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Abudoubari S, Bu K, Mei Y, Maimaitiyiming A, An H, Tao N. Preliminary study on miRNA in prostate cancer. World J Surg Oncol 2023; 21:270. [PMID: 37641123 PMCID: PMC10464187 DOI: 10.1186/s12957-023-03151-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023] Open
Abstract
OBJECTIVE To screen for miRNAs differentially expressed in prostate cancer and prostate hyperplasia tissues and to validate their association with prostate cancer. METHODS Patients diagnosed by pathology in the Department of Urology of the First Affiliated Hospital of Xinjiang Medical University from October 2021 to June 2022 were selected, and their general clinical information, blood samples, and prostate tissue samples were collected. miRNA microarray technology was performed to obtain differentially expressed miRNAs in prostate cancer and hyperplasia tissues, and miRNAs to be studied were screened by microarray results and review of relevant literature. The detection of miRNA expression in the patients' blood and prostate tissue samples was measured. The miRNA-222-mimics were transfected into PC3 cells, and cell biology experiments such as CCK8, scratch, Transwell, and flow cytometry were performed to detect the effects of overexpressed miRNA-222 on the growth and proliferation, invasive ability, apoptotic ability, and metastatic ability of prostate cancer cells. RESULTS The results of the miRNA microarray showed that there were many differentially expressed miRNAs in prostate cancer and hyperplasia tissues, and four miRNAs, miRNA-144, miRNA-222, miRNA-1248, and miRNA-3651 were finally selected as the subjects by reviewing relevant literature. The results showed that the expression of miRNA-222 in prostate cancer tissues was lower than that in prostate hyperplasia tissues (P < 0.05). The expression of miRNA-222, miRNA-1248, and miRNA-3651 in blood samples of prostate cancer patients was lower than that in prostate hyperplasia patients (P < 0.05). The analysis results indicated that the f/t ratio and the relative expression of miRNA-222 and miRNA-1248 were independent influences of prostate cancer (P < 0.05), in which overexpression of miRNA-222 decreased the proliferative, invasive, and metastatic abilities of PC3 cells and enhanced the level of apoptosis of cancer cells. CONCLUSIONS Although there was no significant change in the overall incidence of prostate cancer in this study, significant changes occurred in the incidence of prostate cancer with different characteristics. In addition, the nomogram prediction model of prostate cancer-specific survival rate constructed based on four factors has a high reference value, which helps physicians to correctly assess the patient-specific survival rate and provides a reference basis for patient diagnosis and prognosis evaluation.
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Affiliation(s)
- Saimaitikari Abudoubari
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Department of Radiology, The First People's Hospital of Kashi Prefecture, Kashi, 844700, Xinjiang, China
| | - Ke Bu
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Yujie Mei
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | | | - Hengqing An
- The First Affiliated Hospital, Xinjiang Medical University, No. 393, Xinyi Road, Xinshi District, Urumqi, 830011, Xinjiang, China.
- Xinjiang Clinical Research Center for Genitourinary System, No. 393, Xinyi Road, Xinshi District, Urumqi, 830011, Xinjiang, China.
| | - Ning Tao
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China.
- Xinjiang Clinical Research Center for Genitourinary System, No. 393, Xinyi Road, Xinshi District, Urumqi, 830011, Xinjiang, China.
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Bagheri M, Lee MK, Muller KE, Miller TW, Pattabiraman DR, Christensen BC. Alteration of DNMT1/DNMT3A by eribulin elicits global DNA methylation changes with potential therapeutic implications for triple-negative breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.09.544426. [PMID: 37333096 PMCID: PMC10274899 DOI: 10.1101/2023.06.09.544426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease subtype with limited treatment options. Eribulin is a chemotherapeutic approved for the treatment of advanced breast cancer that has been shown to elicit epigenetic changes. We investigated the effect of eribulin treatment on genome-scale DNA methylation patterns in TNBC cells. Following repeated treatment, The results showed that eribulin-induced changes in DNA methylation patterns evident in persister cells. Eribulin also affected the binding of transcription factors to genomic ZEB1 binding sites and regulated several cellular pathways, including ERBB and VEGF signaling and cell adhesion. Eribulin also altered the expression of epigenetic modifiers including DNMT1, TET1, and DNMT3A/B in persister cells. Data from primary human TNBC tumors supported these findings: DNMT1 and DNMT3A levels were altered by eribulin treatment in human primary TNBC tumors. Our results suggest that eribulin modulates DNA methylation patterns in TNBC cells by altering the expression of epigenetic modifiers. These findings have clinical implications for using eribulin as a therapeutic agent.
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Affiliation(s)
- Meisam Bagheri
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766
- Dartmouth Cancer Center, Lebanon, NH, 03756
| | - Min Kyung Lee
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756
| | - Kristen E. Muller
- Dartmouth Cancer Center, Lebanon, NH, 03756
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon NH 03756, USA
| | - Todd W. Miller
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766
- Dartmouth Cancer Center, Lebanon, NH, 03756
| | - Diwakar R. Pattabiraman
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766
- Dartmouth Cancer Center, Lebanon, NH, 03756
| | - Brock C. Christensen
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756
- Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756
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Islam R, Zhao L, Wang Y, Lu-Yao G, Liu LZ. Epigenetic Dysregulations in Arsenic-Induced Carcinogenesis. Cancers (Basel) 2022; 14:4502. [PMID: 36139662 PMCID: PMC9496897 DOI: 10.3390/cancers14184502] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Arsenic is a crucial environmental metalloid whose high toxicity levels negatively impact human health. It poses significant health concerns to millions of people in developed and developing countries such as the USA, Canada, Bangladesh, India, China, and Mexico by enhancing sensitivity to various types of diseases, including cancers. However, how arsenic causes changes in gene expression that results in heinous conditions remains elusive. One of the proposed essential mechanisms that still has seen limited research with regard to causing disease upon arsenic exposure is the dysregulation of epigenetic components. In this review, we have extensively summarized current discoveries in arsenic-induced epigenetic modifications in carcinogenesis and angiogenesis. Importantly, we highlight the possible mechanisms underlying epigenetic reprogramming through arsenic exposure that cause changes in cell signaling and dysfunctions of different epigenetic elements.
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Affiliation(s)
| | | | | | | | - Ling-Zhi Liu
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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4
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Taefehshokr S, Taefehshokr N, Derakhshani A, Baghbanzadeh A, Astamal RV, Safaei S, Abbasi S, Hajazimian S, Maroufi NF, Isazadeh A, Hajiasgharzadeh K, Baradaran B. The regulatory role of pivotal microRNAs in the AKT signaling pathway in breast cancer. Curr Mol Med 2021; 22:263-273. [PMID: 34238182 DOI: 10.2174/1566524021666210708095051] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 04/29/2021] [Accepted: 05/06/2021] [Indexed: 11/22/2022]
Abstract
Breast cancer is the most prevalent type of cancer among women, and it remains the main challenge despite improved treatments. MicroRNAs (miRNAs) are a small non-coding family of RNAs that play an indispensable role in regulating major physiological processes, including differentiation, proliferation, invasion, migration, cell cycle regulation, stem cell maintenance, apoptosis, and organ development. The dysregulation of these tiny molecules is associated with various human malignancies. More than 50% of these non-coding RNA sequences estimated have been placed on genomic regions or fragile sites linked to cancer. Following the discovery of the first signatures of specific miRNA in breast cancer, numerous researches focused on involving these tiny RNAs in breast cancer physiopathology as a new therapeutic approach or as reliable prognostic biomarkers. In the current review, we focus on recent findings related to the involvement of miRNAs in breast cancer via the AKT signaling pathway and the related clinical implications.
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Affiliation(s)
- Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Taefehshokr
- Division of Biosciences, Department of Life Sciences, Brunel University London, Kingston Lane, UB8 3PH, United Kingdom
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Vaezi Astamal
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samane Abbasi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Saba Hajazimian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Fathi Maroufi
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Isazadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Ouyang YX, Feng J, Wang Z, Zhang GJ, Chen M. miR-221/222 sponge abrogates tamoxifen resistance in ER-positive breast cancer cells through restoring the expression of ERα. MOLECULAR BIOMEDICINE 2021; 2:20. [PMID: 35006452 PMCID: PMC8607419 DOI: 10.1186/s43556-021-00045-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/21/2021] [Indexed: 02/05/2023] Open
Abstract
Tamoxifen resistance (TamR) prevents ER-positive breast cancer patients from benefitting from endocrine therapy, and miR-221 or miR-222 plays vital roles in inducing TamR. In this study, we designed synthetic sponges to reverse TamR by targeting these two miRs. First, we established a tamoxifen resistant breast cancer cell line (MCF-7TamR), we verified the high expressing level of these two miRs in TamR cells. miR-221 or miR-222 inhibitors rendered MCF-7TamR cells responsive to tamoxifen. Next, we designed a miR-221/222 sponge, which contains total 8 multi-antisense binding sites (MBSs) for these two onco-miRs, and inserted it into CMV promoter- or hTERT promoter-driven expressing vectors. After transfected miR-221/222 sponge expressing vectors into MCF-7TamR cells, we identified a strong interaction between miR-221/222 sponge and endogenous miR-221 or miR-222 by RNA pulldown assay. We also found that miR-221/222 sponge restored the expression of ERα and PTEN, arrested cells in G1 phase, and finally resulted in reduced cell growth and cell migration. Notably, miR-221/222 sponge expressing cells abrogates tamoxifen resistance through restoring the expression of ERα, suggesting that miR-221/222 sponge gene therapy especially driven by tumor specific promoter could provide an effective therapeutic approach against TamR in breast cancer.
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Affiliation(s)
- Yan Xiu Ouyang
- Cancer Center & Department of Breast and Thyroid Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China
- Clinical Central Research Core, Xiang'an Hospital of Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China
- ChangJiang Scholar's Laboratory, Shantou University Medical College, Shantou, 515041, China
| | - Jun Feng
- Cancer Center & Department of Breast and Thyroid Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China
- Clinical Central Research Core, Xiang'an Hospital of Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China
- ChangJiang Scholar's Laboratory, Shantou University Medical College, Shantou, 515041, China
| | - Zun Wang
- Cancer Center & Department of Breast and Thyroid Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China
- Clinical Central Research Core, Xiang'an Hospital of Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China
- ChangJiang Scholar's Laboratory, Shantou University Medical College, Shantou, 515041, China
- Department of Breast and Thyroid Surgery, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Shenzhen, 518102, China
| | - Guo Jun Zhang
- Cancer Center & Department of Breast and Thyroid Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China.
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China.
- Key Laboratory for Endocrine-Related Cancer Precision Medicine of Xiamen, Xiang'an Hospital of Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China.
| | - Min Chen
- Cancer Center & Department of Breast and Thyroid Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China.
- Clinical Central Research Core, Xiang'an Hospital of Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China.
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China.
- Key Laboratory for Endocrine-Related Cancer Precision Medicine of Xiamen, Xiang'an Hospital of Xiamen University, No. 2000, Xiang'an Road East, Xiamen, 361101, Fujian, China.
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Chen J, Wan R, Li Q, Rao Z, Wang Y, Zhang L, Teichmann AT. Utilizing the Hippo pathway as a therapeutic target for combating endocrine-resistant breast cancer. Cancer Cell Int 2021; 21:306. [PMID: 34112175 PMCID: PMC8194146 DOI: 10.1186/s12935-021-01999-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/27/2021] [Indexed: 12/14/2022] Open
Abstract
Drug resistance is always a great obstacle in any endocrine therapy of breast cancer. Although the combination of endocrine therapy and targeted therapy has been shown to significantly improve prognosis, refractory endocrine resistance is still common. Dysregulation of the Hippo pathway is often related to the occurrence and the development of many tumors. Targeted therapies of this pathway have played important roles in the study of triple negative breast cancer (TNBC). Targeting the Hippo pathway in combination with chemotherapy or other targeted therapies has been shown to significantly improve specific antitumor effects and reduce cancer antidrug resistance. Further exploration has shown that the Hippo pathway is closely related to endocrine resistance, and it plays a "co-correlation point" role in numerous pathways involving endocrine resistance, including related pathways in breast cancer stem cells (BCSCs). Agents and miRNAs targeting the components of the Hippo pathway are expected to significantly enhance the sensitivity of breast cancer cells to endocrine therapy. This review initially explains the possible mechanism of the Hippo pathway in combating endocrine resistance, and it concludes by recommending endocrine therapy in combination with therapies targeting the Hippo pathway in the study of endocrine-resistant breast cancers.
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Affiliation(s)
- Jing Chen
- Department of Gynaecology and Obstetrics, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, 646000, People's Republic of China.,Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Runlan Wan
- Department of Gynaecology and Obstetrics, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, 646000, People's Republic of China
| | - Qinqin Li
- Department of Gynaecology and Obstetrics, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, 646000, People's Republic of China.,Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Zhenghuan Rao
- Department of Gynaecology and Obstetrics, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, 646000, People's Republic of China.,Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yanlin Wang
- North Sichuan Medical College, Nanchong, 637000, China
| | - Lei Zhang
- Department of Gynaecology, The Second People's Hospital of Yibin, Yibin, 644000, China
| | - Alexander Tobias Teichmann
- Department of Gynaecology and Obstetrics, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, 646000, People's Republic of China. .,Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
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Abstract
Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in U.S. women. The invasion-metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules. The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment. Each of these processes is regulated by changes in gene expression. Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression. miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs). The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer. We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade. We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis. It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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Gu C, Luo Y, Zhang S, Xu J, Zhang J, Ju H, Liu J, Zhang L, Zhang Y, Wu L, Xie E, Xu T, Pan S. MAb NJ001 inhibits lung adenocarcinoma invasiveness by directly regulating TIMP-3 promoter activity via FOXP1 binding sites. Thorac Cancer 2020; 11:2630-2638. [PMID: 32744429 PMCID: PMC7471035 DOI: 10.1111/1759-7714.13593] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/27/2022] Open
Abstract
Background Previously, we developed a monoclonal antibody (mAb) NJ001 that binds to the antigen SP70 in human non‐small cell lung cancer (NSCLC) cells and showed it could inhibit lung adenocarcinoma (AD) growth. Here, we investigated the effect and mechanisms of NJ001 in lung AD metastasis. Methods Human lung AD cells (SPC‐A1 and A549) were treated with different concentrations of mAb NJ001, and the effects of NJ001 on cell migration and invasive activity were investigated using wound‐healing and Matrigel assays, respectively. The molecular mechanism of this inhibition was explored by microarrays, qRT‐PCR, western blot, luciferase assays and electrophoretic mobility shift assays (EMSA). Results MAb NJ001 markedly suppressed lung AD cell migration; and the invasiveness of SPC‐A1 and A549 cells treated with mAb NJ001 was diminished by 65%. Tissue inhibitor of matrix metalloproteinase‐3 (TIMP‐3) was highly expressed in SPC‐A1 cells treated with mAb NJ001, whereas knockdown of TIMP‐3 by shRNA significantly increased SPC‐A1 and A549 invasiveness. MAb NJ001 affects lung AD by inhibiting TIMP‐3 through direct transcriptional regulation of FOXP1 binding sites in the TIMP‐3 promoter region, as shown in luciferase assays and EMSA. Conclusions MAb NJ001 inhibits invasiveness and metastasis in lung AD through the FOXP1 binding sites in the TIMP‐3 promoter region. It may have clinical applications in preventing and treating metastatic lung AD.
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Affiliation(s)
- Chunrong Gu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Ying Luo
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Shichang Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Jian Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Jiexin Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Huanyu Ju
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Jingping Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Lixia Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Yan Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Lei Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Erfu Xie
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Ting Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Shiyang Pan
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
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9
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Dissecting miRNA facilitated physiology and function in human breast cancer for therapeutic intervention. Semin Cancer Biol 2020; 72:46-64. [PMID: 32497683 DOI: 10.1016/j.semcancer.2020.05.017] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/17/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are key epigenomic regulators of biological processes in animals and plants. These small non coding RNAs form a complex networks that regulate cellular function and development. MiRNAs prevent translation by either inactivation or inducing degradation of mRNA, a major concern in post-transcriptional gene regulation. Aberrant regulation of gene expression by miRNAs is frequently observed in cancer. Overexpression of various 'oncomiRs' and silencing of tumor suppressor miRNAs are associated with various types of human cancers, although overall downregulation of miRNA expression is reported as a hallmark of cancer. Modulations of the total pool of cellular miRNA by alteration in genetic and epigenetic factors associated with the biogenesis of miRNA machinery. It also depends on the availability of cellular miRNAs from its store in the organelles which affect tumor development and cancer progression. Here, we have dissected the roles and pathways of various miRNAs during normal cellular and molecular functions as well as during breast cancer progression. Recent research works and prevailing views implicate that there are two major types of miRNAs; (i) intracellular miRNAs and (ii) extracellular miRNAs. Concept, that the functions of intracellular miRNAs are driven by cellular organelles in mammalian cells. Extracellular miRNAs function in cell-cell communication in extracellular spaces and distance cells through circulation. A detailed understanding of organelle driven miRNA function and the precise role of extracellular miRNAs, pre- and post-therapeutic implications of miRNAs in this scenario would open several avenues for further understanding of miRNA function and can be better exploited for the treatment of breast cancers.
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Alizadeh S, Isanejad A, Sadighi S, Khalighfard S, Alizadeh AM. Effect of a high-intensity interval training on serum microRNA levels in women with breast cancer undergoing hormone therapy. A single-blind randomized trial. Ann Phys Rehabil Med 2019; 62:329-335. [PMID: 31400480 DOI: 10.1016/j.rehab.2019.07.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 07/07/2019] [Accepted: 07/07/2019] [Indexed: 01/28/2023]
Abstract
BACKGROUND The role of microRNAs (miRs) in hormone therapy (HT) is of keen interest in developing biomarkers and treatments for individuals with breast cancer. Although miRs are often moderate regulators under homeostatic conditions, their function is changed more in response to physical activity. OBJECTIVE This single-blind randomized trial aimed to explore the effect of high-intensity interval training (HIIT) on serum levels of miRs in individuals with early-stage breast cancer undergoing HT. METHODS Hormone receptor-positive women with breast cancer and healthy women were randomly assigned to a healthy control group (n=15), healthy group with HIIT (n=15), breast cancer group with HT (HT, n=26), and breast cancer group with HT and HIIT (HT+HIIT, n=26). The exercise groups underwent interval uphill walking training on a treadmill 3 times a week for 12weeks. At the end of the study, we analyzed changes in levels of cancer-related miRs (oncomiRs) and tumour suppressor miRs (TSmiRs) in response to the HT and HIIT. RESULTS In women with breast cancer versus healthy controls, the expression of some oncomiRs was significantly increased - miR-21 (P<0.001), miR-155 (P=0.001), miR-221 (P=0.008), miR-27a (P<0.001), and miR-10b (P=0.007) - and that of some TSmiRs was significantly decreased - miR-206 (P=0.048), miR-145 (P=0.011), miR-143 (P=0.008), miR-9 (P=0.020), and let-7a (P=0.005). Moreover, HT considerably downregulated oncomiRs and upregulated TSmiRs. HIIT for 12weeks with HT significantly decreased the expression of the oncomiRs and significantly increased that of the TSmiRs as compared with HT alone. CONCLUSIONS HITT could amplify the decrease and/or increase in expression of miRs associated with HT in women with breast cancer. A prospective trial could determine whether the use of circulating miRs for monitoring treatment can be useful in therapy decisions. TRIAL REGISTRATION Iranian Registry of Clinical Trials (No.: IRCT201202289171N1).
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Affiliation(s)
- Shaban Alizadeh
- Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran
| | - Amin Isanejad
- Immunoregulation Research Center, Shahed University, Tehran, Iran; Physical Education Department, Shahed University, Tehran, Iran
| | - Sanambar Sadighi
- Medical Oncology and Hematology Department, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Solmaz Khalighfard
- Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ali Mohammad Alizadeh
- Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran; Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Zhang W, Jiang H, Chen Y, Ren F. Resveratrol chemosensitizes adriamycin-resistant breast cancer cells by modulating miR-122-5p. J Cell Biochem 2019; 120:16283-16292. [PMID: 31155753 DOI: 10.1002/jcb.28910] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 03/17/2019] [Accepted: 03/22/2019] [Indexed: 01/09/2023]
Abstract
Breast cancer is one of the major malignancies threatening women's health worldwide, and chemotherapy tolerance has become a severe limitation of clinical treatment. Recent findings have revealed that resveratrol, as a dietary agent with antitumour activity, could prevent cancer progression by regulating microRNAs (miRNAs). Additionally, dysregulated miRNAs have been found to contribute significantly to chemoresistance by an increasing number of studies. In this study, experiments were designed to study the functional role of resveratrol in MCF-7 cells (low-invasive breast cancer) in chemosensitivity to adriamycin and to determine the targeted miRNAs of resveratrol and their key target proteins linked to cell activity. We demonstrated that in resveratrol-induced chemosensitivity, cell cycle and apoptosis were arrested in adriamycin-resistant breast cancer cells after modulation of the critical suppresser, miR-122-5p. Further miRNA modulation with miR-122-5p mimics or miR-122-5p inhibitors indicated a major effect of miR-122-5p on the regulation of key antiapoptotic proteins (B-cell lymphoma 2 [Bcl-2]) and cyclin-dependent kinases (CDK2, CDK4, and CDK6) in drug-resistant breast cancer cells in response to resveratrol. In conclusion, our results indicate that resveratrol acts as a potential inducer to enhance the chemosensitivity of breast cancer and also suggest that miR-122-5p is involved in the pathway of cell-cycle arrest by targeting Bcl-2 and CDKs.
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Affiliation(s)
- Wei Zhang
- Department of Breast Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Haitao Jiang
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Yunjie Chen
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Feng Ren
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
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12
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Klinge CM. Non-Coding RNAs in Breast Cancer: Intracellular and Intercellular Communication. Noncoding RNA 2018; 4:E40. [PMID: 30545127 PMCID: PMC6316884 DOI: 10.3390/ncrna4040040] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/29/2018] [Accepted: 12/04/2018] [Indexed: 02/07/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are regulators of intracellular and intercellular signaling in breast cancer. ncRNAs modulate intracellular signaling to control diverse cellular processes, including levels and activity of estrogen receptor α (ERα), proliferation, invasion, migration, apoptosis, and stemness. In addition, ncRNAs can be packaged into exosomes to provide intercellular communication by the transmission of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) to cells locally or systemically. This review provides an overview of the biogenesis and roles of ncRNAs: small nucleolar RNA (snRNA), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), miRNAs, and lncRNAs in breast cancer. Since more is known about the miRNAs and lncRNAs that are expressed in breast tumors, their established targets as oncogenic drivers and tumor suppressors will be reviewed. The focus is on miRNAs and lncRNAs identified in breast tumors, since a number of ncRNAs identified in breast cancer cells are not dysregulated in breast tumors. The identity and putative function of selected lncRNAs increased: nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), steroid receptor RNA activator 1 (SRA1), colon cancer associated transcript 2 (CCAT2), colorectal neoplasia differentially expressed (CRNDE), myocardial infarction associated transcript (MIAT), and long intergenic non-protein coding RNA, Regulator of Reprogramming (LINC-ROR); and decreased levels of maternally-expressed 3 (MEG3) in breast tumors have been observed as well. miRNAs and lncRNAs are considered targets of therapeutic intervention in breast cancer, but further work is needed to bring the promise of regulating their activities to clinical use.
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Affiliation(s)
- Carolyn M Klinge
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA.
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13
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Javadian M, Gharibi T, Shekari N, Abdollahpour‐Alitappeh M, Mohammadi A, Hossieni A, Mohammadi H, Kazemi T. The role of microRNAs regulating the expression of matrix metalloproteinases (MMPs) in breast cancer development, progression, and metastasis. J Cell Physiol 2018; 234:5399-5412. [DOI: 10.1002/jcp.27445] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Mahsa Javadian
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Najibeh Shekari
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | | | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Arezoo Hossieni
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
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14
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Bian G, Yu C, Liu L, Fang C, Chen K, Ren P, Zhang Q, Liu F, Zhang K, Xue Q, Xiang J, Guo H, Song J, Zhao Y, Wu W, Chung SK, Sun R, Ju G, Wang J. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling. Sci Signal 2018; 11:11/553/eaat1470. [DOI: 10.1126/scisignal.aat1470] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. We identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Our results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.
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15
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Wang W, Wang Z, Chen S, Zang X, Miao J. Interleukin-1β/nuclear factor-κB signaling promotes osteosarcoma cell growth through the microRNA-181b/phosphatase and tensin homolog axis. J Cell Biochem 2018; 120:1763-1772. [PMID: 30977354 DOI: 10.1002/jcb.27477] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 07/19/2018] [Indexed: 02/06/2023]
Abstract
So far, microRNA has attracted plenty of interest due to its role in tumorigenesis. Reportedly, miR-181b may be involved in the tumorigenesis of osteosarcoma (OS). In the current study, we attempted to investigate the detailed function and mechanism of miR-181b in OS carcinogenesis. Herein, miR-181a, miR-181b, miR-181c, and miR-181d expressions in OS tissues were higher than that in nontumor tissue samples as examined real-time polymerase chain reaction. Via direct targeting, miR-181b negatively regulated the expression of phosphatase and tensin homolog (PTEN), a well-known tumor suppressor. Furthermore, a small interfering RNA strategy was used to find that interleukin (IL)-1B and nuclear factor-κB (NF-κB) regulate miR-181b and PTEN expression. Consequently, the repression of PTEN by miR-181b promotes OS cell proliferation. In summary, our data support a critical role for NF-κB-dependent upregulation of miR-181b, which further inhibited PTEN expression and promoted the cell proliferation of OS cell lines. The above findings represent a new pathway for the repression of PTEN and the promotion of cell proliferation upon IL-1β induction.
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Affiliation(s)
- Weiguo Wang
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhengguang Wang
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Shijie Chen
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiaofang Zang
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jinglei Miao
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
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16
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Gao K, Wang P, Peng J, Xue J, Chen K, Song Y, Wang J, Li G, An X, Cao B. Regulation and function of runt-related transcription factors (RUNX1 and RUNX2) in goat granulosa cells. J Steroid Biochem Mol Biol 2018; 181:98-108. [PMID: 29626608 DOI: 10.1016/j.jsbmb.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 03/16/2018] [Accepted: 04/03/2018] [Indexed: 12/16/2022]
Abstract
Transcription factors, runt-related transcription factor 1 (RUNX1) and 2 (RUNX2), belong to the runt-related (RUNX) gene family and play critical roles in mammalian reproduction processes. However, the regulatory mechanisms of RUNX1 and RUNX2 expression or their functions in goat follicles remain largely unknown. Herein, RUNX1 and RUNX2 proteins were detected in the oocytes and granulosa cells of preantral and antral follicles, as well as corpus luteum by immunohistochemistry. Treatments with human chorionic gonadotropin (hCG) or with the agonists and inhibitors of hCG-induced intracellular signaling pathways in granulosa cells in vitro, we found that hCG increased RUNX1 expression by activating PKC and PI3K signaling molecules, and increased RUNX2 expression by activating adenylate cyclase, PKC, and PI3K signaling molecules. We also demonstrated that miR-181b expression is dependent on the hCG-induced activation of PKC and PKA, and miR-222 expression is dependent on the hCG-induced activation of PI3K and PKC in cultured granulosa cells. Meanwhile, miR-181b and miR-222 suppressed RUNX1 and RUNX2 expression by targeting RUNX1 and RUNX2 3' untranslated regions (3'UTRs) with or without hCG, respectively. These results suggested that hCG-mediated miR-181b and miR-222 expression are important for the regulation of RUNX1 and RUNX2 expression levels in granulosa cells. To explore the specific functions of RUNX1 and RUNX2, we transfected RUNX1 and RUNX2 small interfering RNAs into primary cultured granulosa cells. Knockdown of RUNX1 and RUNX2 significantly decreased progesterone productions and the mRNA abundance of key steroidogenic enzymes (StAR, CYP11A1 and HSD3B) after hCG treatment. But only miR-222 increased estradiol secretion in goat granulosa cells. In addition, knockdown of RUNX1 and RUNX2 also promoted granulosa cell proliferation. The hormonally regulated expression of RUNX1 and RUNX2 in granulosa cells, their involvement in progesterone production, and promoted granulosa cell proliferation suggest important roles of RUNX1 and RUNX2 in follicular development and luteinization.
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Affiliation(s)
- Kexin Gao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Peijie Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Jiayin Peng
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Junjun Xue
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Kaiwen Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Yuxuan Song
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Jiangang Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Guang Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Xiaopeng An
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
| | - Binyun Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
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17
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Zhang Y, Yan J, Wang L, Dai H, Li N, Hu W, Cai H. HIF-1α Promotes Breast Cancer Cell MCF-7 Proliferation and Invasion Through Regulating miR-210. Cancer Biother Radiopharm 2018; 32:297-301. [PMID: 29053417 DOI: 10.1089/cbr.2017.2270] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Many malignant tumors grow in hypoxic condition, which is associated with tumor growth, invasion, and metastasis. MicroRNAs are of great significance in the development of multiple malignant tumors. This study cultured breast cancer cell MCF-7 under the condition of different concentrations of oxygen, to test cell proliferation and invasion, and detect miR-210 expression, aiming to analyze the influence of hypoxia on breast cancer cell behaviors as well as miR-210 expressions. MATERIALS AND METHODS Breast cancer cell MCF-7 was cultured under normoxia, hypoxia, or anaerobic conditions for 12, 24, or 48 hours. Cell proliferation was detected by MTT assay. Cell invasion and migration were tested by transwell assay. HIF-1α mRNA and miR-210 expressions were determined by real-time polymerase chain reaction. RESULTS MCF-7 cell proliferation was gradually increased following time extension (p < 0.05). MCF-7 cell exhibited higher proliferation, invasion, and migration activities in hypoxic and anaerobic groups compared with those in normoxic group during the same time period. HIF-1α mRNA and miR-210 were significantly upregulated in anaerobic group compared with those in other groups (p < 0.05). HIF-1α mRNA and miR-210 were obviously elevated at 12, 24, and 48 hours (p < 0.05). CONCLUSION MCF-7 cell proliferation was increased, invasion and migration were enhanced, with upregulated expression of HIF-1α mRNA and miR-210 in the hypoxic and anaerobic group following time extension.
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Affiliation(s)
- Yang Zhang
- Department of Surgical Oncology, Tangshan People's Hospital , Tangshan, China
| | - Jinyin Yan
- Department of Surgical Oncology, Tangshan People's Hospital , Tangshan, China
| | - Lu Wang
- Department of Surgical Oncology, Tangshan People's Hospital , Tangshan, China
| | - Hao Dai
- Department of Surgical Oncology, Tangshan People's Hospital , Tangshan, China
| | - Ning Li
- Department of Surgical Oncology, Tangshan People's Hospital , Tangshan, China
| | - Wanning Hu
- Department of Surgical Oncology, Tangshan People's Hospital , Tangshan, China
| | - Haifeng Cai
- Department of Surgical Oncology, Tangshan People's Hospital , Tangshan, China
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18
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ADAMTS6 suppresses tumor progression via the ERK signaling pathway and serves as a prognostic marker in human breast cancer. Oncotarget 2018; 7:61273-61283. [PMID: 27542224 PMCID: PMC5308650 DOI: 10.18632/oncotarget.11341] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Accepted: 07/27/2016] [Indexed: 02/05/2023] Open
Abstract
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is involved in tumor development. However, how ADAMTS6 influences cancer remains unknown. We investigated the biological function and clinical implications of ADAMTs6 in breast cancer (BC). Its functional significance in BC cell lines was confirmed by ADAMTs6 overexpression or downregulation both in vitro and in vivo studies. Enhanced ADAMTS6 expression suppressed cell migration, invasion, and tumorigenesis, whereas knockdown promoted these characteristics. The extracellular signal-regulated kinase (ERK) pathway was partially involved in ADAMTS6-mediated inhibition of BC development, and miR-221-3p was identified as a predicted target for ADAMTS6. Results from the luciferase assay confirmed that miR-221-3p directly inhibited ADAMTS6 expression by binding its 3′-untranslated region. In addition, immunohistochemistry data from specimens from 182 BC patients showed that high ADAMTS6 expression was significantly correlated with favorable disease-free survival (DFS, p = 0.045). Subgroup analysis of patients with ER positive, PR positive or HER-2 negative tumors revealed that high ADAMTS6 expression more strongly extended DFS compared to low expression (p = 0.004, p = 0.009, p = 0.017). Multivariate analyses confirmed that ADAMTS6 expression was an independent risk factor for DFS (p = 0.011). Together, these data demonstrate that ADAMTS6 inhibits tumor development by regulating the ERK pathway via binding of miR-221-3p. Thus, its expression may be a potential prognostic biomarker for BC.
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19
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Kim YS, Park SJ, Lee YS, Kong HK, Park JH. miRNAs involved in LY6K and estrogen receptor α contribute to tamoxifen-susceptibility in breast cancer. Oncotarget 2018; 7:42261-42273. [PMID: 27304060 PMCID: PMC5173133 DOI: 10.18632/oncotarget.9950] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 05/25/2016] [Indexed: 01/03/2023] Open
Abstract
Estrogen receptor-alpha (ERα) is a clinically important therapeutic target for breast cancer. However, tumors that lose ERα are less responsive to anti-estrogens such as tamoxifen. MicroRNAs (miRNAs) are small RNAs that regulate expression of their target gene and dysregulations of miRNA has been identified in many diseases including human cancer. However, only a few miRNAs associated with tamoxifen resistance has been reported. In this study, we found that lymphocyte antigen 6 complex (LY6K), which is a member of the Ly-6/μPAR superfamily and related to breast cancer progression and metastasis, is inversely correlated with ERα expression. We, for the first time, found miRNAs involved in the regulatory molecular mechanism between ERα and LY6K and related to tamoxifen susceptibility in breast cancer. miR-192-5p, induced by LY6K, downregulates ERα directly and induced tamoxifen resistance in ERα-positive breast cancer cells. In addition, re-expression of ERα in ERα-negative breast cancer cells increased miR-500a-3p expression and directly inhibits LY6K expression. Ectopic expression of miR-500a-3p sensitized ERα-negative cells to tamoxifen by increasing apoptosis. Finally, we observed an inverse correlation between LY6K and ERα in primary breast cancer samples. We found that patients with recurrence showed high expression of miR-192-5p after tamoxifen treatments. In addition, expression of miR-500a-3p was significantly correlated to survival outcome. As miRNAs involved in the regulatory mechanism between LY6K and ERα can affect tamoxifen resistance, downregulating miR-192-5p or re-expressing miR-500a-3p could be a potential therapeutic approach for treating tamoxifen resistant patients.
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Affiliation(s)
- Ye Sol Kim
- Department of Biological Science, Sookmyung Women's University, Seoul, Korea
| | - Sae Jeong Park
- Department of Biological Science, Sookmyung Women's University, Seoul, Korea
| | - Yeon Seon Lee
- Department of Biological Science, Sookmyung Women's University, Seoul, Korea
| | - Hyun Kyung Kong
- Department of Biological Science, Sookmyung Women's University, Seoul, Korea
| | - Jong Hoon Park
- Department of Biological Science, Sookmyung Women's University, Seoul, Korea
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20
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Ying X, Wu Q, Wu X, Zhu Q, Wang X, Jiang L, Chen X, Wang X. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages. Oncotarget 2018; 7:43076-43087. [PMID: 27172798 PMCID: PMC5190009 DOI: 10.18632/oncotarget.9246] [Citation(s) in RCA: 289] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 04/19/2016] [Indexed: 12/14/2022] Open
Abstract
Cancer secreted exosomal miRNAs are emerging as mediators between tumor-stoma crosstalk. Here, we show epithelial ovarian cancer (EOC)-derived exosomes activated macrophages to a tumor-associated macrophage (TAM)-like phenotype with SOCS3/STAT3 pathway involvement, which could facilitate the progression of cancer. MiR-222-3p was enrichment in exosomes released from EOC cells and it could be transferred to macrophages. Overexpression of miR-222-3p in macrophages induced polarization of the M2 phenotype. Luciferase assay verified miR-222-3p targeted SOCS3 genes and expression of SOCS3 was decreased after transfection with a miR-222-3p mimic. Down-regulation of SOCS3 correlated with an increased expression of STAT3 activation. MiR-222-3p could be detected in the exosomes from serum and its levels were related to EOC. These observations propose tumor-derived exosomal miR-222-3p is an effective regulator in the polarization of tumor-promoting M2 macrophages and may be a biomarker of EOC.
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Affiliation(s)
- Xiang Ying
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Quanfeng Wu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoli Wu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qinyi Zhu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinjing Wang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lu Jiang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xin Chen
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xipeng Wang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
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21
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Asiaf A, Ahmad ST, Arjumand W, Zargar MA. MicroRNAs in Breast Cancer: Diagnostic and Therapeutic Potential. Methods Mol Biol 2018; 1699:23-43. [PMID: 29086366 DOI: 10.1007/978-1-4939-7435-1_2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are a large family of small, approximately 20-22 nucleotide, noncoding RNAs that regulate the expression of target genes, at the post-transcriptional level. miRNAs are involved in virtually diverse biological processes and play crucial roles in cellular processes, such as cell differentiation, proliferation, and apoptosis. Accumulating lines of evidence have indicated that miRNAs play important roles in the maintenance of biological homeostasis and that aberrant expression levels of miRNAs are associated with the onset of many diseases, including cancer. It is possible that the diverse roles that miRNAs play, have potential to provide valuable information in a clinical setting, demonstrating the potential to act as both screening tools for the stratification of high-risk patients, while informing the treatment decision-making process. Increasing evidence suggests that some miRNAs may even provide assistance in the diagnosis of patients with breast cancer. In addition, miRNAs may themselves be considered therapeutic targets, with inhibition or reintroduction of a particular miRNA capable of inducing a response in-vivo. This chapter discusses the role of miRNAs as oncogenes and tumor suppressors in breast cancer development and metastasis . It focuses on miRNAs that have prognostic, diagnostic, or predictive potential in breast cancer as well as the possible challenges in the translation of such observations to the clinic.
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Affiliation(s)
- Asia Asiaf
- Department of Biochemistry, Faculty of Science, University of Kashmir, Hazratbal Srinagar, J&K, 190006, India
| | - Shiekh Tanveer Ahmad
- Clarke H. Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, 2A25 HRIC, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Wani Arjumand
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, 2A32 HRIC, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Mohammad Afzal Zargar
- Department of Biochemistry, Faculty of Science, University of Kashmir, Hazratbal Srinagar, J&K, 190006, India.
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22
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Prathipati P, Nandi SS, Mishra PK. Stem Cell-Derived Exosomes, Autophagy, Extracellular Matrix Turnover, and miRNAs in Cardiac Regeneration during Stem Cell Therapy. Stem Cell Rev Rep 2017; 13:79-91. [PMID: 27807762 DOI: 10.1007/s12015-016-9696-y] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Stem cell therapy (SCT) raises the hope for cardiac regeneration in ischemic hearts. However, underlying molecular mechanisms for repair of dead myocardium by SCT in the ischemic heart is poorly understood. Growing evidences suggest that cardiac matrix stiffness and differential expressions of miRNAs play a crucial role in stem cell survival and differentiation. However, their roles on transplanted stem cells, for myocardial repair of the ischemic heart, remain unclear. Transplanted stem cells may act in an autocrine and/or paracrine manner to regenerate the dead myocardium. Paracrine mediators such as stem cell-derived exosomes are emerging as a novel therapeutic strategy to overcome some of the limitations of SCT. These exosomes carry microRNAs (miRNAs) that may regulate stem cell differentiation into a specific lineage. MicroRNAs may also contribute to stiffness of surrounding matrix by regulating extracellular matrix (ECM) turnover. The survival of transplanted stem cell depends on its autophagic process that maintains cellular homeostasis. Therefore, exosomes, miRNAs, extracellular matrix turnover, and autophagy may have an integral role in improving the efficacy of SCT. This review elaborates the specific roles of these regulatory components on cardiac regeneration in the ischemic heart during SCT.
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Affiliation(s)
- Priyanka Prathipati
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Shyam Sundar Nandi
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Paras Kumar Mishra
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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23
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Strotbek M, Schmid S, Sánchez-González I, Boerries M, Busch H, Olayioye MA. miR-181 elevates Akt signaling by co-targeting PHLPP2 and INPP4B phosphatases in luminal breast cancer. Int J Cancer 2017; 140:2310-2320. [DOI: 10.1002/ijc.30661] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 02/01/2017] [Accepted: 02/13/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Michaela Strotbek
- Institute of Cell Biology and Immunology, University of Stuttgart; 70569 Stuttgart Germany
| | - Simone Schmid
- Institute of Cell Biology and Immunology, University of Stuttgart; 70569 Stuttgart Germany
| | | | - Melanie Boerries
- Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg; 79104 Freiburg Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ); Heidelberg 69120 Germany
| | - Hauke Busch
- Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg; 79104 Freiburg Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ); Heidelberg 69120 Germany
- Lübeck Institute of Experimental Dermatology, University of Lübeck; Lübeck Germany
| | - Monilola A. Olayioye
- Institute of Cell Biology and Immunology, University of Stuttgart; 70569 Stuttgart Germany
- Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart; Stuttgart Germany
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24
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Role of Nerve Growth Factor (NGF) and miRNAs in Epithelial Ovarian Cancer. Int J Mol Sci 2017; 18:ijms18030507. [PMID: 28245631 PMCID: PMC5372523 DOI: 10.3390/ijms18030507] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/12/2017] [Accepted: 02/20/2017] [Indexed: 12/17/2022] Open
Abstract
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 3'-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression.
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25
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Abstract
A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, and human cancers invariably show TIMP deregulation in the tumour or stroma. Of the four TIMPs, TIMP1 overexpression or TIMP3 silencing is consistently associated with cancer progression or poor patient prognosis. Future efforts will align mouse model systems with changes in TIMPs in patients, will delineate protease-independent TIMP function, will pinpoint therapeutic targets within the TIMP-metalloproteinase-substrate network and will use TIMPs in liquid biopsy samples as biomarkers for cancer prognosis.
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Affiliation(s)
- Hartland W Jackson
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
- Bodenmiller Laboratory, University of Zürich, Institute for Molecular Life Sciences, Winterthurstrasse 190, 8057 Zürich, Switzerland
| | - Virginie Defamie
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
| | - Paul Waterhouse
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
| | - Rama Khokha
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
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26
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Graham A, Holbert J, Nothnick WB. miR-181b-5p Modulates Cell Migratory Proteins, Tissue Inhibitor of Metalloproteinase 3, and Annexin A2 During In Vitro Decidualization in a Human Endometrial Stromal Cell Line. Reprod Sci 2016; 24:1264-1274. [PMID: 28256954 DOI: 10.1177/1933719116682877] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Decidualization is essential for successful embryo implantation and is regulated by concerted actions of growth factors and hormones. More recently, microRNAs, small RNA molecules that regulate posttranscriptional gene expression, have been implicated to play a role in the decidualization process. Of these microRNAs, miR-181b-5p has been associated with decidualization but its precise role and targets are not well established. To address this gap in our knowledge, we assessed the expression of miR-181b-5p, and its target tissue inhibitor of metalloproteinase 3 (TIMP-3), during in vitro decidualization using the well-characterized human endometrial stromal cell line, t-HESC. miR-181b-5p expression was highest prior to decidualization and significantly decreased in response to decidualization stimulus. In contrast, TIMP-3 expression was absent prior to in vitro decidualization and increased during decidualization. Regulation of TIMP-3 expression by miR-181b-5p was confirmed in vitro by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot analysis, and 3' untranslated region reporter constructs. To identify unforeseen targets of miR-181b-5p during in vitro decidualization, t-HESC cells were transfected with pre- miR-181b-5p, and protein profiles were determined by 2-dimensional differential in-gel electrophoresis followed by matrix-assisted laser desorption-ionization time-of-flight/time-of-flight (MALDI TOF/TOF) tandem mass spectrometry. Of these proteins, several downregulated proteins associated with cell migration were identified including annexin A2, which we subsequently confirmed by qRT-PCR and Western blot analysis to be regulated by miR-181b-5p. In conclusion, miR-181b-5p is downregulated during the process of in vitro decidualization and may regulate the expression of proteins associated with cell migration including TIMP-3 and annexin A2.
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Affiliation(s)
- Amanda Graham
- 1 Department of Molecular and Integrative Physiology, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Joshua Holbert
- 1 Department of Molecular and Integrative Physiology, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Warren B Nothnick
- 1 Department of Molecular and Integrative Physiology, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS, USA
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27
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O'Bryan S, Dong S, Mathis JM, Alahari SK. The roles of oncogenic miRNAs and their therapeutic importance in breast cancer. Eur J Cancer 2016; 72:1-11. [PMID: 27997852 DOI: 10.1016/j.ejca.2016.11.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 11/16/2016] [Indexed: 12/19/2022]
Abstract
Since the discovery of tumour suppressive miRNA in 2002, the dysregulation of miRNAs was implicated in many cancers, exhibiting both tumour suppressive and oncogenic roles. Dysregulation of miRNAs was found to be involved in the initiation of oncogenesis, as well as the progression, invasion and metastasis of cancers. While normal miRNA inhibitory functions help regulate gene expression in the cell, oncogenic miRNA, when dysregulated can lead to suppression of critical pathways that control apoptosis, cell cycle progression, growth and proliferation. This suppression allows for the upregulation of pro-oncogenic factors that drive cell survival, growth and proliferation. Due to emerging discoveries, oncogenic miRNAs are proving to be a critical component in cancers, such as breast cancer, and may provide novel avenues for cancer treatment. In this article, we discuss the roles of the most studied oncogenic miRNAs in breast cancer including clusters and families involved as well as the less studied and recently discovered oncogenic miRNAs. These miRNAs provide valuable information into the complexity of regulatory elements affected by their overexpression and the overall impact in the progression of breast cancer. Also, identifying miRNAs causing or leading to resistance or sensitivity to current anti-cancer drugs prior to treatment may lead to an improvement in treatment selection and overall patient response. This review summarizes known and recently discovered miRNAs in literature found to have oncogenic roles in breast cancer initiation and the progression, invasion and metastasis of the disease.
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Affiliation(s)
- Samia O'Bryan
- Department of Comparative Biomedical Science, School of Veterinary Science, Louisiana State University, Baton Rouge, LA, USA
| | - Shengli Dong
- Department of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, LSU School of Medicine, New Orleans, LA 70112, USA
| | - J Michael Mathis
- Department of Comparative Biomedical Science, School of Veterinary Science, Louisiana State University, Baton Rouge, LA, USA.
| | - Suresh K Alahari
- Department of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, LSU School of Medicine, New Orleans, LA 70112, USA.
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28
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Pollutri D, Gramantieri L, Bolondi L, Fornari F. TP53/MicroRNA Interplay in Hepatocellular Carcinoma. Int J Mol Sci 2016; 17:ijms17122029. [PMID: 27918441 PMCID: PMC5187829 DOI: 10.3390/ijms17122029] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 11/23/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023] Open
Abstract
The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the “personalized-medicine” era.
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Affiliation(s)
- Daniela Pollutri
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Laura Gramantieri
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Luigi Bolondi
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy.
| | - Francesca Fornari
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy.
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29
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Petrovic N, Davidovic R, Jovanovic-Cupic S, Krajnovic M, Lukic S, Petrovic M, Roganovic J. Changes in miR-221/222 Levels in Invasive and In Situ Carcinomas of the Breast: Differences in Association with Estrogen Receptor and TIMP3 Expression Levels. Mol Diagn Ther 2016; 20:603-615. [PMID: 27488105 DOI: 10.1007/s40291-016-0230-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Breast cancer (BC) is a heterogeneous group of diseases that still represents a major cause of death in the female population. MicroRNAs (miRNAs, miRs), such as miR-221 and miR-222, have been shown to be involved in BC pathology by acting via its target genes such as tissue inhibitor of metalloproteinase 3 (TIMP3). OBJECTIVES The main goals of this study were to find differences in miR-221/222 levels of expression in BC groups based on invasiveness, and to investigate the association with estrogen receptor (ER), TIMP3 messenger RNA (mRNA) levels, and clinicopathological characteristics of patients and tumors. METHODS In this study, we measured levels of miR-221/222 in 63 breast tissue samples by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using TaqMan® technology and immunohistochemistry. RESULTS miR-221/222 levels varied significantly across groups based on invasiveness (P < 0.001). In in situ tumors, miR-221 and miR-222 were negatively associated with ER (P = 0.001, r = -0.714, and P = 0.013, r = -0.585, respectively). In invasive breast carcinomas associated with non-invasive tumors, miR-222 was inversely associated with ER (P = 0.039, r = -0.620). Pure invasive BCs showed a positive correlation of miR-221 and miR-222 with TIMP3 mRNA levels (P = 0.008, r = 0.508, and P = 0.010, r = 0.497, respectively). CONCLUSION An increase in miR-221/222 might be an important event for in situ carcinoma formation, and miR-221/222 may be important molecules that highlight potential differences between invasive breast carcinomas associated with non-invasive and pure invasive BCs.
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Affiliation(s)
- Nina Petrovic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia.
| | - Radoslav Davidovic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia
| | - Snezana Jovanovic-Cupic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia
| | - Milena Krajnovic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia
| | - Silvana Lukic
- Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia
| | - Milan Petrovic
- Clinic of Maxillofacial Surgery, School of Dental Medicine, University of Belgrade, Dr. Subotica 4, 11000, Belgrade, Serbia
| | - Jelena Roganovic
- Department of Pharmacology, School of Dental Medicine, University of Belgrade, Dr. Subotica 8, 11000, Belgrade, Serbia
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30
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Sun Y, He N, Dong Y, Jiang C. MiR-24-BIM-Smac/DIABLO axis controls the sensitivity to doxorubicin treatment in osteosarcoma. Sci Rep 2016; 6:34238. [PMID: 27681638 PMCID: PMC5041092 DOI: 10.1038/srep34238] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Accepted: 09/09/2016] [Indexed: 12/16/2022] Open
Abstract
Emerging evidence shows that microRNAs (miRNAs) act as critical regulators in the progression and chemoresistance of multiple tumors, including osteosarcoma (OS). In this study, we found that the level of miR-24 was increased in OS patients’ serum, tumor tissues and OS cell lines. Furthermore, we found that knockdown of miR-24 by its specific inhibitors significantly increased the therapeutic effect of doxorubicin (DOX) on OS cell lines (MG-63 and HOS). Moreover, miR-24 inhibitors resensitized the doxorubicin-resistant MG-63 cells (MG-63/R) and HOS cells (HOS/R) to DOX. As the gene of Bcl-2 interacting mediator of cell death (BIM) was proved to be a target of miR-24 in MG-63/R cells, we further observed that the miR-24 inhibitors promoted the DOX-induced apoptosis via mitochondrial pathway. In addition, results of immunoprecipitation showed the release of second mitochondria derived activator of caspase/ direct IAP binding protein with low pI (Smac/DIABLO) abolished the biological activity of X-linked inhibitor of apoptosis protein (XIAP) by binding with it, which subsequently induced the activation of caspase 9, 7 and 3. In summary, those results strongly suggest that the miR-24-BIM-Smac/DIABLO axis might be a novel target for the treatment of OS.
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Affiliation(s)
- Yangbai Sun
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Nengbin He
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yang Dong
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Chaoyin Jiang
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China
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31
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Joshi T, Elias D, Stenvang J, Alves CL, Teng F, Lyng MB, Lykkesfeldt AE, Brünner N, Wang J, Gupta R, Workman CT, Ditzel HJ. Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer. Oncotarget 2016; 7:57239-57253. [PMID: 27528030 PMCID: PMC5302986 DOI: 10.18632/oncotarget.11136] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 07/27/2016] [Indexed: 12/27/2022] Open
Abstract
Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies. Although the target genes affected by the altered miRNA in the three TamRs differed, good agreement in terms of affected molecular pathways was observed. Moreover, we found evidence of miRNA-mediated regulation of ESR1, PGR1, FOXM1 and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors and siRNA-mediated gene knockdown, we showed that both SNAI2 and FYN significantly affect the growth of TamR cell lines. Finally, we show that a combination of 2 miRNAs (miR-190b and miR-516a-5p) exhibiting altered expression in TamR cell lines were predictive of treatment outcome in a cohort of ER+ breast cancer patients receiving adjuvant tamoxifen mono-therapy. Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer.
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Affiliation(s)
- Tejal Joshi
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Daniel Elias
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Jan Stenvang
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Section of Molecular Disease Biology, Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark
| | - Carla L. Alves
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Fei Teng
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- BGI (Beijing Genomics Institute), Beishan Industrial Zone, Shenzhen, China
| | - Maria B. Lyng
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Anne E. Lykkesfeldt
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Nils Brünner
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Section of Molecular Disease Biology, Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark
| | - Jun Wang
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- BGI (Beijing Genomics Institute), Beishan Industrial Zone, Shenzhen, China
| | - Ramneek Gupta
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Christopher T. Workman
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Henrik J. Ditzel
- Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Department of Oncology, Odense University Hospital, Odense, Denmark
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32
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Tamoxifen Resistance: Emerging Molecular Targets. Int J Mol Sci 2016; 17:ijms17081357. [PMID: 27548161 PMCID: PMC5000752 DOI: 10.3390/ijms17081357] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/10/2016] [Accepted: 08/16/2016] [Indexed: 12/12/2022] Open
Abstract
17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer.
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33
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Zhou Z, Kennell C, Lee JY, Leung YK, Tarapore P. Calcium phosphate-polymer hybrid nanoparticles for enhanced triple negative breast cancer treatment via co-delivery of paclitaxel and miR-221/222 inhibitors. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 13:403-410. [PMID: 27520723 DOI: 10.1016/j.nano.2016.07.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 07/05/2016] [Accepted: 07/28/2016] [Indexed: 12/19/2022]
Abstract
In this study, a development of a novel calcium phosphate-polymer hybrid nanoparticle system is reported.The nanoparticle system can co-encapsulate and co-deliver a combination of therapeutic agents with different physicochemical properties (i.e., inhibitors for microRNA-221 and microRNA-222 (miRi-221/222) and paclitaxel (pac)).miRi-221/222 are hydrophilic and were encapsulated with calcium phosphate by co-precipitation in a water-in-oil emulsion.The precipitates were then coated with an anionic lipid, dioleoylphosphatidic acid (DOPA), to co-encapsulate hydrophobic paclitaxel outside the hydrophilic precipitates and inside the same nanoparticle.The nanoparticles formed by following this approach had a size of about ≤100nm and contained both lipid-coated calcium phosphate/miRi and paclitaxel.This nanoparticle system was found to simultaneously deliver paclitaxel and miRi-221/222 to their intracellular targets, leading to inhibit proliferative mechanisms of miR-221/222 and thus significantly enhancing the therapeutic efficacy of paclitaxel.
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Affiliation(s)
- Zilan Zhou
- Chemical Engineering Program, Department of Biomedical, Environmental, and Chemical Engineering, University of Cincinnati, Cincinnati, OH, USA
| | - Carly Kennell
- Chemical Engineering Program, Department of Biomedical, Environmental, and Chemical Engineering, University of Cincinnati, Cincinnati, OH, USA
| | - Joo-Youp Lee
- Chemical Engineering Program, Department of Biomedical, Environmental, and Chemical Engineering, University of Cincinnati, Cincinnati, OH, USA.
| | - Yuet-Kin Leung
- Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Pheruza Tarapore
- Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
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34
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Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes. J Hum Genet 2016; 62:15-24. [PMID: 27439682 DOI: 10.1038/jhg.2016.89] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/11/2016] [Accepted: 06/13/2016] [Indexed: 12/17/2022]
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate the function of target genes at the post-transcriptional phase. miRNAs are considered to have roles in the development, progression and metastasis of cancer. Recent studies have indicated that particular miRNA signatures are correlated with tumor aggressiveness, response to drug therapy and patient outcome in breast cancer. On the other hand, in routine clinical practice, the treatment regimens for breast cancer are determined based on the intrinsic subtype of the primary tumor. Previous studies have shown that miRNA expression profiles of each intrinsic subtypes of breast cancer differ. In hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, miRNA expressions are found to be correlated with endocrine therapy resistance, progesterone receptor expression and heat shock protein activity. Some miRNAs are associated with resistance to HER2-targeted therapy and HER3 expression in HER2-positive breast cancer. In triple-negative breast cancer, miRNA expressions are found to be associated with BRCA mutations, immune system, epithelial-mesenchymal transition, cancer stem cell properties and androgen receptor expression. As it has been clarified that the expression levels and functions of miRNA differ among the various subtypes of breast cancer, and it is necessary to take account of the characteristics of each breast cancer subtype during research into the roles of miRNA in breast cancer. In addition, the discovery of the roles played by miRNAs in breast cancer might provide new opportunities for the development of novel strategies for diagnosing and treating breast cancer.
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35
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Wang M, Ge X, Zheng J, Li D, Liu X, Wang L, Jiang C, Shi Z, Qin L, Liu J, Yang H, Liu LZ, He J, Zhen L, Jiang BH. Role and mechanism of miR-222 in arsenic-transformed cells for inducing tumor growth. Oncotarget 2016; 7:17805-14. [PMID: 26909602 PMCID: PMC4951251 DOI: 10.18632/oncotarget.7525] [Citation(s) in RCA: 22] [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: 09/26/2015] [Accepted: 01/14/2016] [Indexed: 12/26/2022] Open
Abstract
High levels of arsenic in drinking water, soil, and air are associated with the higher incidences of several kinds of cancers worldwide, but the mechanism is yet to be fully discovered. Recently, a number of evidences show that dysregulation of microRNAs (miRNAs) induces carcinogenesis. In this study, we found miR-222 was upregulated in arsenic-transformed human lung epithelial BEAS-2B cells (As-T cells). Anti-miR-222 inhibitor treatment decreased cell proliferation, migration, tube formation, and induced apoptosis. In addition, anti-miR-222 inhibitor expression decreased tumor growth in vivo. We also found that inhibition of miR-222 induced the expression of its direct targets ARID1A and phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and activated apoptosis of As-T cells in part through ARID1A downregulation. These results indicate that miR-222 plays an important role in arsenic-induced tumor growth.
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Affiliation(s)
- Min Wang
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Ge
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jitai Zheng
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dongmei Li
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
- Ninggao Personalized Medicine and Technology Innovation Center, Nanjing, Jiangsu, China
| | - Xue Liu
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lin Wang
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
- Ninggao Personalized Medicine and Technology Innovation Center, Nanjing, Jiangsu, China
| | - Chengfei Jiang
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhumei Shi
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lianju Qin
- Center of Clinical Reproductive Medicine, Jiangsu Province Hospital, Nanjing, Jiangsu, China
| | - Jiayin Liu
- Center of Clinical Reproductive Medicine, Jiangsu Province Hospital, Nanjing, Jiangsu, China
| | - Hushan Yang
- Division of Population Science, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ling-Zhi Liu
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jun He
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Linlin Zhen
- Department of Breast and Thyroid Surgery, Huai'an First People's Hospital, Huai'an, Jiangsu, China
| | - Bing-Hua Jiang
- State Key Laboratory of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
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Li B, Lu Y, Wang H, Han X, Mao J, Li J, Yu L, Wang B, Fan S, Yu X, Song B. RETRACTED: miR-221/222 enhance the tumorigenicity of human breast cancer stem cells via modulation of PTEN/Akt pathway. Biomed Pharmacother 2016; 79:93-101. [PMID: 27044817 DOI: 10.1016/j.biopha.2016.01.045] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 01/31/2016] [Accepted: 01/31/2016] [Indexed: 12/21/2022] Open
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concerns were raised in the public domain and also reported by the authors to the journal regarding the similarity between various panels from Figures 2 and 3. Given also the institutional investigation, the journal requested the authors to provide the raw data. However, the authors were not able to provide raw data of sufficient quality and detail for the journal to independently audit the provenance and validity of the data, and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Bailong Li
- Department of Clinical Medicine, Grade 2013, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Ying Lu
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Honghai Wang
- Academic Affairs Department, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Xiaocui Han
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Jun Mao
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Jiazhi Li
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Lihui Yu
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Bo Wang
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Shujun Fan
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Xiaotang Yu
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China
| | - Bo Song
- Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China.
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Lv JF, Hu L, Zhuo W, Zhang CM, Zhou HH, Fan L. Epigenetic alternations and cancer chemotherapy response. Cancer Chemother Pharmacol 2015; 77:673-84. [DOI: 10.1007/s00280-015-2951-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 12/17/2015] [Indexed: 12/29/2022]
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38
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Klinge CM. miRNAs regulated by estrogens, tamoxifen, and endocrine disruptors and their downstream gene targets. Mol Cell Endocrinol 2015; 418 Pt 3:273-97. [PMID: 25659536 PMCID: PMC4523495 DOI: 10.1016/j.mce.2015.01.035] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 01/22/2015] [Accepted: 01/23/2015] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are short (22 nucleotides), single-stranded, non-coding RNAs that form complimentary base-pairs with the 3' untranslated region of target mRNAs within the RNA-induced silencing complex (RISC) and block translation and/or stimulate mRNA transcript degradation. The non-coding miRBase (release 21, June 2014) reports that human genome contains ∼ 2588 mature miRNAs which regulate ∼ 60% of human protein-coding mRNAs. Dysregulation of miRNA expression has been implicated in estrogen-related diseases including breast cancer and endometrial cancer. The mechanism for estrogen regulation of miRNA expression and the role of estrogen-regulated miRNAs in normal homeostasis, reproduction, lactation, and in cancer is an area of great research and clinical interest. Estrogens regulate miRNA transcription through estrogen receptors α and β in a tissue-specific and cell-dependent manner. This review focuses primarily on the regulation of miRNA expression by ligand-activated ERs and their bona fide gene targets and includes miRNA regulation by tamoxifen and endocrine disrupting chemicals (EDCs) in breast cancer and cell lines.
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Affiliation(s)
- Carolyn M Klinge
- Department of Biochemistry & Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
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39
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Matrix Metalloproteinases and Their Inhibitors in Chronic Obstructive Pulmonary Disease. Arch Immunol Ther Exp (Warsz) 2015; 64:177-93. [DOI: 10.1007/s00005-015-0375-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 09/25/2015] [Indexed: 01/04/2023]
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40
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Di Leva G, Cheung DG, Croce CM. miRNA clusters as therapeutic targets for hormone-resistant breast cancer. Expert Rev Endocrinol Metab 2015; 10:607-617. [PMID: 27721895 PMCID: PMC5053393 DOI: 10.1586/17446651.2015.1099430] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
MicroRNAs are small non coding RNAs that typically inhibit the translation and stability of messenger RNAs, controlling genes involved in cellular processes such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration. Not surprisingly, microRNAs are also aberrantly expressed in cancer and promote tumorigenesis by disrupting these vital cellular functions. In this review, we first broadly summarize the role of microRNAs in breast cancer and Estrogen Receptor alpha signaling. Then we focus on what is currently known about the role of microRNAs in anti-hormonal therapy or resistance to endocrine agents. Specifically, we will discuss key miRNAs involved in tamoxifen (miR-221/222, 181, 101, 519a, 301, 375, 342, 451, and the let-7 family), fulvestrant (miR-221/222, miR-200 family), and aromatase inhibitor (miR-128 and the let-7 family) resistance.
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Affiliation(s)
- Gianpiero Di Leva
- Department of Molecular Virology Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
| | - Douglas G Cheung
- Department of Molecular Virology Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
| | - Carlo M Croce
- Department of Molecular Virology Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
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41
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Abstract
Therapies targeting estrogen receptor alpha (ERα), including selective ER modulators such as tamoxifen, selective ER downregulators such as fulvestrant (ICI 182 780), and aromatase inhibitors such as letrozole, are successfully used in treating breast cancer patients whose initial tumor expresses ERα. Unfortunately, the effectiveness of endocrine therapies is limited by acquired resistance. The role of microRNAs (miRNAs) in the progression of endocrine-resistant breast cancer is of keen interest in developing biomarkers and therapies to counter metastatic disease. This review focuses on miRNAs implicated as disruptors of antiestrogen therapies, their bona fide gene targets and associated pathways promoting endocrine resistance.
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Affiliation(s)
- Penn Muluhngwi
- Department of Biochemistry and Molecular GeneticsCenter for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry and Molecular GeneticsCenter for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA
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42
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Zhao JJ, Chu ZB, Hu Y, Lin J, Wang Z, Jiang M, Chen M, Wang X, Kang Y, Zhou Y, Ni Chonghaile T, Johncilla ME, Tai YT, Cheng JQ, Letai A, Munshi NC, Anderson KC, Carrasco RD. Targeting the miR-221-222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma. Cancer Res 2015; 75:4384-4397. [PMID: 26249174 DOI: 10.1158/0008-5472.can-15-0457] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 06/29/2015] [Indexed: 12/22/2022]
Abstract
Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma, intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. miRNAs are noncoding small RNAs that play important roles in the regulation of gene expression and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221-222 family in dexamethasone-induced drug resistance in multiple myeloma using the isogenic cell lines MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization data revealed gain of chromosome X regions at band p11.3, wherein the miR-221-222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221-222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely proapoptotic target. We confirmed PUMA mRNA as a direct target of miR-221-222 in MM1S and MM1R cells by both gain-of-function and loss-of-function studies. In addition, miR-221-222 treatment rendered MM1S cells resistant to dexamethasone, whereas anti-miR-221-222 partially restored the dexamethasone sensitivity of MM1R cells. These studies have uncovered a role for miR-221-222 in multiple myeloma drug resistance and suggest a potential therapeutic role for inhibitors of miR-221-222 binding to PUMA mRNA as a means of overcoming dexamethasone resistance in patients. The clinical utility of this approach is predicated on the ability of antisense miR-221-222 to increase survival while reducing tumor burden and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of multiple myeloma. Moreover, our observation of increased levels of miR-221-222 with decreased PUMA expression in multiple myeloma cells from patients at relapse versus untreated controls suggests an even broader role for miR-221-222 in drug resistance and provides a rationale for the targeting of miR-221-222 as a means of improving patient outcomes.
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Affiliation(s)
- Jian-Jun Zhao
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Zhang-Bo Chu
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.,Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianhong Lin
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA
| | - Zhongqiu Wang
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Meng Jiang
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Ming Chen
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Xujun Wang
- Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China
| | - Yue Kang
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Yangsheng Zhou
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Triona Ni Chonghaile
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | | | - Yu-Tzu Tai
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA
| | - Jin Q Cheng
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Antony Letai
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Nikhil C Munshi
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.,Boston VA Healthcare System, Boston, MA
| | - Kenneth C Anderson
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA
| | - Ruben D Carrasco
- Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.,Department of Pathology, Brigham & Women's Hospital, Boston, MA
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43
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Zhang W, Xu J, Shi Y, Sun Q, Zhang Q, Guan X. The novel role of miRNAs for tamoxifen resistance in human breast cancer. Cell Mol Life Sci 2015; 72:2575-84. [PMID: 25782411 PMCID: PMC11113898 DOI: 10.1007/s00018-015-1887-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/09/2015] [Accepted: 03/12/2015] [Indexed: 01/04/2023]
Abstract
The selective estrogen receptor modulator tamoxifen is the most commonly used treatment for patients with ER-positive breast cancer. However, tumor cells often develop resistance to tamoxifen therapy, which is a major obstacle limiting the success of breast cancer treatment. miRNAs, as oncogenic or tumor suppressor genes, regulate the expression and function of their related target genes to affect the biological behaviors of cancer cells, including cancer initiation, progression, metastasis, and therapeutic resistance. In detail, many miRNAs associated with breast cancer tamoxifen resistance have been identified, which offer new targets for breast cancer therapy. Here, we review the miRNAs involved in regulation of tamoxifen resistance in human breast cancer and the mechanism of how the modulation of miRNAs may regulate the sensitivity of breast cancer cells to tamoxifen. We also discuss the future prospects of studies about miRNAs in regulation of tamoxifen resistance and miRNA-based therapeutics for tamoxifen resistance breast cancer patients.
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Affiliation(s)
- Wenwen Zhang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 China
| | - Jing Xu
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 China
| | - Yaqin Shi
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 China
| | - Qian Sun
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 China
| | - Qun Zhang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 China
| | - Xiaoxiang Guan
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 China
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44
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Jackson HW, Hojilla CV, Weiss A, Sanchez OH, Wood GA, Khokha R. Timp3 deficient mice show resistance to developing breast cancer. PLoS One 2015; 10:e0120107. [PMID: 25807548 PMCID: PMC4373869 DOI: 10.1371/journal.pone.0120107] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3−⁄− mice have delayed tumor onset and 36% of MMTV-Neu Timp3−⁄− mice remain tumor free. TIMP3 is a regulator of TNF signaling and similar to Timp3, Tnf or Tnfr1 loss delays early tumorigenesis. The tumor suppression in Timp3 null mice requires Tnfr1, but does not result in alterations in the local immune compartment. In the mammary gland, Timps are highly expressed in the stroma and through the transplantation of tumor cells we observe that Timp3 deficiency in the host is sufficient to delay the growth of early, but not advanced tumor cells. Together our data is the first to identify a tumor promoting role of endogenous Timp3 in vivo, the spatial and temporal windows of this effect, and its dependence on Tnfr1.
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Affiliation(s)
| | - Carlo V. Hojilla
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Ashley Weiss
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Otto H. Sanchez
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Geoffrey A. Wood
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Rama Khokha
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
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45
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He Y, Wang J, Wang J, Yung VYW, Hsu E, Li A, Kang Q, Ma J, Han Q, Jin P, Xing R, Lu Y, Sheng J. MicroRNA-135b regulates apoptosis and chemoresistance in colorectal cancer by targeting large tumor suppressor kinase 2. Am J Cancer Res 2015; 5:1382-1395. [PMID: 26101704 PMCID: PMC4473317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 03/12/2015] [Indexed: 06/04/2023] Open
Abstract
Colorectal cancer remains the third most common cause of death from cancer worldwide. MicroRNA emerges as a good area of research for current cancer therapy. Here, we identified miR-135b to be a contributor to anti-apoptosis and chemoresistance in colorectal cancer. We observed high levels of miR-135b in colorectal cancer cell lines and clinical tissues, compared to colorectal epithelium cell line and noncancerous tissues. Furthermore, enforced expression of miR-135b attenuated doxorubicin-induced apoptosis in colorectal cells. (Doxorubicin alone can trigger significant apoptosis). In elucidating the molecular mechanism by which miR-135b participate in the regulation of apoptosis and chemoresistance in colorectal cancer, we discovered that large tumor suppressor kinase 2 (LATS2) is a direct target of miR-135b. The role of miR-135b was confirmed in colorectal tumor xenograft models. The growth of established tumors was suppressed by an inhibition of miR-135b expression and enhanced apoptosis was further assessed by TUNEL assay. Taken together, our results reveal that miR-135b and LATS2 axis may be a novel therapeutic target for colorectal cancer.
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Affiliation(s)
- Yuqi He
- Department of Gastroenterology, Beijing Military General HospitalBeijing 100700, China
| | - Jianxun Wang
- Institute for Translational Medicine, College of Medicine, Qingdao UniversityQingdao 266021, China
| | - Jiheng Wang
- Department of Gastroenterology, Beijing Military General HospitalBeijing 100700, China
| | - Victoria Yee-Wa Yung
- Department of Gastroenterology & Hepatology, University of California Davis, UC Davis Medical CenterSacramento, CA 95817
| | - Emily Hsu
- Department of Microbiology, Immunology, and Molecular Genetics, University of California Los AngelesLos Angeles, CA 90095
| | - Aiqin Li
- Department of Gastroenterology, Beijing Military General HospitalBeijing 100700, China
| | - Qian Kang
- Department of Gastroenterology, Beijing Military General HospitalBeijing 100700, China
| | - Junbiao Ma
- Department of Coloproctology, The People’s Hospital of Renqiu CityRenqiu 062550, China
| | - Qingfeng Han
- Department of Coloproctology, The People’s Hospital of Renqiu CityRenqiu 062550, China
| | - Peng Jin
- Department of Gastroenterology, Beijing Military General HospitalBeijing 100700, China
| | - Rui Xing
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteBeijing, 100142, China
| | - Youyong Lu
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteBeijing, 100142, China
| | - Jianqiu Sheng
- Department of Gastroenterology, Beijing Military General HospitalBeijing 100700, China
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46
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MiR-221/222 promote human glioma cell invasion and angiogenesis by targeting TIMP2. Tumour Biol 2015; 36:3763-73. [PMID: 25731730 DOI: 10.1007/s13277-014-3017-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 12/23/2014] [Indexed: 12/11/2022] Open
Abstract
miR-221/222 are two highly homologous microRNAs that are frequently upregulated in solid tumors. However, the effects of miR-221/222 in malignant gliomas have not been investigated thoroughly. In this study, we found that miR-221/222 were significantly upregulated in human glioma samples and glioma cell lines. Both gain- and loss-of-function studies showed that miR-221/222 regulate cell proliferation, the cell cycle and apoptosis, in addition to, invasion, metastasis, and angiogenesis in glioma cell lines. Subsequent investigations revealed that TIMP2 is a direct target of miR-221/222, and overexpression of TIMP2 reduced the miR-221/222-mediated invasion, metastasis, and angiogenesis of glioma cells. Taken together, our results suggest that the suppression of miR-221/222 may be a feasible approach for inhibiting the malignant behaviors of glioma.
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47
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Xue J, Niu J, Wu J, Wu ZH. MicroRNAs in cancer therapeutic response: Friend and foe. World J Clin Oncol 2014; 5:730-743. [PMID: 25302173 PMCID: PMC4129536 DOI: 10.5306/wjco.v5.i4.730] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Revised: 03/15/2014] [Accepted: 06/18/2014] [Indexed: 02/06/2023] Open
Abstract
Cancer initiation and development engage extremely complicated pathological processes which involve alterations of a large number of cell signaling cascades and functional networks in temporal and spatial orders. During last decades, microRNAs (miRNAs), a class of non-coding RNAs, have emerged as critical players in cancer pathogenesis and progression by modulating many pathological aspects related to tumor development, growth, metastasis, and drug resistance. The major function of miRNAs is to post-transcriptionally regulate gene expression depending on recognition of complementary sequence residing in target mRNAs. Commonly, a particular miRNA recognition sequence could be found in a number of genes, which allows a single miRNA to regulate multiple functionally connected genes simultaneously and/or chronologically. Furthermore, a single gene can be targeted and regulated by multiple miRNAs. However, previous studies have demonstrated that miRNA functions are highly context-dependent, which leads to distinct pathological outcomes in different types of cancer as well as at different stages by alteration of the same miRNA. Here we summarize recent progress in studies on miRNA function in cancer initiation, metastasis and therapeutic response, focusing on breast cancer. The varying functions of miRNAs and potential application of using miRNAs as biomarkers as well as therapeutic approaches are further discussed in the context of different cancers.
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48
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Zhi F, Wang Q, Deng D, Shao N, Wang R, Xue L, Wang S, Xia X, Yang Y. MiR-181b-5p downregulates NOVA1 to suppress proliferation, migration and invasion and promote apoptosis in astrocytoma. PLoS One 2014; 9:e109124. [PMID: 25299073 PMCID: PMC4192361 DOI: 10.1371/journal.pone.0109124] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 08/28/2014] [Indexed: 11/30/2022] Open
Abstract
MicroRNAs (miRNAs) are small, short noncoding RNAs that modulate the expression of numerous genes by targeting their mRNA. Numerous abnormal miRNA expression patterns are observed in various human malignancies, and certain miRNAs can act as oncogenes or tumor suppressors. Astrocytoma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans. In our previous studies, we found that the downregulation of miR-181b-5p in astrocytomas is associated with a poor prognosis. The aim of the present study was to investigate the functional role of miR-181b-5p and its possible target genes. miR-181b-5p was significantly downregulated in astrocytoma specimens, and the reduced expression of miR-181b-5p was inversely correlated with the clinical stage. The ectopic expression of miR-181b-5p inhibited proliferation, migration and invasion and induced apoptosis in astrocytoma cancer cells in vitro. The NOVA1 (neuro-oncological ventral antigen 1) gene was further identified as a novel direct target of miR-181b-5p. Specifically, miR-181b-5p bound directly to the 3'-untranslated region (UTR) of NOVA1 and suppressed its expression. In clinical specimens, NOVA1 was overexpressed, and its protein levels were inversely correlated with miR-181b-5p expression. Furthermore, the changing level of NOVA1 was significantly associated with a poor survival outcome. Similar to restoring miR-181b-5p expression, downregulating NOVA1 inhibited cell growth, migration and invasion. Overexpression of NOVA1 reversed the inhibitory effects of miR-181b-5p. Our results indicate that miR-181b-5p is a tumor suppressor in astrocytoma that inhibits tumor progression by targeting NOVA1. These findings suggest that miR-181b-5p may serve as a novel therapeutic target for astrocytoma.
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Affiliation(s)
- Feng Zhi
- Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Qiang Wang
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Danni Deng
- Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Naiyuan Shao
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Rong Wang
- Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Lian Xue
- Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Suinuan Wang
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Xiwei Xia
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Yilin Yang
- Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
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Liu K, Liu S, Zhang W, Ji B, Wang Y, Liu Y. miR‑222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma. Int J Oncol 2014; 45:1537-1546. [PMID: 25096647 DOI: 10.3892/ijo.2014.2577] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 07/24/2014] [Indexed: 11/06/2022] Open
Abstract
The miR‑222 cluster has been demonstrated to function as oncomiR in human hepatocellular carcinoma (HCC). miR‑222 confers chemotherapy drug resistance in various cancers, including HCC. However, the effects and mechanisms by which miR‑222 regulates liver tumorigenicity and confers sorafenib (SOR) resistance remain unclear. Here we first investigated the miR‑222 effect on proliferation, cell cycle, apoptosis, migration and invasion of HCC. Our results demonstrated that miRNA inhibitors specially targeting miR‑222 significantly suppressed cellular proliferation, migration, invasion and G1/S transition of the cell cycle, and induced cell apoptosis in HepG2 cells. In addition, we investigated whether miR‑222 confers SOR resistance in HepG2 cells to explore it roles in acquisition of drug resistance. The results showed that miR‑222 inhibitors induced sensitivity to the antitumor effect of sorafenib in human HepG2 cells. Importantly, our study also showed that miR‑222 could regulate the expression of phosphorylation PI3K and AKT, which might contribute to miR‑222 conferred SOR resistance in HepG2 cells. In conclusion, this study demonstrates that miR‑222 can promote cell proliferation, migration and invasion, and decrease cell apoptosis, as well as enhance the resistance of HCC cells to sorafenib miR‑222 through activating the PI3K/AKT signaling pathway.
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Affiliation(s)
- Kai Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Songyang Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Wei Zhang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Bai Ji
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Yingchao Wang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Yahui Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
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50
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Zhao M, Ramaswamy B. Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol 2014; 5:248-262. [PMID: 25114842 PMCID: PMC4127598 DOI: 10.5306/wjco.v5.i3.248] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 03/11/2014] [Accepted: 06/20/2014] [Indexed: 02/06/2023] Open
Abstract
The estrogen receptor (ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, post-translational modification of ER, deregulation of ER co-activators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin (mTOR), Mitogen activated kinase (MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modification including dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific microRNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the mTOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in PubMed, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at ClinicalTrials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.
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