level, and decreased E-cadherin protein and mRNA expression in TGF-β1-treated HK-2 cells were significantly reversed by miR-363-3p mimics. However, all the effects were suppressed by a TGF-β2-plasmid. The results suggested that miR-363-3p plays a protective role in RF by regulating the TGF-β2/Smad3 signaling pathway.
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Affiliation(s)
- Xiangnan Dong
- Department of Urinary Medicine, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Yang Li
- Department of Nephrology, Qingdao Municipal Hospital, 1 Jiaozhou Road, Shibei, Qingdao, 266000, Shandong, China
| | - Rui Cao
- Department of Blood Purification Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Honglan Xu
- Department of Nephrology, Qingdao Municipal Hospital, 1 Jiaozhou Road, Shibei, Qingdao, 266000, Shandong, China.
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11
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Dong S, Xue S, Sun Y, Han Z, Sun L, Xu J, Liu J. MicroRNA-363-3p downregulation in papillary thyroid cancer inhibits tumor progression by targeting NOB1. J Investig Med 2021; 69:66-74. [PMID: 33077486 PMCID: PMC7803892 DOI: 10.1136/jim-2020-001562] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2020] [Indexed: 12/29/2022]
Abstract
MicroRNA-363-3 p (miR-363-3 p) has been reported to play a crucial role in tumor development and progression, and function as a tumor suppressor in many types of cancer. In our previous studies, we found that miRNA-363-3 p inhibited papillary thyroid carcinoma (PTC) progression by targeting PIK3CA. Meanwhile, we found that NIN1/RPN12 binding protein 1 (NOB1) was significantly upregulated in thyroid carcinoma tissue and downregulation of NOB1 expression significantly inhibited cell proliferation, migration and invasion in PTC. However, the correlation of NOB1 and miR-363-3 p has not been investigated. Here, we performed bioinformatic analysis to explore miRNA targeting NOB1. We found that NOB1 was a target of miR-363-3 p and miR-363-3 p regulated NOB1 expression at the translational and transcriptional levels by targeting its 3' untranslated region (3'-UTR). Further, we showed that miR-363-3 p inhibited tumor progression by targeting NOB1 in vitro and in vivo. We found that overexpression miR-363-3 p or silencing NOB1 significantly increased G0/G1-phase and decreased S-phase in the human papillary thyroid cells, which led to a significant delay in cell proliferation, indicating miR-363-3 p and NOB1 are crucial for human papillary thyroid cancer tumorigenesis. Collectively, our data unveil that miR-363-3 p negatively regulates NOB1 activity by reducing its stability. This study provides a new therapeutic target for regulation of NOB1 stability to modulate human papillary thyroid cancer progression.
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Affiliation(s)
- Su Dong
- Anesthesia, First Hospital of Jilin University, Changchun, China
| | - Shuai Xue
- Thyroid Surgery, First Hospital of Jilin University, Changchun, China
| | - Yue Sun
- First Operating Room, First Hospital of Jilin University, Changchun, China
| | - Zhe Han
- Thyroid Surgery, First Hospital of Jilin University, Changchun, China
| | - Lele Sun
- Thyroid Surgery, First Hospital of Jilin University, Changchun, China
| | - Jialu Xu
- Thyroid Surgery, First Hospital of Jilin University, Changchun, China
| | - Jia Liu
- Thyroid Surgery, First Hospital of Jilin University, Changchun, China
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12
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Moussa Agha D, Rouas R, Najar M, Bouhtit F, Naamane N, Fayyad-Kazan H, Bron D, Meuleman N, Lewalle P, Merimi M. Identification of Acute Myeloid Leukemia Bone Marrow Circulating MicroRNAs. Int J Mol Sci 2020; 21:7065. [PMID: 32992819 PMCID: PMC7583041 DOI: 10.3390/ijms21197065] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In addition to their roles in different biological processes, microRNAs in the tumor microenvironment appear to be potential diagnostic and prognostic biomarkers for various malignant diseases, including acute myeloid leukemia (AML). To date, no screening of circulating miRNAs has been carried out in the bone marrow compartment of AML. Accordingly, we investigated the circulating miRNA profile in AML bone marrow at diagnosis (AMLD) and first complete remission post treatment (AMLPT) in comparison to healthy donors (HD). METHODS Circulating miRNAs were isolated from AML bone marrow aspirations, and a low-density TaqMan miRNA array was performed to identify deregulated miRNAs followed by quantitative RT-PCR to validate the results. Bioinformatic analysis was conducted to evaluate the diagnostic and prognostic accuracy of the highly and significantly identified deregulated miRNA(s) as potential candidate biomarker(s). RESULTS We found several deregulated miRNAs between the AMLD vs. HD vs. AMLPT groups, which were involved in tumor progression and immune suppression pathways. We also identified significant diagnostic and prognostic signatures with the ability to predict AML patient treatment response. CONCLUSIONS This study provides a possible role of enriched circulating bone marrow miRNAs in the initiation and progression of AML and highlights new markers for prognosis and treatment monitoring.
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Affiliation(s)
- Douâa Moussa Agha
- Laboratory of Experimental Hematology, Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium; (D.M.A.); (R.R.); (F.B.); (H.F.-K.); (D.B.); (P.L.)
| | - Redouane Rouas
- Laboratory of Experimental Hematology, Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium; (D.M.A.); (R.R.); (F.B.); (H.F.-K.); (D.B.); (P.L.)
| | - Mehdi Najar
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Department of Medicine, University of Montreal, Montreal, QC H2X 0A9, Canada;
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco
| | - Fatima Bouhtit
- Laboratory of Experimental Hematology, Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium; (D.M.A.); (R.R.); (F.B.); (H.F.-K.); (D.B.); (P.L.)
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco
| | - Najib Naamane
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
| | - Hussein Fayyad-Kazan
- Laboratory of Experimental Hematology, Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium; (D.M.A.); (R.R.); (F.B.); (H.F.-K.); (D.B.); (P.L.)
| | - Dominique Bron
- Laboratory of Experimental Hematology, Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium; (D.M.A.); (R.R.); (F.B.); (H.F.-K.); (D.B.); (P.L.)
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium; (D.M.A.); (R.R.); (F.B.); (H.F.-K.); (D.B.); (P.L.)
| | - Makram Merimi
- Laboratory of Experimental Hematology, Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium; (D.M.A.); (R.R.); (F.B.); (H.F.-K.); (D.B.); (P.L.)
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco
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13
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Li XF, Zhang SH, Liu GF, Yu SN. miR-363 Alleviates Detrusor Fibrosis via the TGF-β1/Smad Signaling Pathway by Targeting Col1a2 in Rat Models of STZ-Induced T2DM. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:1142-1153. [PMID: 33294298 PMCID: PMC7695978 DOI: 10.1016/j.omtn.2020.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 07/06/2020] [Indexed: 01/13/2023]
Abstract
Dysregulated expression of microRNAs (miRNAs or miRs) has been implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). However, their underlying role in the complication of detrusor fibrosis remains poorly understood. Therefore, this study aimed to examine the potential functional relevance of miR-363 in detrusor fibrosis of rats with streptozotocin (STZ)-induced T2DM through the predicted target gene collagen type I alpha 2 (Col1a2). Immunohistochemical analysis found an increase in the positive expression of collagen type III alpha 1 (Col3a1) and Col1a2 in detrusor tissues, where miR-363 expression was decreased. Next, gain- and loss-of-function experiments were performed to clarify the effects of miR-363 and Col1a2 on the activities of bladder detrusor cells. Of note, binding affinity between miR-363 and Col1a2 was verified by a dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. Upregulated miR-363 inhibited Col1a2 expression, which led to increased expression of B-cell lymphoma 2 (Bcl-2) and Smad7 and accelerated cell viability, along with decreases in cell apoptosis and Col3a1, Bcl-2-associated X protein (Bax), transforming growth factor (TGF)-β1, and Smad4 expressions. In conclusion, miR-363 upregulation reduces detrusor fibrosis in rats with STZ-induced T2DM through suppression of the TGF-β1/Smad signaling pathway by targeting Col1a2. Therefore, our study provided further insights for the development of new therapeutic targets for T2DM.
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Affiliation(s)
- Xue-Feng Li
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
| | - Shu-Hua Zhang
- Operation Room, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
| | - Gui-Feng Liu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
| | - Shao-Nan Yu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
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14
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Liu L, Wang Q, Qiu Z, Kang Y, Liu J, Ning S, Yin Y, Pang D, Xu S. Noncoding RNAs: the shot callers in tumor immune escape. Signal Transduct Target Ther 2020; 5:102. [PMID: 32561709 PMCID: PMC7305134 DOI: 10.1038/s41392-020-0194-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 01/17/2023] Open
Abstract
Immunotherapy, designed to exploit the functions of the host immune system against tumors, has shown considerable potential against several malignancies. However, the utility of immunotherapy is heavily limited due to the low response rate and various side effects in the clinical setting. Immune escape of tumor cells may be a critical reason for such low response rates. Noncoding RNAs (ncRNAs) have been identified as key regulatory factors in tumors and the immune system. Consequently, ncRNAs show promise as targets to improve the efficacy of immunotherapy in tumors. However, the relationship between ncRNAs and tumor immune escape (TIE) has not yet been comprehensively summarized. In this review, we provide a detailed account of the current knowledge on ncRNAs associated with TIE and their potential roles in tumor growth and survival mechanisms. This review bridges the gap between ncRNAs and TIE and broadens our understanding of their relationship, providing new insights and strategies to improve immunotherapy response rates by specifically targeting the ncRNAs involved in TIE.
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Affiliation(s)
- Lei Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Qin Wang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Zhilin Qiu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yujuan Kang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiena Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Shipeng Ning
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yanling Yin
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China. .,Heilongjiang Academy of Medical Sciences, Harbin, 150086, China.
| | - Shouping Xu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
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15
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Zhang L, Wang L, Lu N, Wang J, Yan R, Yan H, Zhang J, Zhang M. Micro RNA-363 inhibits esophageal squamous cell carcinoma progression by directly targeting sperm-associated antigen 5. J Int Med Res 2020; 48:300060520932795. [PMID: 32586155 PMCID: PMC7323308 DOI: 10.1177/0300060520932795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 05/18/2020] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE Micro RNA (miR)-363 has many important biological functions in cancers, but its roles in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS We used reverse transcription PCR to quantify the expression of miR-363 in 80 ESCC tissues and analyzed its relationship with clinicopathological factors and overall survival. The effects of miR-363 on cell proliferation, apoptosis, and invasion were detected using the MTT assay, flow cytometry, and Transwell invasion assays, respectively. Further, we investigated the post-transcriptional regulation of sperm-associated antigen 5 (SPAG5) expression by miR-363 using luciferase reporter assays. Finally, the effects of SPAG5 on miR-363 were studied by SPAG5 overexpression. RESULTS miR-363 expression was decreased in both ESCC specimens and cell lines, compared with controls, and correlated with lymph node metastasis and tumor differentiation. Low miR-363 expression was identified as an independent prognostic factor for ESCC. miR-363 overexpression decreased ESCC cell proliferation and invasion and increased apoptosis, while the opposite was seen after miR-363 inhibition. Moreover, SPAG5 was identified as a direct target of miR-363, and the reintroduction of SPAG5 restored miR-363-induced effects. CONCLUSIONS miR-363 acts as a tumor suppressor by post-transcriptionally regulating SPAG5 expression, suggesting its potential as a diagnostic biomarker and therapeutic target for ESCC.
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Affiliation(s)
- Lingmin Zhang
- Department of Thoracic Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi’an, Shaanxi, China
| | - Li Wang
- Department of Scientific Research, The Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China
| | - Ning Lu
- Department of Gastroenterology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China
| | - Jia Wang
- Department of Gastroenterology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China
| | - Rong Yan
- Department of Gastroenterology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China
| | - Honglin Yan
- Department of Gastroenterology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China
| | - Jia Zhang
- Department of Thoracic Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi’an, Shaanxi, China
| | - Mingxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China
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16
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Identification of miRNA-Based Signature as a Novel Potential Prognostic Biomarker in Patients with Breast Cancer. DISEASE MARKERS 2019; 2019:3815952. [PMID: 31976020 PMCID: PMC6954483 DOI: 10.1155/2019/3815952] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/03/2019] [Accepted: 10/17/2019] [Indexed: 12/15/2022]
Abstract
To identify the novel, noninvasive biomarkers to assess the outcome and prognosis of breast cancer (BC), patients with high sensitivity and specificity are greatly desired. Herein, the miRNA expression profile and matched clinical features of BC patients were extracted from The Cancer Genome Atlas (TCGA) database. The preliminary candidates were screened out by the univariate Cox regression test. Then, with the help of LASSO Cox regression analysis, the hsa-let-7b, hsa-mir-101-2, hsa-mir-135a-2, hsa-mir-22, hsa-mir-30a, hsa-mir-31, hsa-mir-3130-1, hsa-mir-320b-1, hsa-mir-3678, hsa-mir-4662a, hsa-mir-4772, hsa-mir-493, hsa-mir-556, hsa-mir-652, hsa-mir-6733, hsa-mir-874, and hsa-mir-9-3 were selected to construct the overall survival (OS) predicting signature, while the hsa-mir-130a, hsa-mir-204, hsa-mir-217, hsa-mir-223, hsa-mir-24-2, hsa-mir-29b-1, hsa-mir-363, hsa-mir-5001, hsa-mir-514a-1, hsa-mir-624, hsa-mir-639, hsa-mir-659, and hsa-mir-6892 were adopted to establish the recurrence-free survival (RFS) predicting signature. Referring to the median risk scores generated by the OS and RFS formulas, respectively, subgroup patients with high risk were strongly related to a poor OS and RFS revealed by Kaplan-Meier (K-M) plots. Meanwhile, receiver operating curve (ROC) analysis validated the accuracy and stability of these two signatures. When stratified by clinical features, such as tumor stage, age, and molecular subtypes, we found that the miRNA-based OS and RFS classifiers were still significant in predicting OS/RFS and showed the best predictive values than any other features. Besides, functional prediction analyses showed that these targeted genes of the enrolled miRNAs were enriched in cancer-associated pathways, such as MAPK/RTK, Ras, and PI3K-Akt signaling pathways. In summary, our observations demonstrate that the novel miRNA-based OS and RFS signatures are independent prognostic indicators for BC patients and worthy to be validated by further prospective studies.
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17
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Shirjang S, Mansoori B, Asghari S, Duijf PHG, Mohammadi A, Gjerstorff M, Baradaran B. MicroRNAs in cancer cell death pathways: Apoptosis and necroptosis. Free Radic Biol Med 2019; 139:1-15. [PMID: 31102709 DOI: 10.1016/j.freeradbiomed.2019.05.017] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/01/2019] [Accepted: 05/14/2019] [Indexed: 02/07/2023]
Abstract
To protect tissues and the organism from disease, potentially harmful cells are removed through programmed cell death processes, including apoptosis and necroptosis. These types of cell death are critically controlled by microRNAs (miRNAs). MiRNAs are short RNA molecules that target and inhibit expression of many cellular regulators, including those controlling programmed cell death via the intrinsic (Bcl-2 and Mcl-1), extrinsic (TRAIL and Fas), p53-and endoplasmic reticulum (ER) stress-induced apoptotic pathways, as well as the necroptosis cell death pathway. In this review, we discuss the current knowledge of apoptosis and necroptosis pathways and how these are impaired in cancer cells. We focus on how miRNAs disrupt apoptosis and necroptosis, thereby critically contributing to malignancy. Understanding which and how miRNAs and their targets affect cell death pathways could open up novel therapeutic opportunities for cancer patients. Indeed, restoration of pro-apoptotic tumor suppressor miRNAs (apoptomiRs) or inhibition of oncogenic miRNAs (oncomiRs) represent strategies that are currently being trialed or are already applied as miRNA-based cancer therapies. Therefore, better understanding the cancer type-specific expression of apoptomiRs and oncomiRs and their underlying mechanisms in cell death pathways will not only advance our knowledge, but also continue to provide new opportunities to treat cancer.
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Affiliation(s)
- Solmaz Shirjang
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
| | - Samira Asghari
- Department of Medical Biotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
| | - Morten Gjerstorff
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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18
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He F, Fang L, Yin Q. miR-363 acts as a tumor suppressor in osteosarcoma cells by inhibiting PDZD2. Oncol Rep 2019; 41:2729-2738. [PMID: 30896877 PMCID: PMC6448123 DOI: 10.3892/or.2019.7078] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 03/13/2019] [Indexed: 12/03/2022] Open
Abstract
PDZ domain containing 2 (PDZD2) is a multi-PDZ domain protein that promotes the proliferation of insulinoma cells, and is upregulated during prostate tumorigenesis. However, the function of PDZD2 in other cancers, including osteosarcoma (OS), remains unclear. Dysregulation of microRNAs (miRNAs) contributes to tumor initiation, proliferation and metastasis, via the regulation of their target genes. The present study investigated the functions of miR-363 and PDZD2 in MG-63 OS cells. The results revealed that MG-63 cells contained low levels of miR-363, and that overexpression of miR-363 in MG-63 cells significantly inhibited the vitality, proliferation, and colony formation ability of the cells, but promoted their apoptosis and G1/S arrest by regulating proliferating cell nuclear antigen (PCNA) and caspase-3 expression. Additionally, miR-363 impaired the migration and invasion of MG-63 cells by regulating the epithelial-mesenchymal transition (EMT) phenotype. Notably, a bioinformatics analysis and luciferase reporter assay indicated that PDZD2 was a direct target of miR-363. miR-363 overexpression reduced PDZD2 protein levels and knockdown of PDZD2 suppressed the colony formation, migration and invasion of MG-63 cells, but promoted their apoptosis by regulating expression of PCNA, caspase-3, and the EMT phenotype. In vivo studies further confirmed that miR-363 functioned as tumor suppressor, by inhibiting tumor growth, promoting cell apoptosis, and reducing PDZD2 and PCNA levels and the prevalence of the EMT phenotype in tumor tissues. The present data demonstrated that downregulation of the tumor suppressor miR-363 may be involved in the development of osteosarcoma via regulation of PDZD2.
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Affiliation(s)
- Fan He
- Department of Orthopedic, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Long Fang
- Department of Orthopedic, Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China
| | - Qingshui Yin
- Department of Orthopedic, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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19
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Cao L, Wan Q, Li F, Tang CE. MiR-363 inhibits cisplatin chemoresistance of epithelial ovarian cancer by regulating snail-induced epithelial-mesenchymal transition. BMB Rep 2018. [PMID: 30037365 PMCID: PMC6177509 DOI: 10.5483/bmbrep.2018.51.9.104] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Chemoresistance is a major barrier to successful cisplatinbased chemotherapy for epithelial ovarian cancer (EOC), and emerging evidences suggest that microRNAs (miRNAs) are involved in the resistance. In this study, it was indicated that miR-363 downregulation was significantly correlated with EOC carcinogenesis and cisplatin resistance. Moreover, miR-363 overexpression could resensitise cisplatin-resistant EOC cells to cisplatin treatment both in vitro and in vivo. In addition, data revealed that EMT inducer Snail was significantly upregulated in cisplatin-resistant EOC cell lines and EOC patients and was a functional target of miR-363 in EOC cells. Furthermore, snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells. Taken together, findings suggest that miR-363 may be a biomarker for predicting responsiveness to cisplatin-based chemotherapy and a potential therapeutic target in EOC. [BMB Reports 2018; 51(9): 456-461].
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Affiliation(s)
- Lanqin Cao
- Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qian Wan
- Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Fengjie Li
- Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Can-E Tang
- The Institute of Medical Science Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R., China
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20
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Pan T, Mao T, Yang H, Wang H, Wang Y. Silencing of TGIF sensitizes MDA-MB-231 human breast cancer cells to cisplatin-induced apoptosis. Exp Ther Med 2018; 15:2978-2984. [PMID: 29456703 PMCID: PMC5795508 DOI: 10.3892/etm.2018.5780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 01/16/2018] [Indexed: 12/20/2022] Open
Abstract
The present study was designed to explore the sensitivity of MDA-MB-231 cells to cisplatin after silencing the expression of TG-interacting factor (TGIF) protein. Cell viability was measured using an MTT assay. Cell apoptosis was detected by the annexin V and dead cell assay and the Hoechst staining assay. Protein expression was analyzed using western blot analysis. A colony formation assay was also performed. It was observed that cisplatin reduced the expression of TGIF protein in a dose- and time-dependent manner. Silencing TGIF significantly suppressed the cell proliferation and colony formation in MDA-MB-231 cells with the treatment of cisplatin. Results indicated that silencing TGIF could dramatically increase the cisplatin-induced apoptosis rate in MDA-MB-231 cells. The expression of PARP and caspase-3 proteins was correlated with the effect that silencing TGIF enhanced cisplatin sensitivity in MDA-MB-231 cells. The present data showed that silencing TGIF promoted apoptotic sensitivity that was induced by cisplatin in MDA-MB-231 human breast cancer cells and suggested that TGIF might be a therapeutic target for improving the chemotherapy response in triple-negative breast cancer.
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Affiliation(s)
- Teng Pan
- Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Tingting Mao
- Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Haiyan Yang
- Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Haiyu Wang
- Department of Toxicology, Henan Center for Disease Control and Prevention, Zhengzhou, Henan 450016, P.R. China
| | - Yadong Wang
- Department of Toxicology, Henan Center for Disease Control and Prevention, Zhengzhou, Henan 450016, P.R. China.,Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
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21
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Wang Y, Chen T, Huang H, Jiang Y, Yang L, Lin Z, He H, Liu T, Wu B, Chen J, Kamp DW, Liu G. miR-363-3p inhibits tumor growth by targeting PCNA in lung adenocarcinoma. Oncotarget 2017; 8:20133-20144. [PMID: 28423618 PMCID: PMC5386750 DOI: 10.18632/oncotarget.15448] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 01/10/2017] [Indexed: 12/22/2022] Open
Abstract
Increasing evidence suggests that microRNAs play key roles in lung cancer. Our previous study demonstrated that microRNA 363-3p (miR-363-3p) is downregulated in lung cancer tissues. In this study, we demonstrated that overexpression of miR-363-3p inhibits the proliferation and colony formation of A549 and H441 cells, while silencing of miR-363-3p has the converse effects. The anti-oncogenic function of miR-363-3p was verified in a mouse tumor xenograft model. Furthermore, cell cycle analysis showed miR-363-3p can induce S phase arrest by downregulating Cyclin-D1 and upregulating Cyclin-dependent kinase-2 in lung adenocarcinoma cells. Additionally, miR-363-3p enhances cell apoptosis, whereas miR-363-3p inhibitor prevents apoptosis and leads to downregulation of Bax and Bak expression. The anti-proliferative function of miR-363-3p toward lung cancer cells may be explained by its ability to inhibit the activation of the mTOR and ERK signaling pathways. Using target prediction software and luciferase reporter assays, we identified PCNA as a specific target of miR-363-3p. miR-363-3p can decreased the accumulation of endogenous PCNA in lung adenocarcinoma cells. Moreover, exogenous expression of PCNA relieve the inhibition of miR-363-3p on cell proliferation, colony formation and mTOR and ERK signaling pathways. Taken together, our data indicate that miR-363-3p suppresses tumor growth by targeting PCNA in lung adenocarcinoma.
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Affiliation(s)
- Yahong Wang
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ting Chen
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Haili Huang
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yun Jiang
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Lawei Yang
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ziying Lin
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Huijuan He
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Tie Liu
- The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China
| | - Bin Wu
- Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jie Chen
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - David W Kamp
- Department of Medicine, Northwestern University Feinberg School of Medicine and Jesse Brown VA Medical Center, Chicago, USA
| | - Gang Liu
- Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.,Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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22
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MicroRNA-363 inhibits ovarian cancer progression by inhibiting NOB1. Oncotarget 2017; 8:101649-101658. [PMID: 29254193 PMCID: PMC5731903 DOI: 10.18632/oncotarget.21417] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 09/04/2017] [Indexed: 01/13/2023] Open
Abstract
In this study, we investigated the role of microRNA-363(miR-363) in ovarian cancer (OC) progression. MiR-363expression was downregulated in OC patient tissues and four OC cell lines (SKOV3, A2780, OVCAR and HO-8910). Low miR-363 levels were associated with advanced stage, lymph node metastasis, and poor prognosis in OC. MiR-363 overexpression decreased growth, colony formation, migration and invasiveness of SKOV3 cells. In addition, miR-363 overexpression in SKOV3 cells also decreased xenograft tumor size and weight in nude mice. Bioinformatics and dual luciferase reporter assays revealed that miR-363 suppresses expression of NIN1/RPN12 binding protein 1 homolog (NOB1) by binding to the 3’-UTR of its transcript. NOB1 expression inversely correlated with miR-363 levels in OC tissues. Thus miR-363 appears to play a tumor suppressor role in OC by inhibiting NOB1.
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Jain A, Jahagirdar D, Nilendu P, Sharma NK. Molecular approaches to potentiate cisplatin responsiveness in carcinoma therapeutics. Expert Rev Anticancer Ther 2017; 17:815-825. [PMID: 28705091 DOI: 10.1080/14737140.2017.1356231] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cisplatin has been considered as the crucial regimen of widely prescribed chemotherapy treatment for cancer. The advancing treatment of cancers has reached the border line, where tumors show resistance to cisplatin and may thwart its use. Other than issues of drug resistance, cisplatin has been reported to evince side effects such as nephrotoxicity and ototoxicity. Therefore, there is a compelling need to untangle the problems associated with cisplatin treatment in carcinoma. Areas covered: In this review, we summarize the current status of combinatorial options to bring about better pre-clinical and clinical cisplatin drug responses in carcinoma. We begin with problems associated with cisplatin drugs and current avenues such as depicting molecular modulation of enhanced influx and reduced efflux. We also discuss the scope of the DNA damage response landscape and contribution of regulatory small RNAs towards potentiation of cisplatin responses. Expert commentary: The extensive use of cisplatin and incessant high drug dose have prompted the scientific community to limit the burden of cisplatin without compromising therapeutic success. Currently, there are reports on the potential use of other non-toxic small molecule inhibitors, interference RNAs and peptide mimetics to get rid of cellular adversities responsible for cisplatin resistance and high dose effects.
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Affiliation(s)
- Aayushi Jain
- a Cancer and Translational Research Lab , Dr. D.Y. Patil Biotechnology & Bioinformatics Institute , Pune , India
| | - Devashree Jahagirdar
- a Cancer and Translational Research Lab , Dr. D.Y. Patil Biotechnology & Bioinformatics Institute , Pune , India
| | - Pritish Nilendu
- a Cancer and Translational Research Lab , Dr. D.Y. Patil Biotechnology & Bioinformatics Institute , Pune , India
| | - Nilesh Kumar Sharma
- a Cancer and Translational Research Lab , Dr. D.Y. Patil Biotechnology & Bioinformatics Institute , Pune , India
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Ying J, Yu X, Ma C, Zhang Y, Dong J. MicroRNA-363-3p is downregulated in hepatocellular carcinoma and inhibits tumorigenesis by directly targeting specificity protein 1. Mol Med Rep 2017; 16:1603-1611. [PMID: 28627662 DOI: 10.3892/mmr.2017.6759] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 03/23/2017] [Indexed: 11/05/2022] Open
Abstract
microRNAs exhibit important regulatory roles in tumorigenesis and tumor development, such as in hepatocellular carcinoma (HCC). The present study aimed to investigate the expression and functional roles of microRNA (miR)‑363‑3p in HCC. miR-363-3p expression levels in a number of HCC tissues and cell lines were measured by reverse transcription-quantitative PCR (RT‑qPCR). The effects of miR‑363‑3p expression on HCC cell proliferation, migration and invasion were exa-mined by MTT assay, Transwell migration and invasion assay, respectively. The effects of miR‑363‑3p on its downstream target gene, specificity protein 1 (SP1), were examined by bioinformatics analysis, luciferase reporter assay, RT‑qPCR and western blotting. An SP1 overexpression vector was subsequently transfected into HCC cells to assess any selective effects on miR‑363‑3p in modulating HCC. The results revealed that miR‑363‑3p expression levels were downregulated in both HCC tissues and cell lines, and this low expression level was correlated with tumor size, tumor‑node‑metastasis stage and venous infiltration in patients with HCC. Upregulation of miR‑363‑3p inhibited cell proliferation, migration and invasion in HCC cell cultures. In HCC cells transfected with an SP1 expression vector the miR‑363‑3p‑induced tumor suppressive roles on cell proliferation, migration and invasion were reversed. In conclusion, results from the present study indicated that miR‑363‑3p is a tumor suppressor in HCC and functions through a mechanism involving SP1, suggesting that miR‑363‑3p may be a potential new therapeutic target for the treatment of HCC.
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Affiliation(s)
- Jie Ying
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Xuechun Yu
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Chaojian Ma
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Yongqi Zhang
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Jingwu Dong
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
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25
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Inhibition of miR-363 protects cardiomyocytes against hypoxia-induced apoptosis through regulation of Notch signaling. Biomed Pharmacother 2017; 90:509-516. [PMID: 28402919 DOI: 10.1016/j.biopha.2017.03.080] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 03/24/2017] [Accepted: 03/26/2017] [Indexed: 12/21/2022] Open
Abstract
Cardiomyocyte apoptosis contributes to the pathological process of ischemic heart diseases, such as myocardial infarction. Emerging evidence suggests that microRNAs (miRNAs) play critical roles in the pathological process of myocardial infarction by regulating cardiomyocyte apoptosis. Previous studies have reported that miR-363 is an apoptosis-related miRNA. However, whether miR-363 is involved in regulating cardiomyocyte apoptosis remains unclear. This study aimed to investigate the potential role of miR-363 in the regulation of hypoxia-induced cardiomyocyte apoptosis. We found that miR-363 expression was significantly increased in hypoxic cardiomyocytes and that inhibition of miR-363 effectively protected cardiomyocytes against hypoxia-induced apoptosis. Bioinformatics analysis predicted that Notch1 is a potential target gene of miR-363. This finding was validated by dual-luciferase reporter assay, real-time quantitative polymerase chain reaction, and Western blot analysis. miR-363 inhibition significantly promoted the activation of Notch signaling in hypoxic cardiomyocytes. However, knockdown of Notch1 markedly reversed the protective effects induced by miR-363 inhibition. Furthermore, blocking the Notch signaling also significantly abrogated the protective effects of miR-363 inhibition. Overall, these findings suggest that inhibition of miR-363 protects cardiomyocytes against hypoxia-induced apoptosis through promotion of Notch1 expression and activation of Notch signaling. Our study provides a novel understanding of the molecular basis of hypoxia-induced cardiomyocyte apoptosis and suggests a potential therapeutic target for myocardial infarction.
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26
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Sun G, Sun L, Liu Y, Xing H, Wang K. Her-2 expression regulated by downregulation of miR-9 and which affects chemotherapeutic effect in breast cancer. Cancer Gene Ther 2017; 24:194-202. [PMID: 28361910 DOI: 10.1038/cgt.2014.82] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 12/21/2014] [Accepted: 12/22/2014] [Indexed: 02/06/2023]
Abstract
This study aimed to identify microRNAs (miRs), the deregulated expression of which leads to the activation of oncogenic pathways in human breast cancer (BC). miRs are classes of endogenous, small, noncoding RNAs that regulate gene expression aberrantly in human tumor tissues. A total of 39 out of 123 tumoral and matched uninvolved peritumoral breast specimens from 3 independent subsets of patients were analyzed for the expression of 851 human miRs using an Agilent platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by quantitative polymerase chain reaction. Animal assay was further used to test the role of miR-9 and Her-2 in the pathogenesis of BC. All 39 matched samples were analyzed by unsupervised cluster analysis. This analytical approach identified a signature of miRs (miR-9, miR-148a, miR-31, miR-375, miR-21, miR-135b, miR-196a and miR-196b) that were significantly modulated between tumoral and peritumoral tissues in both subsets of patients. Her-2 protein staining increased in tumoral specimens when miR-9 downregulation correlated with the prognostic value. The ectopic expression of miR-9 inhibited the colony-forming ability, migration and tumor engraftment of BC cells. miR-9 targeted the Her-2 messenger RNA and increased responsiveness of BC cells to docetaxel (DOC) or cyclophosphamide treatment. The ectopic expression of Her-2 protein counteracted the miR-9 proapoptotic activity in response to DOC. These findings suggested that the modulation of aberrant expression of miR-9, which in turn induces oncogenic Her-2 protein activity, might hold promise for preventive and therapeutic management of BC.
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Affiliation(s)
- G Sun
- Mammary Surgery Department of China-Japan Union Hospital of Jilin University, Changchun, PRC
| | - L Sun
- Mammary Surgery Department of China-Japan Union Hospital of Jilin University, Changchun, PRC
| | - Y Liu
- Mammary Surgery Department of China-Japan Union Hospital of Jilin University, Changchun, PRC
| | - H Xing
- Mammary Surgery Department of China-Japan Union Hospital of Jilin University, Changchun, PRC
| | - K Wang
- Mammary Surgery Department of China-Japan Union Hospital of Jilin University, Changchun, PRC
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Hou XF, Xu LP, Song HY, Li S, Wu C, Wang JF. ECRG2 enhances the anti-cancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PCNA. World J Gastroenterol 2017; 23:1796-1803. [PMID: 28348485 PMCID: PMC5352920 DOI: 10.3748/wjg.v23.i10.1796] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/06/2017] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the anti-tumor effects of esophageal cancer-related gene 2 (ECRG2) in combination with cisplatin (DDP) in DDP-resistant esophageal cancer cells (EC9706/DDP).
METHODS A drug-resistant cell model was established, with EC9706/DDP cells being treated with ECRG2 and/or DDP. Cell viability was examined by MTT assay. The rate of cell apoptosis was determined by flow cytometry. The mRNA expression levels of proliferating cell nuclear antigen (PCNA), metallothionein (MT), and p53 were determined by RT-PCR and PCNA, while MT and p53 protein expression levels were determined by western blotting.
RESULTS The anti-proliferative effect of ECRG2 in combination with DDP was superior when compared to ECRG2 or DDP alone. The inhibition rate for the combination reached its peak (51.33%) at 96 h. The early apoptotic rates of the control, ECRG2 alone, DDP alone, and ECRG2 plus DDP groups were 5.71% ± 0.27%, 12.68% ± 0.61%, 14.15% ± 0.87%, and 27.96% ± 0.36%, respectively. Although all treatment groups were significantly different from the control group (P < 0.05), the combination treatment of ECRG2 plus DDP performed significantly better when compared to either ECRG2 or DDP alone (P < 0.05). The combination of ECRG2 and DDP significantly upregulated p53 mRNA and protein levels and downregulated PCNA mRNA and protein levels compared to ECRG2 or DDP alone (P < 0.05). However, no changes were seen in the expression of MT mRNA or protein.
CONCLUSION ECRG2 in combination with DDP can inhibit viability and induce apoptosis in esophageal cancer DDP-resistant cells, possibly via upregulation of p53 expression and downregulation of PCNA expression. These findings suggest that the combination of ECRG2 and DDP may be a promising strategy for the clinical treatment of esophageal cancers that are resistant to DDP.
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Jin HY, Oda H, Chen P, Yang C, Zhou X, Kang SG, Valentine E, Kefauver JM, Liao L, Zhang Y, Gonzalez-Martin A, Shepherd J, Morgan GJ, Mondala TS, Head SR, Kim PH, Xiao N, Fu G, Liu WH, Han J, Williamson JR, Xiao C. Differential Sensitivity of Target Genes to Translational Repression by miR-17~92. PLoS Genet 2017; 13:e1006623. [PMID: 28241004 PMCID: PMC5348049 DOI: 10.1371/journal.pgen.1006623] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 03/13/2017] [Accepted: 02/08/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes. MicroRNAs (miRNAs) are small RNAs encoded by our genome. Each miRNA binds hundreds of target mRNAs and performs specific functions. It is thought that miRNAs exert their function by reducing the expression of all these target genes and each to a small degree. However, these target genes often have very diverse functions. It has been unclear how small changes in hundreds of target genes with diverse functions are translated into the specific function of a miRNA. Here we take advantage of recent technical advances to globally examine the mRNA and protein levels of 868 target genes regulated by miR-17~92, the first oncogenic miRNA, in mutant mice with transgenic overexpression or deletion of this miRNA gene. We show that miR-17~92 regulates target gene expression mainly at the protein level, with little effect on mRNA. Surprisingly, only a small fraction of target genes respond to miR-17~92 expression changes. Further studies show that the sensitivity of target genes to miR-17~92 is determined by a non-coding region of target mRNA. Our findings demonstrate that not every target gene is equal, and suggest that the function of a miRNA is mediated by a small number of key target genes.
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Affiliation(s)
- Hyun Yong Jin
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Hiroyo Oda
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Pengda Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Chao Yang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Xiaojuan Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Seung Goo Kang
- Division of Biomedical Convergence/Institute of Bioscience & Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Elizabeth Valentine
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Jennifer M. Kefauver
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Lujian Liao
- Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), School of Life Sciences, East China Normal University, Shanghai, China
| | - Yaoyang Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Alicia Gonzalez-Martin
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Jovan Shepherd
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Gareth J. Morgan
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
| | - Tony S. Mondala
- Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, United States of America
| | - Steven R. Head
- Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, United States of America
| | - Pyeung-Hyeun Kim
- Department of Molecular Bioscience/Institute of Bioscience & Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Nengming Xiao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Guo Fu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Wen-Hsien Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jiahuai Han
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - James R. Williamson
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Changchun Xiao
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- * E-mail:
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Karatas OF, Suer I, Yuceturk B, Yilmaz M, Oz B, Guven G, Cansiz H, Creighton CJ, Ittmann M, Ozen M. Identification of microRNA profile specific to cancer stem-like cells directly isolated from human larynx cancer specimens. BMC Cancer 2016; 16:853. [PMID: 27816053 PMCID: PMC5097853 DOI: 10.1186/s12885-016-2863-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 10/04/2016] [Indexed: 12/14/2022] Open
Abstract
Background Emerging evidences proposed that microRNAs are associated with regulation of distinct physio-pathological processes including development of normal stem cells and carcinogenesis. In this study we aimed to investigate microRNA profile of cancer stem-like cells (CSLCs) isolated form freshly resected larynx cancer (LCa) tissue samples. Methods CD133 positive (CD133+) stem-like cells were isolated from freshly resected LCa tumor specimens. MicroRNA profile of 12 pair of CD133+ and CD133− cells was determined using microRNA microarray and differential expressions of selvected microRNAs were validated by quantitative real time PCR (qRT-PCR). Results MicroRNA profiling of CD133+ and CD133− LCa samples with microarray revealed that miR-26b, miR-203, miR-200c, and miR-363-3p were significantly downregulated and miR-1825 was upregulated in CD133+ larynx CSLCs. qRT-PCR analysis in a total of 25 CD133+/CD133− sample pairs confirmed the altered expressions of these five microRNAs. Expressions of miR-26b, miR-200c, and miR-203 were significantly correlated with miR-363-3p, miR-203, and miR-363-3p expressions, respectively. Furthermore, in silico analysis revealed that these microRNAs target both cancer and stem-cell associated signaling pathways. Conclusions Our results showed that certain microRNAs in CD133+ cells could be used as cancer stem cell markers. Based on these results, we propose that this panel of microRNAs might carry crucial roles in LCa pathogenesis through regulating stem cell properties of tumor cells. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2863-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Omer Faruk Karatas
- Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey
| | - Ilknur Suer
- Department of Medical Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey
| | - Betul Yuceturk
- Department of Medical Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey.,Advanced Genomics and Bioinformatics Research Center, The Scientific and Technological Research Council of Turkey (TUBITAK), Gebze, Kocaeli, Turkey
| | - Mehmet Yilmaz
- Department of Otorhinolaryngology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Buge Oz
- Department of Pathology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Gulgun Guven
- Department of Medical Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey
| | - Harun Cansiz
- Department of Otorhinolaryngology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Chad J Creighton
- Department of Medicine and Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA
| | - Michael Ittmann
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77030, USA.,Michael E. DeBakey VAMC, Houston, TX, 77030, USA
| | - Mustafa Ozen
- Department of Medical Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey. .,Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77030, USA.
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30
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Wu BL, Wang D, Bai WJ, Zhang F, Zhao X, Yi Y, Zhang T, Shen WJ, Li EM, Xu LY, Xu JZ. An integrative framework to identify cell death-related microRNAs in esophageal squamous cell carcinoma. Oncotarget 2016; 7:56758-56766. [PMID: 27462775 PMCID: PMC5302951 DOI: 10.18632/oncotarget.10779] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 07/06/2016] [Indexed: 02/05/2023] Open
Abstract
Cell death is a critical biological process involved in many important functions, and defects in this system are usually linked with numerous human diseases including cancers. Esophageal squamous cell carcinoma is one of the most chemo- and biological therapy resistant cancers. Based on knowledge repository and four miRNAs profiling data, we proposed a general framework to hunt for cell death miRNAs in a context dependent manner. We predicted 12 candidate miRNAs from hundreds of others. Follow-up experimental verification of 7 miRNAs indicated at least 3 miRNAs (MIR20b, MIR498 and MIR196) were involved in both apoptosis and autophagy processes. These results indicated miRNAs intimately connected the two cell death modules in esophageal squamous cell carcinoma. This integrative framework can also be easily extended to identify miRNAs in other key cellular signaling pathways or may find conditional specific miRNAs in other cancer types.
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Affiliation(s)
- Bing-Li Wu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
| | - Dong Wang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Wen-Jing Bai
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
| | - Fan Zhang
- Department of Bioinformatics, Shantou University Medical College, Shantou 515041, China
| | - Xing Zhao
- Department of Bioinformatics, Shantou University Medical College, Shantou 515041, China
| | - Ying Yi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Ting Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Wen-Jun Shen
- Department of Bioinformatics, Shantou University Medical College, Shantou 515041, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China
| | - Jian-Zhen Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Computational Systems Biology Laboratory, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
- Department of Bioinformatics, Shantou University Medical College, Shantou 515041, China
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Hu F, Min J, Cao X, Liu L, Ge Z, Hu J, Li X. MiR-363-3p inhibits the epithelial-to-mesenchymal transition and suppresses metastasis in colorectal cancer by targeting Sox4. Biochem Biophys Res Commun 2016; 474:35-42. [PMID: 27084453 DOI: 10.1016/j.bbrc.2016.04.055] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 04/12/2016] [Indexed: 12/18/2022]
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Bucur O. microRNA regulators of apoptosis in cancer. Discoveries (Craiova) 2016; 4:e57. [PMID: 32309578 PMCID: PMC7159826 DOI: 10.15190/d.2016.4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 03/31/2016] [Accepted: 03/31/2016] [Indexed: 12/12/2022] Open
Abstract
This brief review summarizes our current knowledge on the microRNAs that regulate apoptosis machinery and are potentially involved in the dysregulation or deregulation of apoptosis, a well known hallmark of cancer. microRNAs are critical regulators of the most important cellular processes, including apoptosis. Expression of microRNAs is found to be dysregulated in many malignancies, leading to apoptosis inhibition in cancer, or resistance to current therapies. To date, there are over 80 microRNAs directly involved in apoptosis regulation or dysregulation that can impact cancer detection, initiation, progression, invasion, metastasis or resistance to anti-cancer therapy. Development of microRNA-based therapeutic strategies is now taking shape in the clinic. Thus, these microRNAs represent potential targets or tools for cancer therapy in the future.
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Affiliation(s)
- Octavian Bucur
- Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA
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Do Canto LM, Marian C, Willey S, Sidawy M, Da Cunha PA, Rone JD, Li X, Gusev Y, Haddad BR. MicroRNA analysis of breast ductal fluid in breast cancer patients. Int J Oncol 2016; 48:2071-8. [PMID: 26984519 PMCID: PMC4809650 DOI: 10.3892/ijo.2016.3435] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 02/20/2016] [Indexed: 12/23/2022] Open
Abstract
Recent studies suggest that microRNAs show promise as excellent biomarkers for breast cancer; however there is still a high degree of variability between studies making the findings difficult to interpret. In addition to blood, ductal lavage (DL) and nipple aspirate fluids represent an excellent opportunity for biomarker detection because they can be obtained in a less invasive manner than biopsies and circumvent the limitations of evaluating blood biomarkers with regards to tissue of origin specificity. In this study, we have investigated for the first time, through a real-time PCR array, the expression of 742 miRNAs in the ductal lavage fluid collected from 22 women with unilateral breast tumors. We identified 17 differentially expressed miRNAs between tumor and paired normal samples from patients with ductal breast carcinoma. Most of these miRNAs have various roles in breast cancer tumorigenesis, invasion and metastasis, therapeutic response, or are associated with several clinical and pathological characteristics of breast tumors. Moreover, some miRNAs were also detected in other biological fluids of breast cancer patients such as serum (miR-23b, -133b, -181a, 338-3p, -625), plasma (miR-200a), and breast milk (miR-181a). A systems biology analysis of these differentially expressed miRNAs points out possible pathways and cellular processes previously described as having an important role in breast cancer such as Wnt, ErbB, MAPK, TGF-β, mTOR, PI3K-Akt, p53 signaling pathways. We also observed a difference in the miRNA expression with respect to the histological type of the tumors. In conclusion, our findings suggest that miRNA analysis of breast ductal fluid is feasible and potentially very useful for the detection of breast cancer.
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Affiliation(s)
- Luisa Matos Do Canto
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Catalin Marian
- Biochemistry Department, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Shawna Willey
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Mary Sidawy
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Patricia A Da Cunha
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Janice D Rone
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Xin Li
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Yuriy Gusev
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Bassem R Haddad
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
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Luo Y, Zhang C, Tang F, Zhao J, Shen C, Wang C, Yu P, Wang M, Li Y, Di JI, Chen R, Rili G. Bioinformatics identification of potentially involved microRNAs in Tibetan with gastric cancer based on microRNA profiling. Cancer Cell Int 2015; 15:115. [PMID: 26692821 PMCID: PMC4676900 DOI: 10.1186/s12935-015-0266-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 11/27/2015] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The incidence of gastric cancer is high in Chinese Tibetan. This study aimed to identify the differentially expressed microRNAs (miRNAs) and further explore their potential roles in Tibetan with gastric cancer so as to predict potential therapeutic targets. METHODS A total of 10 Tibetan patients (male:female = 6:4) with gastric cancer were enrolled for isolation of matched gastric cancer and adjacent non-cancerous tissue samples. Affymetrix GeneChip microRNA 3.0 Array was employed for detection of miRNA expression in samples. Differential expression analysis between two sample groups was analyzed using Limma package. Then, MultiMiR package was used to predict targets for miRNAs. Following, the target genes were put into DAVID (Database for Annotation, Visualization and Integrated Discovery) to identify the significant pathways of miRNAs. RESULTS Using Limma package in R, a total of 27 differentially expressed miRNAs were screened out in gastric cancer, including 25 down-regulated (e.g. hsa-miR-148a-3p, hsa-miR-148b-3p and hsa-miR-363-3p) and 2 up-regulated miRNAs. According to multiMiR package, a number of 1445 target genes (e.g. Wnt1, KLF4 and S1PR1) of 13 differentially expressed miRNAs were screened out. Among those miRNAs, hsa-miR-148a-3p, hsa-miR-148b-3p and hsa-miR-363-3p were identified with the most target genes. Furthermore, three miRNAs were significantly enriched in numerous common cancer-related pathways, including "Wnt signaling pathway", "MAPK signaling pathway" and "Jak-STAT signaling pathway". CONCLUSIONS The present study identified a downregulation and enrichment in cancer-related pathways of hsa-miR-148a-3p, hsa-miR-148b-3p and hsa-miR-363-3p in Tibetan with gastric cancer, which can be suggested as therapeutic targets.
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Affiliation(s)
- Yushuang Luo
- />Research Center for High Altitude Medicine, Qinghai University of Medical School, Kunlong Road 16, Xining, 810001 China
- />Department of Oncology, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Chengwu Zhang
- />Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Feng Tang
- />Research Center for High Altitude Medicine, Qinghai University of Medical School, Kunlong Road 16, Xining, 810001 China
| | - Junhui Zhao
- />Department of Oncology, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Cunfang Shen
- />Department of Oncology, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Cheng Wang
- />Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Pengjie Yu
- />Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Miaozhou Wang
- />Department of Oncology, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Yan Li
- />Department of Oncology, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - J. I. Di
- />Department of Oncology, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Rong Chen
- />Department of Oncology, Affiliated Hospital of Qinghai University, Xining, 810001 China
| | - Ge Rili
- />Research Center for High Altitude Medicine, Qinghai University of Medical School, Kunlong Road 16, Xining, 810001 China
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Chapman BV, Wald AI, Akhtar P, Munko AC, Xu J, Gibson SP, Grandis JR, Ferris RL, Khan SA. MicroRNA-363 targets myosin 1B to reduce cellular migration in head and neck cancer. BMC Cancer 2015; 15:861. [PMID: 26545583 PMCID: PMC4635687 DOI: 10.1186/s12885-015-1888-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 10/30/2015] [Indexed: 01/07/2023] Open
Abstract
Background Squamous cell carcinoma of the head and neck (SCCHN) remains a prevalent and devastating disease. Recently, there has been an increase in SCCHN cases that are associated with high-risk human papillomavirus (HPV) infection. The clinical characteristics of HPV-positive and HPV-negative SCCHN are known to be different but their molecular features are only recently beginning to emerge. MicroRNAs (miRNAs, miRs) are small, non-coding RNAs that are likely to play significant roles in cancer initiation and progression where they may act as oncogenes or tumor suppressors. Previous studies in our laboratory showed that miR-363 is overexpressed in HPV-positive compared to HPV-negative SCCHN cell lines, and the HPV type 16-E6 oncoprotein upregulates miR-363 in SCCHN cell lines. However, the functional role of miR-363 in SCCHN in the context of HPV infection remains to be elucidated. Methods We analyzed miR-363 levels in SCCHN tumors with known HPV-status from The Cancer Genome Atlas (TCGA) and an independent cohort from our institution. Cell migration studies were conducted following the overexpression of miR-363 in HPV-negative cell lines. Bioinformatic tools and a luciferase reporter assay were utilized to confirm that miR-363 targets the 3’-UTR of myosin 1B (MYO1B). MYO1B mRNA and protein expression levels were evaluated following miR-363 overexpression in HPV-negative SCCHN cell lines. Small interfering RNA (siRNA) knockdown of MYO1B was performed to assess the phenotypic implication of reduced MYO1B expression in SCCHN cell lines. Results MiR-363 was found to be overexpressed in HPV-16-positive compared to the HPV-negative SCCHN tumors. Luciferase reporter assays performed in HPV-negative JHU028 cells confirmed that miR-363 targets one of its two potential binding sites in the 3’UTR of MYO1B. MYO1B mRNA and protein levels were reduced upon miR-363 overexpression in four HPV-negative SCCHN cell lines. Increased miR-363 expression or siRNA knockdown of MYO1B expression reduced Transwell migration of SCCHN cell lines, indicating that the miR-363-induced migration attenuation of SCCHN cells may act through MYO1B downregulation. Conclusions These findings demonstrate that the overexpression of miR-363 reduces cellular migration in head and neck cancer and reveal the biological relationship between miR-363, myosin 1b, and HPV-positive SCCHN. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1888-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bhavana V Chapman
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. .,Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. .,Medical Research Fellows Program, Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
| | - Abigail I Wald
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
| | - Parvez Akhtar
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
| | - Ana C Munko
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
| | - Jingjing Xu
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
| | - Sandra P Gibson
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15216, USA. .,Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA.
| | - Jennifer R Grandis
- Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. .,Department of Pharmacology and Chemical Biology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. .,Present address: Clinical and Translational Science Institute,, Box 0558, 550 16th Street, 6th Floor, San Francisco, CA, 94158, USA.
| | - Robert L Ferris
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15216, USA. .,Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA.
| | - Saleem A Khan
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
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36
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Li JT, Jia LT, Liu NN, Zhu XS, Liu QQ, Wang XL, Yu F, Liu YL, Yang AG, Gao CF. MiRNA-101 inhibits breast cancer growth and metastasis by targeting CX chemokine receptor 7. Oncotarget 2015; 6:30818-30830. [PMID: 26360780 PMCID: PMC4741570 DOI: 10.18632/oncotarget.5067] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 08/21/2015] [Indexed: 12/17/2022] Open
Abstract
Whereas miR-101 is involved in the development and progression of breast cancer, the underlying molecular mechanisms remain to be elucidated. Here, we report that miR-101 expression is inversely correlated with the clinical stage, lymph node metastasis and prognosis in breast cancers. Introduction of miR-101 inhibited breast cancer cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis of in vivo. CX chemokine receptor 7 (CXCR7) is a direct target of miR-101, positively correlating with the histological grade and the incidence of lymph node metastasis in breast cancer patients. The effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. STAT3 signaling downstream of CXCR7 is involved in miR-101 regulation of breast cancer cell behaviors. These findings have implications for the potential application of miR-101 in breast cancer treatment.
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Affiliation(s)
- Jun-Tang Li
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Lin-Tao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Ning-Ning Liu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Xiao-Shan Zhu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Qin-Qin Liu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Xiu-Li Wang
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Feng Yu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Yan-Li Liu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - An-Gang Yang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Chun-Fang Gao
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
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miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1. BIOMED RESEARCH INTERNATIONAL 2015; 2015:373574. [PMID: 26526790 PMCID: PMC4615858 DOI: 10.1155/2015/373574] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 05/14/2015] [Accepted: 05/24/2015] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1). In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR) cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3'-UTR (3'-Untranslated Regions). Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer.
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38
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Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy. Tumour Biol 2015. [DOI: 10.1007/s13277-015-3591-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Yin W, Nie Y, Zhang Z, Xie L, He X. miR-193b acts as a cisplatin sensitizer via the caspase-3-dependent pathway in HCC chemotherapy. Oncol Rep 2015; 34:368-74. [PMID: 25997995 DOI: 10.3892/or.2015.3996] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 04/30/2015] [Indexed: 11/06/2022] Open
Abstract
Mounting evidence suggests that microRNAs (miRNAs) play important roles in the development of cancer by targeting expression of tumor-related genes. In the present study, downregulation of miR-193b was observed in hepatocellular carcinoma (HCC) tissues and HCC cell lines by quantitative RT-PCR analyses, suggesting that miR-193b is a tumor-suppressor in HCC. More importantly, miR-193b significantly enhanced the cytotoxicity of cisplatin in HepG2 cells by targeting Mcl-1. Knockdown of the Mcl-1 gene by specific siRNA exhibited a function similar to miR-193b on sensitizing HepG2 cells to cisplatin-inducing cytotoxicity. Furthermore, the miR-193b-induced sensitization of HepG2 cells to cisplatin cytotoxicity was abolished by the transfection of Mcl-1 expression plasmid that lacked the 3'-untranslated region (3'-UTR). In addition, activation of caspase-3 was needed for sensitization by miR-193b to cisplatin-mediated cell death. Thus, the present study revealed the downregulation of miR-193b in HCC cells and illustrated a synergistic effect on cisplatin-induced apoptosis by targeting Mcl-1.
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Affiliation(s)
- Wenjun Yin
- Cancer Research Institute of Medical College, University of Southern China, University Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang, Hunan 421001, P.R. China
| | - Yuehua Nie
- Department of Radiation Oncology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Zhiwei Zhang
- Cancer Research Institute of Medical College, University of Southern China, University Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang, Hunan 421001, P.R. China
| | - Liming Xie
- Department of Chemotherapy Oncology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiusheng He
- Cancer Research Institute of Medical College, University of Southern China, University Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang, Hunan 421001, P.R. China
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The role of miR-125b-mitochondria-caspase-3 pathway in doxorubicin resistance and therapy in human breast cancer. Tumour Biol 2015; 36:7185-94. [PMID: 25894378 DOI: 10.1007/s13277-015-3438-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Accepted: 04/07/2015] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of naturally occurring, small, non-coding RNAs which play important roles in diverse biological processes and are acting as key regulators of tumorigenesis and chemotherapy resistance. In this study, a downregulation of miR-125b was observed in breast cancer cell lines, suggesting miR-125b is a tumor suppressor in breast cancer. Moreover, the miR-125b levels were significantly decreased in doxorubicin-resistant MCF-7 (MCF-7/DR) cells compared with MCF-7 cells. Transfection of miR-125b significantly enhanced the cytotoxicity of doxorubicin to MCF-7/DR cells. However, the overexpression of miR-125b did not influence the doxorubicin accumulation but downregulated the myeloid cell leukemia-1 (Mcl-1) levels, which may be the mechanism of apoptosis induction caused by doxorubicin combining with miR-125b in MCF-7/DR cells. Furthermore, luciferase reporter assay proved that Mcl-1 is the target of miR-125b. Importantly, we found that the sensitization of miR-125b to doxorubicin cytotoxicity is caspase-dependent in MCF-7/DR cells, which can be inhibited by zVAD-fmk. Finally, we indicated that the treatment of miR-125b plus doxorubicin leads to loss of mitochondrial membrane potential (MMP) and mitochondria outer membrane permeability (MOMP), which were interacted with the activation of caspases. Thus, this study revealed the role of miR-125b in doxorubicin resistance and therapy, which may provide novel approaches for the treatment of breast cancer.
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Mognato M, Celotti L. MicroRNAs Used in Combination with Anti-Cancer Treatments Can Enhance Therapy Efficacy. Mini Rev Med Chem 2015; 15:1052-62. [PMID: 26156420 PMCID: PMC4997954 DOI: 10.2174/1389557515666150709115355] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Revised: 06/23/2015] [Accepted: 07/08/2015] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs), a recently discovered class of small non-coding RNAs, constitute a promising approach to anti-cancer treatments when they are used in combination with other agents. MiRNAs are evolutionarily conserved non-coding RNAs that negatively regulate gene expression by binding to the complementary sequence in the 3'-untranslated region (UTR) of target genes. MiRNAs typically suppress gene expression by direct association with target transcripts, thus decreasing the expression levels of target proteins. The delivery to cells of synthetic miRNAs that mimic endogenous miRNA targeting genes involved in the DNA-Damage Response (DDR) can perturb the process, making cells more sensitive to chemotherapy or radiotherapy. This review examines how cells respond to combined therapy and it provides insights into the role of miRNAs in targeting the DDR repair pathway when they are used in combination with chemical compounds or ionizing radiation to enhance cellular sensitivity to treatments.
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Affiliation(s)
- Maddalena Mognato
- Department of Biology, School of Science, University of Padova, Padova, Italy.
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