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1
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Márquez-Mendoza JM, Baranda-Ávila N, Lizano M, Langley E. Micro-RNAs targeting the estrogen receptor alpha involved in endocrine therapy resistance in breast cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167783. [PMID: 40057206 DOI: 10.1016/j.bbadis.2025.167783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 03/03/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025]
Abstract
Endocrine therapy resistance (ETR) in breast cancer (BC) is a multicausal phenomenon with diverse alterations in the tumor cell interactome. Within these alterations, non-coding RNAs (ncRNAs) such as micro-RNAs (miRNAs) modulate the expression of tumor suppressor genes and proto-oncogenes, such as the ESR1 gene encoding estrogen receptor alpha (ERα). This work aims to review the effects of miRNAs targeting ERα mRNA and their mechanisms related to ETR in BC. A thorough review of the literature and an in silico study were carried out to elucidate the involvement of each miRNA, thus contributing to the understanding of ETR in BC.
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Affiliation(s)
- J M Márquez-Mendoza
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico
| | - N Baranda-Ávila
- Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | - M Lizano
- Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico
| | - E Langley
- Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
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2
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Park MN, Choi J, Maharub Hossain Fahim M, Asevedo EA, Nurkolis F, Ribeiro RIMA, Kang HN, Kang S, Syahputra RA, Kim B. Phytochemical synergies in BK002: advanced molecular docking insights for targeted prostate cancer therapy. Front Pharmacol 2025; 16:1504618. [PMID: 40034825 PMCID: PMC11872924 DOI: 10.3389/fphar.2025.1504618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 01/20/2025] [Indexed: 03/05/2025] Open
Abstract
Achyranthes japonica (Miq.) Nakai (AJN) and Melandrium firmum (Siebold and Zucc.) Rohrb. (MFR) are medicinal plants recognized for their bioactive phytochemicals, including ecdysteroids, anthraquinones, and flavonoids. This study investigates the anticancer properties of key constituents of these plants, focusing on the BK002 formulation, a novel combination of AJN and MFR. Specifically, the research employs advanced molecular docking and in silico analyses to assess the interactions of bioactive compounds ecdysterone, inokosterone, and 20-hydroxyecdysone (20-HE) with key prostate cancer-related network proteins, including 5α-reductase, CYP17, DNMT1, Dicer, PD-1, and PD-L1. Molecular docking techniques were applied to evaluate the binding affinities contributions of the bioactive compounds in BK002 against prostate cancer-hub network targets. The primary focus was on enzymes like 5α-reductase and CYP17, which are central to androgen biosynthesis, as well as on cancer-related proteins such as DNA methyltransferase 1 (DNMT1), Dicer, programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1). Based on data from prostate cancer patients, key target networks were identified, followed by in silico analysis of the primary bioactive components of BK002.In silico assessments were conducted to evaluate the safety profiles of these compounds, providing insights into their therapeutic potential. The docking studies revealed that ecdysterone, inokosterone, and 20-hydroxyecdysonec demonstrated strong binding affinities to the critical prostate cancer-related enzymes 5α-reductase and CYP17, contributing to a potential reduction in androgenic activity. These compounds also exhibited significant inhibitory interactions with DNMT1, Dicer, PD-1, and PD-L1, suggesting a capacity to interfere with key oncogenic and immune evasion pathways. Ecdysterone, inokosterone, and 20-hydroxyecdysone have demonstrated the ability to target key oncogenic pathways, and their favorable binding affinity profiles further underscore their potential as novel therapeutic agents for prostate cancer. These findings provide a strong rationale for further preclinical and clinical investigations, supporting the integration of BK002 into therapeutic regimens aimed at modulating tumor progression and immune responses.
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Affiliation(s)
- Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jinwon Choi
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | | | - Estéfani Alves Asevedo
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
- Experimental Pathology Laboratory, Midwest Campus, Federal University of São João del-Rei, Divinópolis, Brazil
| | - Fahrul Nurkolis
- Department of Biological Sciences, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, Indonesia
| | | | - Han Na Kang
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Sojin Kang
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Rony Abdi Syahputra
- Department of Biological Sciences, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, Indonesia
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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3
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Kumar S, Ranga A. Role of miRNAs in breast cancer development and progression: Current research. Biofactors 2025; 51:e2146. [PMID: 39601401 DOI: 10.1002/biof.2146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/16/2024] [Indexed: 11/29/2024]
Abstract
Breast cancer, a complex and heterogeneous ailment impacting numerous women worldwide, persists as a prominent cause of cancer-related fatalities. MicroRNAs (miRNAs), small non-coding RNAs, have garnered significant attention for their involvement in breast cancer's progression. These molecules post-transcriptionally regulate gene expression, influencing crucial cellular processes including proliferation, differentiation, and apoptosis. This review provides an overview of the current research on the role of miRNAs in breast cancer. It discusses the role of miRNAs in breast cancer, including the different subtypes of breast cancer, their molecular characteristics, and the mechanisms by which miRNAs regulate gene expression in breast cancer cells. Additionally, the review highlights recent studies identifying specific miRNAs that are dysregulated in breast cancer and their potential use as diagnostic and prognostic biomarkers. Furthermore, the review explores the therapeutic potential of miRNAs in breast cancer treatment. Preclinical studies have shown the effectiveness of miRNA-based therapies, such as antagomir and miRNA mimic therapies, in inhibiting tumor growth and metastasis. Emerging areas, including the application of artificial intelligence (AI) to advance miRNA research and the "One Health" approach that integrates human and animal cancer insights, are also discussed. However, challenges remain before these therapies can be fully translated into clinical practice. In conclusion, this review emphasizes the significance of miRNAs in breast cancer research and their potential as innovative diagnostic and therapeutic tools. A deeper understanding of miRNA dysregulation in breast cancer is essential for their successful application in clinical settings. With continued research, miRNA-based approaches hold promise for improving patient outcomes in this devastating disease.
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Affiliation(s)
- Sachin Kumar
- Department of Pharmacology, DIPSAR, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Abhishek Ranga
- Department of Pharmacology, DIPSAR, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
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4
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Chen SY, Zhang FL, Zhang YL, Liao L, Deng L, Shao ZM, Liu GY, Li DQ. Spermatid perinuclear RNA-binding protein promotes UBR5-mediated proteolysis of Dicer to accelerate triple-negative breast cancer progression. Cancer Lett 2024; 586:216672. [PMID: 38280476 DOI: 10.1016/j.canlet.2024.216672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/17/2023] [Accepted: 01/20/2024] [Indexed: 01/29/2024]
Abstract
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with no targeted therapy. Spermatid perinuclear RNA binding protein (STRBP), a poorly characterized RNA-binding protein (RBP), has an essential role in normal spermatogenesis and sperm function, but whether and how its dysregulation contributing to cancer progression has not yet been explored. Here, we report that STRBP functions as a novel oncogene to drive TNBC progression. STRBP expression was upregulated in TNBC tissues and correlated with poor disease prognosis. Functionally, STRBP promoted TNBC cell proliferation, migration, and invasion in vitro, and enhanced xenograft tumor growth and lung colonization in mice. Mechanistically, STRBP interacted with Dicer, a core component of the microRNA biogenesis machinery, and promoted its proteasomal degradation through enhancing its interaction with E3 ubiquitin ligase UBR5. MicroRNA-sequencing analysis identified miR-200a-3p as a downstream effector of STRBP, which was regulated by Dicer and affected epithelial-mesenchymal transition. Importantly, the impaired malignant phenotypes of TNBC cells caused by STRBP depletion were largely rescued by knockdown of Dicer, and these effects were compromised by transfection of miR-200a-3p mimics. Collectively, these findings revealed a previously unrecognized oncogenic role of STRBP in TNBC progression and identified STRBP as a promising target against TNBC.
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Affiliation(s)
- Si-Yu Chen
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Fang-Lin Zhang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yin-Ling Zhang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Li Liao
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ling Deng
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhi-Min Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Guang-Yu Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
| | - Da-Qiang Li
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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5
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Su CM, Hsu TW, Chen HA, Wang WY, Huang CY, Hung CC, Yeh MH, Su YH, Huang MT, Liao PH. Chaperone-mediated autophagy degrade Dicer to promote breast cancer metastasis. J Cell Physiol 2023; 238:829-841. [PMID: 36815383 DOI: 10.1002/jcp.30979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 02/05/2023] [Accepted: 02/07/2023] [Indexed: 02/24/2023]
Abstract
Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.
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Affiliation(s)
- Chih-Ming Su
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Tung-Wei Hsu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsin-An Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wan-Yu Wang
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Hualien, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taichung, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung City, Taichung, Taiwan
| | - Chih-Chiang Hung
- Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Applied Cosmetology, College of Human Science and Social Innovation, Hungkuang University, Taichung, Taiwan
| | - Ming-Hsin Yeh
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yen-Hao Su
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ming-Te Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Xin Tai General Hospital, New Taipei, Taiwan
| | - Po-Hsiang Liao
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
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6
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Zou L, Yang Y, Zhou B, Li W, Liu K, Li G, Miao H, Song X, Yang J, Geng Y, Li M, Bao R, Liu Y. tRF-3013b inhibits gallbladder cancer proliferation by targeting TPRG1L. Cell Mol Biol Lett 2022; 27:99. [PMID: 36401185 PMCID: PMC9673407 DOI: 10.1186/s11658-022-00398-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 10/25/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND tRNA-derived fragments (tRFs) are newly discovered noncoding RNAs and regulate tumor progression via diverse molecular mechanisms. However, the expression and biofunction of tRFs in gallbladder cancer (GBC) have not been reported yet. METHODS The expression of tRFs in GBC was detected by tRF and tiRNA sequencing in GBC tissues and adjacent tissues. The biological function of tRFs was investigated by cell proliferation assay, clonal formation assay, cell cycle assay, and xenotransplantation model in GBC cell lines. The molecular mechanism was discovered and verified by transcriptome sequencing, fluorescence in situ hybridization (FISH), target gene site prediction, and RNA binding protein immunoprecipitation (RIP). RESULTS tRF-3013b was significantly downregulated in GBC compared with para-cancer tissues. Decreased expression of tRF-3013b in GBC patients was correlated with poor overall survival. Dicer regulated the production of tRF-3013b, and its expression was positively correlated with tRF-3013b in GBC tissues. Functional experiments demonstrated that tRF-3013b inhibited GBC cell proliferation and induced cell-cycle arrest. Mechanically, tRF-3013b exerted RNA silencing effect on TPRG1L by binding to AGO3, and then inhibited NF-κB. TPRG1L overexpression could rescue the effects of tRF-3013b on GBC cell proliferation. CONCLUSIONS This study indicated that Dicer-induced tRF-3013b inhibited GBC proliferation by targeting TPRG1L and repressed NF-κB, pointing to tRF-3013b as a novel potential therapeutic target of GBC.
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Affiliation(s)
- Lu Zou
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Yang Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Biyu Zhou
- Department of Plastic and Reconstructive Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
| | - Weijian Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Ke Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Guoqiang Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Huijie Miao
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Xiaoling Song
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665, Kongjiang Road, Shanghai, 200092, China
| | - Jiahua Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Yajun Geng
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Maolan Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China.
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
| | - Runfa Bao
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China.
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665, Kongjiang Road, Shanghai, 200092, China.
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China.
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
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7
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Hua X, Xiang D, Guo M, Qian X, Chen R, Li T, Tian Z, Xu J, Huang C, Xie Q, Huang C. Induction of RAC1 protein translation and MKK7/JNK-dependent autophagy through dicer/miR-145/SOX2/miR-365a axis contributes to isorhapontigenin (ISO) inhibition of human bladder cancer invasion. Cell Death Dis 2022; 13:753. [PMID: 36045117 PMCID: PMC9433410 DOI: 10.1038/s41419-022-05205-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 01/21/2023]
Abstract
Although our previous studies have identified that isorhapontigenin (ISO) is able to initiate autophagy in human bladder cancer (BC) cells by activating JNK/C-Jun/SESN2 axis and possesses an inhibitory effect on BC cell growth, association of autophagy directly with inhibition of BC invasion has never been explored. Also, upstream cascade responsible for ISO activating JNK remains unknown. Thus, we explored both important questions in the current study and discovered that ISO treatment initiated RAC1 protein translation, and its downstream kinase MKK7/JNK phosphorylation/activation, and in turn promoted autophagic responses in human BC cells. Inhibition of autophagy abolished ISO inhibition of BC invasion, revealing that autophagy inhibition was crucial for ISO inhibition of BC invasion. Consistently, knockout of RAC1 also attenuated induction of autophagy and inhibition of BC invasion by ISO treatment. Mechanistic studies showed that upregulation of RAC1 translation was due to ISO inhibition of miR-365a transcription, which reduced miR-365a binding to the 3'-UTR of RAC1 mRNA. Further study indicated that inhibition of miR-365a transcription was caused by downregulation of its transcription factor SOX2, while ISO-promoted Dicer protein translation increased miR-145 maturation, and consequently downregulating SOX2 expression. These findings not only provide a novel insight into the understanding association of autophagy induction with BC invasion inhibition by ISO, but also identify an upstream regulatory cascade, Dicer/miR145/SOX2/miR365a/RAC1, leading to MKK7/JNKs activation and autophagy induction.
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Affiliation(s)
- Xiaohui Hua
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China ,grid.186775.a0000 0000 9490 772XDepartment of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 China
| | - Daimin Xiang
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127 China
| | - Mengxin Guo
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Xiaohui Qian
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Ruifan Chen
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Tengda Li
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Zhongxian Tian
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Jiheng Xu
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Chao Huang
- grid.33199.310000 0004 0368 7223Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Qipeng Xie
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Chuanshu Huang
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
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8
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Antoniali G, Dalla E, Mangiapane G, Zhao X, Jing X, Cheng Y, De Sanctis V, Ayyildiz D, Piazza S, Li M, Tell G. APE1 controls DICER1 expression in NSCLC through miR-33a and miR-130b. Cell Mol Life Sci 2022; 79:446. [PMID: 35876890 PMCID: PMC9314295 DOI: 10.1007/s00018-022-04443-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 12/04/2022]
Abstract
Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in the development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an important cause of poor chemotherapeutic response in lung cancer and its involvement in onco-miRNAs biogenesis has been recently described. Whether APE1 regulates miRNAs acting as prognostic biomarkers of lung cancer has not been investigated, yet. In this study, we analyzed miRNAs differential expression upon APE1 depletion in the A549 lung cancer cell line using high-throughput methods. We defined a signature of 13 miRNAs that strongly correlate with APE1 expression in human lung cancer: miR-1246, miR-4488, miR-24, miR-183, miR-660, miR-130b, miR-543, miR-200c, miR-376c, miR-218, miR-146a, miR-92b and miR-33a. Functional enrichment analysis of this signature revealed its biological relevance in cancer cell proliferation and survival. We validated DICER1 as a direct functional target of the APE1-regulated miRNA-33a-5p and miR-130b-3p. Importantly, IHC analyses of different human tumors confirmed a negative correlation existing between APE1 and Dicer1 protein levels. DICER1 downregulation represents a prognostic marker of cancer development but the mechanisms at the basis of this phenomenon are still completely unknown. Our findings, suggesting that APE1 modulates DICER1 expression via miR-33a and miR-130b, reveal new mechanistic insights on DICER1 regulation, which are of relevance in lung cancer chemoresistance and cancer invasiveness.
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Affiliation(s)
- Giulia Antoniali
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Emiliano Dalla
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Giovanna Mangiapane
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Xiaolong Zhao
- Cancer Center of Daping Hospital, Third Military Medical University, Chongqing, China
| | - Xinming Jing
- Cancer Center of Daping Hospital, Third Military Medical University, Chongqing, China
| | - Yi Cheng
- Cancer Center of Daping Hospital, Third Military Medical University, Chongqing, China
| | - Veronica De Sanctis
- Next Generation Sequence Facility, Department CIBIO, University of Trento, Trento, Italy
| | - Dilara Ayyildiz
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Silvano Piazza
- Bioinformatics Core Facility, Department CIBIO, University of Trento, Trento, Italy.,Computational Biology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy
| | - Mengxia Li
- Cancer Center of Daping Hospital, Third Military Medical University, Chongqing, China.
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy.
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9
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Ansari-Pour N, Zheng Y, Yoshimatsu TF, Sanni A, Ajani M, Reynier JB, Tapinos A, Pitt JJ, Dentro S, Woodard A, Rajagopal PS, Fitzgerald D, Gruber AJ, Odetunde A, Popoola A, Falusi AG, Babalola CP, Ogundiran T, Ibrahim N, Barretina J, Van Loo P, Chen M, White KP, Ojengbede O, Obafunwa J, Huo D, Wedge DC, Olopade OI. Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes. Nat Commun 2021; 12:6946. [PMID: 34836952 PMCID: PMC8626467 DOI: 10.1038/s41467-021-27079-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 11/02/2021] [Indexed: 02/08/2023] Open
Abstract
Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies. Breast cancer heterogeneity and tumour evolutionary trajectories remain largely unknown among women of African ancestry. Here, the authors perform whole genome and transcriptome sequencing of Nigerian breast cancer patients and identify unique evolutionary phenomena.
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Affiliation(s)
- Naser Ansari-Pour
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LF, UK.,MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Yonglan Zheng
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Toshio F Yoshimatsu
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Ayodele Sanni
- Department of Pathology and Forensic Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria
| | - Mustapha Ajani
- Department of Pathology, University of Ibadan, Ibadan, Oyo, Nigeria
| | - Jean-Baptiste Reynier
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Avraam Tapinos
- Manchester Cancer Research Centre, University of Manchester, Manchester, M20 4GJ, UK
| | - Jason J Pitt
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Stefan Dentro
- European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, CB10 1SD, UK.,Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
| | - Anna Woodard
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.,Department of Computer Science, The University of Chicago, Chicago, IL, 60637, USA
| | - Padma Sheila Rajagopal
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Dominic Fitzgerald
- Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, 60637, USA
| | - Andreas J Gruber
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LF, UK.,Manchester Cancer Research Centre, University of Manchester, Manchester, M20 4GJ, UK
| | - Abayomi Odetunde
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria
| | - Abiodun Popoola
- Oncology Unit, Department of Radiology, Lagos State University, Ikeja, Lagos, Nigeria
| | - Adeyinka G Falusi
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria
| | - Chinedum Peace Babalola
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Oyo, Nigeria
| | - Temidayo Ogundiran
- Department of Surgery, University College Hospital, Ibadan, Oyo, Nigeria
| | - Nasiru Ibrahim
- Department of Surgery, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria
| | - Jordi Barretina
- Girona Biomedical Research Institute (IDIBGI), Hospital Universitari de Girona Dr Josep Trueta, Girona, Spain
| | | | - Mengjie Chen
- Department of Human Genetics, The University of Chicago, Chicago, IL, 60637, USA.,Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | | | - Oladosu Ojengbede
- Centre for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria
| | - John Obafunwa
- Department of Pathology and Forensic Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria
| | - Dezheng Huo
- Department of Public Health Sciences, The University of Chicago, Chicago, IL, 60637, USA
| | - David C Wedge
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LF, UK. .,Manchester Cancer Research Centre, University of Manchester, Manchester, M20 4GJ, UK.
| | - Olufunmilayo I Olopade
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.
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10
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Ma Y, Shen N, Wicha MS, Luo M. The Roles of the Let-7 Family of MicroRNAs in the Regulation of Cancer Stemness. Cells 2021; 10:cells10092415. [PMID: 34572067 PMCID: PMC8469079 DOI: 10.3390/cells10092415] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/01/2021] [Accepted: 09/08/2021] [Indexed: 12/17/2022] Open
Abstract
Cancer has long been viewed as a disease of normal development gone awry. Cancer stem-like cells (CSCs), also termed as tumor-initiating cells (TICs), are increasingly recognized as a critical tumor cell population that drives not only tumorigenesis but also cancer progression, treatment resistance and metastatic relapse. The let-7 family of microRNAs (miRNAs), first identified in C. elegans but functionally conserved from worms to human, constitutes an important class of regulators for diverse cellular functions ranging from cell proliferation, differentiation and pluripotency to cancer development and progression. Here, we review the current state of knowledge regarding the roles of let-7 miRNAs in regulating cancer stemness. We outline several key RNA-binding proteins, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) involved in the regulation of let-7 biogenesis, maturation and function. We then highlight key gene targets and signaling pathways that are regulated or mutually regulated by the let-7 family of miRNAs to modulate CSC characteristics in various types of cancer. We also summarize the existing evidence indicating distinct metabolic pathways regulated by the let-7 miRNAs to impact CSC self-renewal, differentiation and treatment resistance. Lastly, we review current preclinical studies and discuss the clinical implications for developing let-7-based replacement strategies as potential cancer therapeutics that can be delivered through different platforms to target CSCs and reduce/overcome treatment resistance when applied alone or in combination with current chemo/radiation or molecularly targeted therapies. By specifically targeting CSCs, these strategies have the potential to significantly improve the efficacy of cancer therapies.
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Affiliation(s)
- Yuxi Ma
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA; (Y.M.); (N.S.)
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Na Shen
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA; (Y.M.); (N.S.)
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Max S. Wicha
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA; (Y.M.); (N.S.)
- Correspondence: (M.S.W.); (M.L.)
| | - Ming Luo
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA; (Y.M.); (N.S.)
- Correspondence: (M.S.W.); (M.L.)
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11
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Patil N, Allgayer H, Leupold JH. MicroRNAs in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1277:1-31. [PMID: 33119862 DOI: 10.1007/978-3-030-50224-9_1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The tumor microenvironment (TME) is decisive for the eradication or survival of any tumor mass. Moreover, it plays a pivotal role for metastasis and for providing the metastatic niche. The TME offers special physiological conditions and is composed of, for example, surrounding blood vessels, the extracellular matrix (ECM), diverse signaling molecules, exosomes and several cell types including, but not being limited to, infiltrated immune cells, cancer-associated endothelial cells (CAEs), and cancer-associated fibroblasts (CAFs). These cells can additionally and significantly contribute to tumor and metastasis progression, especially also by acting via their own deregulated micro (mi) RNA expression or activity. Thus, miRNAs are essential players in the crosstalk between cancer cells and the TME. MiRNAs are small non-coding (nc) RNAs that typically inhibit translation and stability of messenger (m) RNAs, thus being able to regulate several cell functions including proliferation, migration, differentiation, survival, invasion, and several steps of the metastatic cascade. The dynamic interplay between miRNAs in different cell types or organelles such as exosomes, ECM macromolecules, and the TME plays critical roles in many aspects of cancer development. This chapter aims to give an overview on the multiple contributions of miRNAs as players within the TME, to summarize the role of miRNAs in the crosstalk between different cell populations found within the TME, and to illustrate how they act on tumorigenesis and the behavior of cells in the TME context. Lastly, the potential clinical utility of miRNAs for cancer therapy is discussed.
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Affiliation(s)
- Nitin Patil
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany
- Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany
| | - Heike Allgayer
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany
- Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany
| | - Jörg H Leupold
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany.
- Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany.
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12
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Wahyuniari IAI, Arijana IGKN, Sriwidyani NP, Suwito H, Widyarini S, Ghufron M, Mustofa M, Haryana SM. The Effect of (E)-1-(4'-aminophenyl)-3-phenylprop-2-en-1-one on MicroRNA-18a, Dicer1, and MMP-9 Expressions against DMBA-Induced Breast Cancer. Asian Pac J Cancer Prev 2020; 21:1213-1219. [PMID: 32458624 PMCID: PMC7541864 DOI: 10.31557/apjcp.2020.21.5.1213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Most of breast cancer patients are estrogen receptor alpha-positive and have high resistance and side effect of chemotherapeutic drug. Therefore, discovering an effective anticancer agent is needed. This research explored the effect of (E)-1-(4'-aminophenyl)-3-phenylprop-2-en-1-one (APE) on miR-18a, Dicer1, and MMP-9 expressions. METHODS Twenty four female Sprague-Dawley rats were invetigated in this study. The rats were divided into 6 groups of 4. G1 was considered as normal rat. G2, G3, T1, T2, and T3 were given DMBA 20 mg/kgBW twice a week for 5 weeks to induce mammary cancer. After being affiliated with cancer, G2 was given vehicle and G3 was treated with tamoxifen. T1, T2, and T3 were treated with APE intraperitoneally everyday for 21 days at doses of 5, 15, and 45 mg/kgBW/day, respectively. Blood plasma was collected to measure miR-18a expression using qRT-PCR. Mammary tissues were also collected to determine Dicer1 and MMP-9 expressions by using immunohistochemistry. RESULTS The results showed significant down-regulation of miR-18a relative expression and up-regulation of Dicer1 expression in G3 and T1 compared to G2 (P<0.05). MMP-9 expression has significant decrease in T1 compared to G2 (P<0.05). CONCLUSION APE can decrease miR-18a and MMP-9 expressions and increase Dicer1 expression in rat mammary cancer. Therefore, this compound could be a candidate of novel anticancer.
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Affiliation(s)
| | | | - Ni Putu Sriwidyani
- Department of Anatomical Pathology, Faculty of Medicine, Udayana University, Bali, Indonesia
| | - Hery Suwito
- Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia
| | - Sitarina Widyarini
- Department of Pathology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Muhammad Ghufron
- Department of Histology and Cell Biology,Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Mustofa Mustofa
- Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
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13
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Rakha EA, Pareja FG. New Advances in Molecular Breast Cancer Pathology. Semin Cancer Biol 2020; 72:102-113. [PMID: 32259641 DOI: 10.1016/j.semcancer.2020.03.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022]
Abstract
Breast cancer (BC) comprises a diverse spectrum of diseases featuring distinct presentation, morphological, biological, and clinical phenotypes. BC behaviour and response to therapy also vary widely. Current evidence indicates that traditional prognostic and predictive classification systems are insufficient to reflect the biological and clinical heterogeneity of BC. Advancements in high-throughput molecular techniques and bioinformatics have contributed to the improved understanding of BC biology, refinement of molecular taxonomies and the development of novel prognostic and predictive molecular assays. Molecular testing has also become increasingly important in the diagnosis and treatment of BC in the era of precision medicine. Despite the enormous amount of research work to develop and refine BC molecular prognostic and predictive assays, it is still in evolution and proper incorporation of these molecular tests into clinical practice to guide patient's management remains a challenge. With the increasing use of more sophisticated high throughput molecular techniques, large amounts of data will continue to emerge, which could potentially lead to identification of novel therapeutic targets and allow more precise classification systems that can accurately predict outcome and response to therapy. In this review, we provide an update on the molecular classification of BC and molecular prognostic assays. Companion diagnostics, contribution of massive parallel sequencing and the use of liquid biopsy are also highlighted.
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Affiliation(s)
- Emad A Rakha
- Department of Histopathology, Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, NG5 1PB, UK.
| | - Fresia G Pareja
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA
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14
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Integrative Analyses of Multilevel Omics Reveal Preneoplastic Breast to Possess a Molecular Landscape That is Globally Shared with Invasive Basal-Like Breast Cancer (Running Title: Molecular Landscape of Basal-Like Breast Cancer Progression). Cancers (Basel) 2020; 12:cancers12030722. [PMID: 32204397 PMCID: PMC7140033 DOI: 10.3390/cancers12030722] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 03/16/2020] [Indexed: 12/21/2022] Open
Abstract
To characterize molecular changes accompanying the stepwise progression to breast cancer and to identify functional target pathways, we performed miRNA and RNA sequencing using MCF10A cell lines based model system that replicates the multi-step progression involving normal, preneoplastic, ductal carcinoma in situ, and invasive carcinoma cells, where the carcinoma most resemble the basal-like subgroup of human breast cancers. These analyses suggest that 70% of miRNA alterations occurred during the initial progression from normal to a preneoplastic stage. Most of these early changes reflected a global upregulation of miRNAs. This was consistent with a global increase in the miRNA-processing enzyme DICER, which was upregulated as a direct result of loss of miRNA let-7b-5p. Several oncogenic and tumor suppressor pathways were also found to change early, prior to histologic stigmata of cancer. Our finding that most genomic changes in the progression to basal-like breast cancer occurred in the earliest stages of histologic progression has implications for breast cancer prevention and selection of appropriate control tissues in molecular studies. Furthermore, in support of a functional significance of let-7b-5p loss, we found its low levels to predict poor disease-free survival and overall survival in breast cancer patients.
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15
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MicroRNAs Contribute to Breast Cancer Invasiveness. Cells 2019; 8:cells8111361. [PMID: 31683635 PMCID: PMC6912645 DOI: 10.3390/cells8111361] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/25/2019] [Accepted: 10/28/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer statistics in 2018 highlight an 8.6 million incidence in female cancers, and 4.2 million cancer deaths globally. Moreover, breast cancer is the most frequent malignancy in females and twenty percent of these develop metastasis. This provides only a small chance for successful therapy, and identification of new molecular markers for the diagnosis and prognostic prediction of metastatic disease and development of innovative therapeutic molecules are therefore urgently required. Differentially expressed microRNAs (miRNAs) in cancers cause multiple changes in the expression of the tumorigenesis-promoting genes which have mostly been investigated in breast cancers. Herein, we summarize recent data on breast cancer-specific miRNA expression profiles and their participation in regulating invasive processes, in association with changes in cytoskeletal structure, cell-cell adhesion junctions, cancer cell-extracellular matrix interactions, tumor microenvironments, epithelial-to-mesenchymal transitions and cancer cell stem abilities. We then focused on the epigenetic regulation of individual miRNAs and their modified interactions with other regulatory genes, and reviewed the function of miRNA isoforms and exosome-mediated miRNA transfer in cancer invasiveness. Although research into miRNA’s function in cancer is still ongoing, results herein contribute to improved metastatic cancer management.
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16
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Mironova N, Vlassov V. Surveillance of Tumour Development: The Relationship Between Tumour-Associated RNAs and Ribonucleases. Front Pharmacol 2019; 10:1019. [PMID: 31572192 PMCID: PMC6753386 DOI: 10.3389/fphar.2019.01019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 08/09/2019] [Indexed: 12/14/2022] Open
Abstract
Tumour progression is accompanied by rapid cell proliferation, loss of differentiation, the reprogramming of energy metabolism, loss of adhesion, escape of immune surveillance, induction of angiogenesis, and metastasis. Both coding and regulatory RNAs expressed by tumour cells and circulating in the blood are involved in all stages of tumour progression. Among the important tumour-associated RNAs are intracellular coding RNAs that determine the routes of metabolic pathways, cell cycle control, angiogenesis, adhesion, apoptosis and pathways responsible for transformation, and intracellular and extracellular non-coding RNAs involved in regulation of the expression of their proto-oncogenic and oncosuppressing mRNAs. Considering the diversity/variability of biological functions of RNAs, it becomes evident that extracellular RNAs represent important regulators of cell-to-cell communication and intracellular cascades that maintain cell proliferation and differentiation. In connection with the elucidation of such an important role for RNA, a surge in interest in RNA-degrading enzymes has increased. Natural ribonucleases (RNases) participate in various cellular processes including miRNA biogenesis, RNA decay and degradation that has determined their principal role in the sustention of RNA homeostasis in cells. Findings were obtained on the contribution of some endogenous ribonucleases in the maintenance of normal cell RNA homeostasis, which thus prevents cell transformation. These findings directed attention to exogenous ribonucleases as tools to compensate for the malfunction of endogenous ones. Recently a number of proteins with ribonuclease activity were discovered whose intracellular function remains unknown. Thus, the comprehensive investigation of physiological roles of RNases is still required. In this review we focused on the control mechanisms of cell transformation by endogenous ribonucleases, and the possibility of replacing malfunctioning enzymes with exogenous ones.
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Affiliation(s)
- Nadezhda Mironova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
| | - Valentin Vlassov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
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17
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Zhang X, Wu M, Chong QY, Zhang W, Qian P, Yan H, Qian W, Zhang M, Lobie PE, Zhu T. Amplification of hsa-miR-191/425 locus promotes breast cancer proliferation and metastasis by targeting DICER1. Carcinogenesis 2019; 39:1506-1516. [PMID: 30084985 DOI: 10.1093/carcin/bgy102] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 07/30/2018] [Indexed: 12/21/2022] Open
Abstract
The dysregulation of micro RNAs (miRNAs) is a crucial characteristic of human cancers. Herein, we observed frequent amplification of the MIR191/425 locus in breast cancer, which is correlated with poor survival outcome. We demonstrated that the miR-191/425 cluster binds the 3' untranslated region of the DICER1 transcript and posttranscriptionally represses DICER1 expression, thereby impairing global miRNAs biogenesis. Functionally, the forced expression of miR-191 or miR-425 stimulated the proliferation, survival, migration and invasion of breast cancer cells, whereas the inhibition of miR-191 or miR-425 suppressed these oncogenic behaviors of breast cancer cells, in a manner dependent on miR-191/425-mediated downregulation of DICER1. Furthermore, the miR-191/425 cluster promoted breast tumor growth, invasion and metastasis in vivo. The let-7 family of miRNAs was downregulated upon forced expression of miR-191 or miR-425, with a corresponding increase in the levels of let-7 target, high-mobility group AT-hook 2 (HMGA2). The forced expression of let-7 partially abrogated the miR-191/425-mediated oncogenic effects in breast cancer cells, suggestive of let-7 as a downstream effector of the miR-191/425-DICER1 axis. Collectively, we proposed that the inhibition of global miRNA processing, through miR-191/425-mediated downregulation of DICER1, promotes breast cancer progression.
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Affiliation(s)
- Xiao Zhang
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Mingming Wu
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Qing-Yun Chong
- Cancer Science Institute of Singapore, Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Weijie Zhang
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Pengxu Qian
- Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Hangzhou, P.R. China.,Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Hong Yan
- Department of Pathology, Anhui Medical University, Hefei, Anhui, P.R. China
| | - Wenchang Qian
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Min Zhang
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Peter E Lobie
- Cancer Science Institute of Singapore, Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore, Singapore.,Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, P.R. China
| | - Tao Zhu
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China
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18
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Hannafon BN, Ding WQ. Functional Role of miRNAs in the Progression of Breast Ductal Carcinoma in Situ. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:966-974. [PMID: 30273605 DOI: 10.1016/j.ajpath.2018.06.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/12/2018] [Accepted: 06/15/2018] [Indexed: 12/17/2022]
Abstract
miRNAs are small RNAs that influence gene expression by targeting mRNAs. Depending on the function of their target genes, miRNAs may regulate the expression of oncogenes and tumor suppressors, thereby contributing to the promotion or inhibition of tumor progression. Ductal carcinoma in situ (DCIS), although often diagnosed as breast cancer, is a potential precursor to invasive ductal carcinoma. Many of the genetic events required for the invasive progression of DCIS occur at the preinvasive stage, and these events include changes in the expression of miRNAs. Aberrant expression of miRNAs can influence specific oncogenic or tumor-suppressive pathways required for breast cancer progression. miRNAs in DCIS have been shown to influence hormone signaling, cell-cell adhesion, epithelial-to-mesenchymal transition, transforming growth factor β signaling, maintenance of cancer stem cells, and modulation of the extracellular matrix. Additionally, extracellular DCIS miRNAs, such as those found in exosomes, may promote invasive progression by modifying the tumor microenvironment. Here, we review the miRNAs that have been identified in DCIS and how they may contribute to the progression to invasive disease. We also touch on the current state of miRNA therapy development, including the current challenges, and discuss the key future perspectives for research into miRNA function for the purpose of miRNA therapy development for DCIS.
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Affiliation(s)
- Bethany N Hannafon
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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19
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Jeong W, Bae H, Lim W, Song G. Dicer1, AGO3, and AGO4 microRNA machinery genes are differentially expressed in developing female reproductive organs and overexpressed in cancerous ovaries of chickens. J Anim Sci 2018; 95:4857-4868. [PMID: 29293730 DOI: 10.2527/jas2017.1846] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
MicroRNA (miRNA)-mediated gene silencing is a key mechanism regulating numerous biological processes such as development of organs and tumorigenesis. The expression of miRNA machinery genes linked to miRNA biogenesis and processing is finely regulated. Despite accumulating evidence for chicken miRNA in the female reproduction system, precise regulatory mechanisms are largely unknown. Therefore, the objective of this study was to determine changes in expression levels of miRNA machinery genes in developmental stages of the oviduct and ovarian carcinogenesis of laying hens. In the present study, differential expression of miRNA machinery genes during ovarian carcinogenesis was determined using cancerous and normal ovaries collected from normal laying hens and hens with cancer. Our results showed that 3 miRNA machinery genes (, , and ) were differentially expressed as laying hens' reproductive organs developed. These genes were simultaneously upregulated in cancerous ovaries compared with those in normal ovaries. Their transcripts were abundantly localized in glandular epithelial cells of cancerous ovaries. Our results indicate that , , and play critical roles in the development of reproductive organs and ovarian carcinogenesis in laying hens, suggesting that simultaneous overexpression of these genes might serve as a prognostic factor for ovarian cancer.
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20
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Shan W, Sun C, Zhou B, Guo E, Lu H, Xia M, Li K, Weng D, Lin X, Meng L, Ma D, Chen G. Role of Dicer as a prognostic predictor for survival in cancer patients: a systematic review with a meta-analysis. Oncotarget 2018; 7:72672-72684. [PMID: 27682871 PMCID: PMC5341936 DOI: 10.18632/oncotarget.12183] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 09/12/2016] [Indexed: 01/17/2023] Open
Abstract
Objective The role of Dicer in the prognosis of cancer patients remains controversial. This systematic review is attempted to assess the influence of Dicer as a prognostic predictor for survival in diverse types of cancers. Methods Studies were selected as candidates if they published an independent evaluation of Dicer expression level together with the correlation with prognosis in cancers. Random-effect model was applied in this meta-analysis. Heterogeneity between studies was assessed by Q-statistic with P < 0.10 to be statistically significant. Publication bias was investigated using funnel plot and test with Begg's and Egger's test. P < 0.05 was regarded as statistically significant. Results 24 of 44 articles revealed low Dicer status as a predictor of poor prognosis. The aggregate result of overall survival (OS) indicated that low Dicer expression level resulted in poor clinical outcomes, and subgroup of IHC and RT-PCR method both revealed the same result. Overall analysis of progression-free survival (PFS) showed the same result as OS, and both the two subgroups divided by laboratory method revealed positive results. Subgroup analysis by tumor types showed low dicer levels were associated with poor prognosis in ovarian cancer (HR = 1.93, 95% CI: 1.19-3.15), otorhinolaryngological tumors (HR = 2.39, 95% CI: 1.70-3.36), hematological malignancies (HR = 2.45, 95% CI: 1.69-3.56) and neuroblastoma (HR = 4.03, 95% CI: 1.91-8.50). Conclusion Low Dicer status was associated with poor prognosis in ovarian cancer, otorhinolaryngological tumors and ematological malignancies. More homogeneous studies with high quality are needed to further confirm our conclusion and make Dicer a useful parameter in clinical application.
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Affiliation(s)
- Wanying Shan
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Chaoyang Sun
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Bo Zhou
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Ensong Guo
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Hao Lu
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Meng Xia
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Kezhen Li
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Danhui Weng
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Xingguang Lin
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Li Meng
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Ding Ma
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Gang Chen
- Cancer Biology Medical Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
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21
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Mansouri S, Singh S, Alamsahebpour A, Burrell K, Li M, Karabork M, Ekinci C, Koch E, Solaroglu I, Chang JT, Wouters B, Aldape K, Zadeh G. DICER governs characteristics of glioma stem cells and the resulting tumors in xenograft mouse models of glioblastoma. Oncotarget 2018; 7:56431-56446. [PMID: 27421140 PMCID: PMC5302925 DOI: 10.18632/oncotarget.10570] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 05/19/2016] [Indexed: 12/21/2022] Open
Abstract
The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently decreased in a variety of malignancies. We characterized the role of DICER in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells (GSCs) to form tumors in a mouse model of GB. DICER silencing in GSCs reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER silencing enhances the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB.
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Affiliation(s)
- Sheila Mansouri
- Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, ON, Canada
| | - Sanjay Singh
- Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, ON, Canada
| | - Amir Alamsahebpour
- Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, ON, Canada
| | - Kelly Burrell
- Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, ON, Canada
| | - Mira Li
- Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, ON, Canada
| | - Merve Karabork
- School of Medicine, Koç University, Rumelifeneri Yolu, Sariyer, Istanbul, Turkey
| | - Can Ekinci
- School of Medicine, Koç University, Rumelifeneri Yolu, Sariyer, Istanbul, Turkey
| | - Elizabeth Koch
- Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Ihsan Solaroglu
- School of Medicine, Koç University, Rumelifeneri Yolu, Sariyer, Istanbul, Turkey.,Loma Linda University, School of Medicine, Loma Linda, CA, USA
| | - Jeffery T Chang
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas, Houston, TX, USA
| | - Bradly Wouters
- Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, Toronto, ON, Canada.,Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Kenneth Aldape
- Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, ON, Canada
| | - Gelareh Zadeh
- Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, ON, Canada.,Department of Neurosurgery, Toronto Western Hospital, University Health Network, 4W-436, Toronto, ON, Canada
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22
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Lai HH, Li JN, Wang MY, Huang HY, Croce CM, Sun HL, Lyu YJ, Kang JW, Chiu CF, Hung MC, Suzuki HI, Chen PS. HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis. J Clin Invest 2017; 128:625-643. [PMID: 29251629 DOI: 10.1172/jci89212] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 10/17/2017] [Indexed: 12/24/2022] Open
Abstract
HIF-1α, one of the most extensively studied oncogenes, is activated by a variety of microenvironmental factors. The resulting biological effects are thought to depend on its transcriptional activity. The RNAse enzyme Dicer is frequently downregulated in human cancers, which has been functionally linked to enhanced metastatic properties; however, current knowledge of the upstream mechanisms regulating Dicer is limited. In the present study, we identified Dicer as a HIF-1α-interacting protein in multiple types of cancer cell lines and different human tumors. HIF-1α downregulated Dicer expression by facilitating its ubiquitination by the E3 ligase Parkin, thereby enhancing autophagy-mediated degradation of Dicer, which further suppressed the maturation of known tumor suppressors, such as the microRNA let-7 and microRNA-200b. Consequently, expression of HIF-1α facilitated epithelial-mesenchymal transition (EMT) and metastasis in tumor-bearing mice. Thus, this study uncovered a connection between oncogenic HIF-1α and the tumor-suppressive Dicer. This function of HIF-1α is transcription independent and occurs through previously unrecognized protein interaction-mediated ubiquitination and autophagic proteolysis.
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Affiliation(s)
- Hui-Huang Lai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University (NCKU), Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, College of Medicine, NCKU, Tainan, Taiwan
| | - Jie-Ning Li
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University (NCKU), Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, College of Medicine, NCKU, Tainan, Taiwan
| | - Ming-Yang Wang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsin-Yi Huang
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Carlo M Croce
- Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
| | - Hui-Lung Sun
- Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
| | - Yu-Jhen Lyu
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, NCKU, Tainan, Taiwan
| | - Jui-Wen Kang
- Department of Internal Medicine, NCKU Hospital, Tainan, Taiwan
| | - Ching-Feng Chiu
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Mien-Chie Hung
- Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hiroshi I Suzuki
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Pai-Sheng Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University (NCKU), Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, College of Medicine, NCKU, Tainan, Taiwan
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23
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Yang Z, Jin P, Xu S, Zhang T, Yang X, Li X, Wei X, Sun C, Chen G, Ma D, Gao Q. Dicer reprograms stromal fibroblasts to a pro-inflammatory and tumor-promoting phenotype in ovarian cancer. Cancer Lett 2017; 415:20-29. [PMID: 29199004 DOI: 10.1016/j.canlet.2017.11.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 10/31/2017] [Accepted: 11/22/2017] [Indexed: 01/01/2023]
Abstract
Inflammation and host stromal activation contribute significantly to ovarian cancer (OC) initiation and malignant progression. However, the complex reciprocal interactions between them are largely unknown. Here, we discovered that the tumor suppressor gene Dicer was paradoxically overexpressed in ovarian tumor stroma, and induced fibroblast activation and stromal inflammation. Dicer transformed normal fibroblasts to a carcinoma-associated fibroblast (CAF)-like state, which was morphologically spread out and functionally activated to fuel tumor invasion and metastasis. Attenuation of Dicer hampered CAF characteristics, diminished stromal inflammation and the role of fibroblasts in supporting tumor growth. Moreover, Dicer drove the expression of an "inflammatory signature" in fibroblasts that could be used to discriminate normal and cancerous stroma and predict the survival of patients with OC. Finally, the nuclear factor κ B (NFκB) signaling was demonstrated to be responsible for Dicer effect on fibroblast activation and stromal inflammation, through microRNA (miR)-6780b. Our study represents the first report that characterizes Dicer expression and function in the tumor stroma, and highlights its pro-metastatic role in this context. Additionally, we suggest that the Dicer-miR6780b-NFκB cascade is an attractive target of choice in stroma-oriented OC therapy.
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Affiliation(s)
- Zongyuan Yang
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ping Jin
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Sen Xu
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Taoran Zhang
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xin Yang
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiaoting Li
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiao Wei
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Chaoyang Sun
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Gang Chen
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ding Ma
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Qinglei Gao
- Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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24
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Penha RCC, Sepe R, De Martino M, Esposito F, Pellecchia S, Raia M, Del Vecchio L, Decaussin-Petrucci M, De Vita G, Pinto LFR, Fusco A. Role of Dicer1 in thyroid cell proliferation and differentiation. Cell Cycle 2017; 16:2282-2289. [PMID: 28933615 DOI: 10.1080/15384101.2017.1380127] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
DICER1 plays a central role in the biogenesis of microRNAs and it is important for normal development. Altered microRNA expression and DICER1 dysregulation have been described in several types of tumors, including thyroid carcinomas. Recently, our group identified a new somatic mutation (c.5438A>G; E1813G) within DICER1 gene of an unknown function. Herein, we show that DICER1 is overexpressed, at mRNA level, in a significant-relative number of papillary (70%) and anaplastic (42%) thyroid carcinoma samples, whereas is drastically downregulated in all the analyzed human thyroid carcinoma cell lines (TPC-1, BCPAP, FRO and 8505c) in comparison with normal thyroid tissue samples. Conversely, DICER1 is downregulated, at protein level, in PTC in comparison with normal thyroid tissues. Our data also reveals that DICER1 overexpression positively regulates thyroid cell proliferation, whereas its silencing impairs thyroid cell differentiation. The expression of DICER1 gene mutation (c.5438A>G; E1813G) negatively affects the microRNA machinery and cell proliferation as well as upregulates DICER1 protein levels of thyroid cells but has no impact on thyroid differentiation. In conclusion, DICER1 protein is downregulated in papillary thyroid carcinomas and affects thyroid proliferation and differentiation, while DICER1 gene mutation (c.5438A>G; E1813G) compromises the DICER1 wild-type-mediated microRNA processing and cell proliferation.
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Affiliation(s)
- Ricardo Cortez Cardoso Penha
- a Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , Naples , Italy.,b Instituto Nacional de Câncer - INCA, Centro de Pesquisas (CPQ) , Rio de Janeiro , RJ , Brazil
| | - Romina Sepe
- a Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , Naples , Italy
| | - Marco De Martino
- a Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , Naples , Italy
| | - Francesco Esposito
- a Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , Naples , Italy
| | - Simona Pellecchia
- a Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , Naples , Italy
| | - Maddalena Raia
- c CEINGE-Biotecnologie Avanzate, Università di Napoli Federico II , Naples , Italy
| | - Luigi Del Vecchio
- c CEINGE-Biotecnologie Avanzate, Università di Napoli Federico II , Naples , Italy.,d Department of Molecular Medicine and Medical Biotechnologies , University of Naples Federico II , Naples , Italy
| | | | - Gabriella De Vita
- d Department of Molecular Medicine and Medical Biotechnologies , University of Naples Federico II , Naples , Italy
| | | | - Alfredo Fusco
- a Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , Naples , Italy.,b Instituto Nacional de Câncer - INCA, Centro de Pesquisas (CPQ) , Rio de Janeiro , RJ , Brazil
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25
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Yoshida A, Kitajima S, Li F, Cheng C, Takegami Y, Kohno S, Wan YS, Hayashi N, Muranaka H, Nishimoto Y, Nagatani N, Nishiuchi T, Thai TC, Suzuki S, Nakao S, Tanaka T, Hirose O, Barbie DA, Takahashi C. MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6. Oncotarget 2017; 8:13872-13885. [PMID: 28099924 PMCID: PMC5355146 DOI: 10.18632/oncotarget.14681] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/03/2017] [Indexed: 12/15/2022] Open
Abstract
We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3′-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.
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Affiliation(s)
- Akiyo Yoshida
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.,Deperment of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Shunsuke Kitajima
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA
| | - Fengkai Li
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Chaoyang Cheng
- DNAFORM Precision Gene Technologies, Yokohama, Kanagawa, 230-0046, Japan
| | - Yujiro Takegami
- DNAFORM Precision Gene Technologies, Yokohama, Kanagawa, 230-0046, Japan
| | - Susumu Kohno
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Yuan Song Wan
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Naoyuki Hayashi
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.,Department of Health and Nutrition, Faculty of Human Health Science, Kanazawa Gakuin University, Kanazawa, Ishikawa, 920-1302, Japan
| | - Hayato Muranaka
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Yuuki Nishimoto
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Naoko Nagatani
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Takumi Nishiuchi
- Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Tran C Thai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA
| | - Sawako Suzuki
- Deperment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670 Japan
| | - Shinji Nakao
- Deperment of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tomoaki Tanaka
- Deperment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670 Japan
| | - Osamu Hirose
- Division of Electrical Engineering and Computer Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - David A Barbie
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA
| | - Chiaki Takahashi
- Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
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26
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Engineered polymeric nanoparticles to guide the cellular internalization and trafficking of small interfering ribonucleic acids. J Control Release 2017; 259:3-15. [DOI: 10.1016/j.jconrel.2017.02.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/15/2017] [Accepted: 02/18/2017] [Indexed: 12/29/2022]
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Ou C, Sun Z, Li X, Li X, Ren W, Qin Z, Zhang X, Yuan W, Wang J, Yu W, Zhang S, Peng Q, Yan Q, Xiong W, Li G, Ma J. MiR-590-5p, a density-sensitive microRNA, inhibits tumorigenesis by targeting YAP1 in colorectal cancer. Cancer Lett 2017; 399:53-63. [PMID: 28433598 DOI: 10.1016/j.canlet.2017.04.011] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 03/16/2017] [Accepted: 04/09/2017] [Indexed: 02/08/2023]
Abstract
YAP1, a transcription co-activator, mediates the biological functions of the Hippo pathway. YAP1 inactivation is involved in cell-cell contact inhibition. In various tumors, YAP1 is upregulated through multiple mechanisms, and it functions as an oncogene. Here, we provided evidence that YAP1 influenced multiple signaling pathways in colorectal cancer (CRC) cells. We reported that miR-590-5p directly targets YAP1 and inhibits tumorigenesis in CRC cells both in vitro and in vivo xenograft model. We analyzed different cell densities and found that increased density caused increased expression of miR-590-5p, and decreased expression of its precursors (pri- and pre-miR-590). Increasing cancer cell density upregulated the expression of a RNase III endonuclease, DICER1. DICER1 increased miR-590 biogenesis and inhibited YAP1. In DICER1-defective CRC cells, addition of pre-miR-590 did not inhibit YAP1 expression. Analyses of clinical data demonstrated that the DICER1-miR-590-5p-YAP1 axis was dysregulated in CRC specimens and affected patient survival. Cell-cell contact inhibition is crucial to prevent uncontrolled cell proliferation. Identification of this cell density-sensitive, DICER1-miR-590-5p-YAP1 axis may provide a basis for developing new biomarkers or targeted therapies for CRC.
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Affiliation(s)
- Chunlin Ou
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Zhenqiang Sun
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Department of Gastrointestinal Surgery, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Xiaoling Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
| | - Weiguo Ren
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Zailong Qin
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
| | - Xuemei Zhang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Weitang Yuan
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jia Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Wentao Yu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Shiwen Zhang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Qiu Peng
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Qun Yan
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Wei Xiong
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
| | - Guiyuan Li
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China.
| | - Jian Ma
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
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MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs. Leukemia 2017; 31:2780-2790. [PMID: 28555079 DOI: 10.1038/leu.2017.163] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 05/02/2017] [Accepted: 05/15/2017] [Indexed: 12/11/2022]
Abstract
The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.
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Khatun A, Fujimoto M, Kito H, Niwa S, Suzuki T, Ohya S. Down-Regulation of Ca 2+-Activated K⁺ Channel K Ca1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists. Int J Mol Sci 2016; 17:ijms17122083. [PMID: 27973439 PMCID: PMC5187883 DOI: 10.3390/ijms17122083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 12/01/2016] [Accepted: 12/08/2016] [Indexed: 12/15/2022] Open
Abstract
Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca2+-activated K+ channel KCa1.1 regulates intracellular Ca2+ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of KCa1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific KCa1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in KCa1.1 protein expression. These results suggest that KCa1.1 is a new downstream target of VDR signaling and the down-regulation of KCa1.1 through the transcriptional repression of KCa1.1 and enhancement of KCa1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells.
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Affiliation(s)
- Anowara Khatun
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
| | - Mayu Fujimoto
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
| | - Hiroaki Kito
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
| | - Satomi Niwa
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
| | - Takayoshi Suzuki
- Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 403-8334, Japan.
| | - Susumu Ohya
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
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Argonaute 2 Expression Correlates with a Luminal B Breast Cancer Subtype and Induces Estrogen Receptor Alpha Isoform Variation. Noncoding RNA 2016; 2:ncrna2030008. [PMID: 29657266 PMCID: PMC5831908 DOI: 10.3390/ncrna2030008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 08/24/2016] [Accepted: 09/09/2016] [Indexed: 12/21/2022] Open
Abstract
Estrogen receptor alpha (ERα) signaling pathways are frequently disrupted in breast cancer and contribute to disease progression. ERα signaling is multifaceted and many ERα regulators have been identified including transcription factors and growth factor pathways. More recently, microRNAs (miRNAs) are shown to deregulate ERα activity in breast carcinomas, with alterations in both ERα and miRNA expression correlating to cancer progression. In this study, we show that a high expression of Argonaute 2 (AGO2), a translation regulatory protein and mediator of miRNA function, correlates with the luminal B breast cancer subtype. We further demonstrate that a high expression of AGO2 in ERα+ tumors correlates with a poor clinical outcome. MCF-7 breast cancer cells overexpressing AGO2 (MCF7-AGO2) altered ERα downstream signaling and selective ERα variant expression. Enhanced ERα-36, a 36 kDa ERα isoform, protein and gene expression was observed in vitro. Through quantitative polymerase chain reaction (qPCR), we demonstrate decreased basal expression of the full-length ERα and progesterone receptor genes, in addition to loss of estrogen stimulated gene expression in vitro. Despite the loss, MCF-7-AGO2 cells demonstrated increased estrogen stimulated tumorigenesis in vivo. Together with our clinical findings on AGO2 expression and the luminal B subtype, we suggest that AGO2 is a regulator of altered ERα signaling in breast tumors.
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Fiskaa T, Knutsen E, Nikolaisen MA, Jørgensen TE, Johansen SD, Perander M, Seternes OM. Distinct Small RNA Signatures in Extracellular Vesicles Derived from Breast Cancer Cell Lines. PLoS One 2016; 11:e0161824. [PMID: 27579604 PMCID: PMC5006963 DOI: 10.1371/journal.pone.0161824] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 08/14/2016] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is a heterogeneous disease, and different subtypes of breast cancer show distinct cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. Understanding the molecular features responsible for this heterogeneity is important for correct diagnosis and better treatment strategies. Extracellular vesicles (EVs) and their associated molecules have gained much attention as players in intercellular communication, ability to precondition specific organs for metastatic invasion, and for their potential role as circulating cancer biomarkers. EVs are released from the cells and contain proteins, DNA, and long and small RNA species. Here we show by high-throughput small RNA-sequencing that EVs from nine different breast cancer cell lines share common characteristics in terms of small RNA content that are distinct from their originating cells. Most strikingly, a highly abundant small RNA molecule derived from the nuclear 28S rRNA is vastly enriched in EVs. The miRNA profiles in EVs correlate with the cellular miRNA expression pattern, but with a few exceptions that includes miR-21. This cancer-associated miRNA is retained in breast cancer cell lines. Finally, we report that EVs from breast cancer cell lines cluster together based on their small RNA signature when compared to EVs derived from other cancer cell lines. Altogether, our data demonstrate that breast cancer cell lines manifest a specific small RNA signature in their released EVs. This opens up for further evaluation of EVs as breast cancer biomarkers.
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Affiliation(s)
- Tonje Fiskaa
- Department of Medical Biology, Faculty of Health Sciences, UiT–The Arctic University of Norway, MH-building Breivika, Tromsø, N-9037, Norway
- Department of Pharmacy, Faculty of Health Sciences, UiT–The Arctic University of Norway, MH-building Breivika, Tromsø, N-9037, Norway
- * E-mail:
| | - Erik Knutsen
- Department of Medical Biology, Faculty of Health Sciences, UiT–The Arctic University of Norway, MH-building Breivika, Tromsø, N-9037, Norway
| | - Marlen Aas Nikolaisen
- Department of Pharmacy, Faculty of Health Sciences, UiT–The Arctic University of Norway, MH-building Breivika, Tromsø, N-9037, Norway
| | - Tor Erik Jørgensen
- Marine Genomics group, Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Steinar Daae Johansen
- Department of Medical Biology, Faculty of Health Sciences, UiT–The Arctic University of Norway, MH-building Breivika, Tromsø, N-9037, Norway
- Marine Genomics group, Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Maria Perander
- Department of Medical Biology, Faculty of Health Sciences, UiT–The Arctic University of Norway, MH-building Breivika, Tromsø, N-9037, Norway
| | - Ole Morten Seternes
- Department of Pharmacy, Faculty of Health Sciences, UiT–The Arctic University of Norway, MH-building Breivika, Tromsø, N-9037, Norway
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High copy number variation of cancer-related microRNA genes and frequent amplification of DICER1 and DROSHA in lung cancer. Oncotarget 2016; 6:23399-416. [PMID: 26156018 PMCID: PMC4695126 DOI: 10.18632/oncotarget.4351] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/08/2015] [Indexed: 11/27/2022] Open
Abstract
A growing body of evidence indicates that miRNAs may be a class of genetic elements that can either drive or suppress oncogenesis. In this study we analyzed the somatic copy number variation of 14 miRNA genes frequently found to be either over- or underexpressed in lung cancer, as well as two miRNA biogenesis genes, DICER1 and DROSHA, in non-small-cell lung cancer (NSCLC). Our analysis showed that most analyzed miRNA genes undergo substantial copy number alteration in lung cancer. The most frequently amplified miRNA genes include the following: miR-30d, miR-21, miR-17 and miR-155. We also showed that both DICER1 and DROSHA are frequently amplified in NSCLC. The copy number variation of DICER1 and DROSHA correlates well with their expression and survival of NSCLC and other cancer patients. The increased expression of DROSHA and DICER1 decreases and increases the survival, respectively. In conclusion, our results show that copy number variation may be an important mechanism of upregulation/downregulation of miRNAs in cancer and suggest an oncogenic role for DROSHA.
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The modulation of Dicer regulates tumor immunogenicity in melanoma. Oncotarget 2016; 7:47663-47673. [PMID: 27356752 PMCID: PMC5216969 DOI: 10.18632/oncotarget.10273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 06/12/2016] [Indexed: 01/31/2023] Open
Abstract
MicroRNAs (miRs) are small non-coding RNAs that regulate most cellular protein networks by targeting mRNAs for translational inhibition or degradation. Dicer, a type III endoribonuclease, is a critical component in microRNA biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. For example, increased Dicer expression in melanoma is associated with more aggressive tumors (higher tumor mitotic index and depth of invasion) and poor patient prognosis. However, the role that Dicer plays in melanoma development and immune evasion remains unclear. Here, we report on a newly discovered relationship between Dicer expression and tumor immunogenicity. To investigate Dicer's role in regulating melanoma immunogenicity, Dicer knockdown studies were performed. We found that B16F0-Dicer deficient cells exhibited decreased tumor growth compared to control cells and were capable of inducing anti-tumor immunity. The decrease in tumor growth was abrogated in immunodeficient NSG mice and was shown to be dependent upon CD8+ T cells. Dicer knockdown also induced a more responsive immune gene profile in melanoma cells. Further studies demonstrated that CD8+ T cells preferentially killed Dicer knockdown tumor cells compared to control cells. Taken together, we present evidence which links Dicer expression to tumor immunogenicity in melanoma.
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Adem BF, Bastos NRA, Dias F, Teixeira AL, Medeiros R. miRNAs: mediators of ErbB family targeted therapy resistance. Pharmacogenomics 2016; 17:1175-1187. [PMID: 27359187 DOI: 10.2217/pgs-2016-0038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The ErbB/HER tyrosine kinase receptors family plays a key regulatory role in different cellular processes by activating several signaling pathways. In different tumor types, mutations or overexpression of the ErbB family members are a common feature, which led to the development of targeted therapies against this receptors. Although with this kind of treatment we are heading to a more personalized medicine, the development of acquired resistance is still an issue, therefore, several studies focused on discovering the mechanisms behind it. More recently, miRNAs have been described as important mediators of acquired resistance, specifically, acquired resistance to ErbB family targeted therapies. Ultimately, miRNA-based therapeutics using exosomes as a drug delivery model can revolutionize today's approach of cancer treatment.
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Affiliation(s)
- Bárbara Filipa Adem
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,FMUP, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Nuno Ricardo Alves Bastos
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,FMUP, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Francisca Dias
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.,LPCC, Research Department Portuguese League Against Cancer (NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal
| | - Ana Luísa Teixeira
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,LPCC, Research Department Portuguese League Against Cancer (NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.,LPCC, Research Department Portuguese League Against Cancer (NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal.,CEBIMED, Health Sciences of Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal
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Spoelstra NS, Cittelly DM, Christenson JL, Gordon MA, Elias A, Jedlicka P, Richer JK. Dicer expression in estrogen receptor-positive versus triple-negative breast cancer: an antibody comparison. Hum Pathol 2016; 56:40-51. [PMID: 27260947 DOI: 10.1016/j.humpath.2016.05.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 05/10/2016] [Accepted: 05/19/2016] [Indexed: 01/20/2023]
Abstract
Dicer is an RNase III enzyme responsible for cleaving double-stranded RNAs into small interfering RNAs and microRNAs, which either target messenger RNA transcripts for degradation or inhibit translation. Dicer protein levels have been examined in breast cancer with contradictory results. Our goal was to resolve whether Dicer levels differ in breast cancer versus normal breast epithelium and between estrogen receptor-α-positive (ER+) or estrogen receptor-α-negative (ER-) primary breast cancers. We compared 3 different Dicer antibodies: Abcam 4A6, Abcam ab5818, and Sigma HPA000694, using immunohistochemistry and Western blot analyses. All 3 Dicer antibodies detected higher levels of Dicer in ER+ breast cancer cell lines versus ER-, and all 3 recognized exogenous overexpressed Dicer. In clinical specimens, all 3 antibodies detected higher Dicer in ER+ breast cancers versus triple-negative breast cancer (TNBC) but had very different staining patterns by immunohistochemistry on the same tumor samples. Using the optimal antibody, ab5818, selected for its sensitivity and specificity, Dicer protein expression was significantly higher in ER+ versus TNBC clinical specimens of primary tumor (P<.0001, unpaired t test). Dicer was also significantly higher in adjacent normal breast epithelium versus TNBC (P<.0001, paired t test; n=18 pairs). Differences in antibody performance may explain contrasting results observed in the literature regarding Dicer protein in breast cancer. If Dicer becomes more clinically relevant as a prognostic indicator, further antibody optimization and standardization will be critical.
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Affiliation(s)
- Nicole S Spoelstra
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Diana M Cittelly
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Jessica L Christenson
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Michael A Gordon
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Anthony Elias
- Division of Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Paul Jedlicka
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Jennifer K Richer
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
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Chang TY, Chen HA, Chiu CF, Chang YW, Kuo TC, Tseng PC, Wang W, Hung MC, Su JL. Dicer Elicits Paclitaxel Chemosensitization and Suppresses Cancer Stemness in Breast Cancer by Repressing AXL. Cancer Res 2016; 76:3916-28. [PMID: 27216190 DOI: 10.1158/0008-5472.can-15-2555] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 03/31/2016] [Indexed: 11/16/2022]
Abstract
Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here, we report that adenovirus-type 5 E1A-mediated elevation of the miRNA-processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting miRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of an MAPK14/CEBPα pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel, which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients. Cancer Res; 76(13); 3916-28. ©2016 AACR.
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Affiliation(s)
- Ting-Yu Chang
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan
| | - Hsin-An Chen
- Department of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ching-Feng Chiu
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan
| | - Yi-Wen Chang
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan
| | - Tsang-Chih Kuo
- Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Po-Chun Tseng
- Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Weu Wang
- Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jen-Liang Su
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
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Regulation of the T-box transcription factor Tbx3 by the tumour suppressor microRNA-206 in breast cancer. Br J Cancer 2016; 114:1125-34. [PMID: 27100732 PMCID: PMC4865973 DOI: 10.1038/bjc.2016.73] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/18/2016] [Accepted: 02/23/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The Tbx3 transcription factor is over-expressed in breast cancer, where it has been implicated in proliferation, migration and regulation of the cancer stem cell population. The mechanisms that regulate Tbx3 expression in cancer have not been fully explored. In this study, we demonstrate that Tbx3 is repressed by the tumour suppressor miR-206 in breast cancer cells. METHODS Bioinformatics prediction programmes and luciferase reporter assays were used to demonstrate that miR-206 negatively regulates Tbx3. We examined the impact of miR-206 on Tbx3 expression in breast cancer cells using miR-206 mimic and inhibitor. Gene/protein expression was examined by quantitative reverse-transcription-PCR and immunoblotting. The effects of miR-206 and Tbx3 on apoptosis, proliferation, invasion and cancer stem cell population was investigated by cell-death detection, colony formation, 3D-Matrigel and tumorsphere assays. RESULTS In this study, we examined the regulation of Tbx3 by miR-206. We demonstrate that Tbx3 is directly repressed by miR-206, and that this repression of Tbx3 is necessary for miR-206 to inhibit breast tumour cell proliferation and invasion, and decrease the cancer stem cell population. Moreover, Tbx3 and miR-206 expression are inversely correlated in human breast cancer. Kaplan-Meier analysis indicates that patients exhibiting a combination of high Tbx3 and low miR-206 expression have a lower probability of survival when compared with patients with low Tbx3 and high miR-206 expression. These studies uncover a novel mechanism of Tbx3 regulation and identify a new target of the tumour suppressor miR-206. CONCLUSIONS The present study identified Tbx3 as a novel target of tumour suppressor miR-206 and characterised the miR-206/Tbx3 signalling pathway, which is involved in proliferation, invasion and maintenance of the cancer stem cell population in breast cancer cells. Our results suggest that restoration of miR-206 in Tbx3-positive breast cancer could be exploited for therapeutic benefit.
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Ren W, Shen S, Sun Z, Shu P, Shen X, Bu C, Ai F, Zhang X, Tang A, Tian L, Li G, Li X, Ma J. Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) to promote colon cancer development. Cancer Lett 2016; 375:209-220. [PMID: 26965998 DOI: 10.1016/j.canlet.2016.02.055] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/06/2016] [Accepted: 02/29/2016] [Indexed: 12/13/2022]
Abstract
Chronic intestinal inflammation is closely associated with colon cancer development and STAT3 seems to take center stage in bridging chronic inflammation to colon cancer progress. Here, we discovered that DICER1 was significantly downregulated in response to IL-6 or LPS stimulation and identified a novel mechanism for DICER1 downregulation via proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) in colon cancer cells. Meanwhile, PI3K-AKT signaling pathway phosphorylated DICER1 and contributed to its proteasomal degradation. The regulation of DICER1 by CUL4A(DCAF1) affected cell growth and apoptosis which is controlled by IL-6 activated Jak-STAT3 pathway. Intervention of CUL4A(DCAF1) ubiquitin ligase complex led to fluctuation in expression levels of DICER1 and microRNAs, and thus affected tumor growth in a mouse xenograft model. A panel of microRNAs that were downregulated by IL-6 stimulation was rescued by siRNA-CUL4A, and their predicated functions are involved in regulation of cell proliferation, apoptosis and motility. Furthermore, clinical specimen analysis revealed that decreased DICER1 expression was negatively correlated with STAT3 activation and cancer progression in human colon cancers. DICER1 and p-STAT3 expression levels correlated with 5-year overall survival of colon cancer patients. Consequently, this study proposes that inflammation-induced Jak-STAT3 signaling leads to colon cancer development through proteasomal degradation of DICER1 by ubiquitin ligase complex of CUL4A(DCAF1), which suggests a novel therapeutic opportunity for colon cancer.
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Affiliation(s)
- Weiguo Ren
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Shourong Shen
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Zhenqiang Sun
- Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Peng Shu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaohua Shen
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chibin Bu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Feiyan Ai
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Xuemei Zhang
- Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Anliu Tang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Li Tian
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Xiayu Li
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.
| | - Jian Ma
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China.
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Weng Y, Chen Y, Chen J, Liu Y, Bao T. RETRACTED ARTICLE: Common genetic variants in microRNA processing machinery genes are associated with risk and survival in patients with osteosarcoma. Mol Genet Genomics 2016. [DOI: 10.1007/s00438-015-1006-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Ai F, Zhang X, Li X, Qin Z, Ye Q, Tian L, Tang A, Li N, Li G, Ma J, Shen S. Up-regulation of matrix metalloproteinases in a mouse model of chemically induced colitis-associated cancer: the role of microRNAs. Oncotarget 2016; 6:5412-25. [PMID: 25742789 PMCID: PMC4467157 DOI: 10.18632/oncotarget.3027] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 01/01/2015] [Indexed: 01/08/2023] Open
Abstract
Emerging evidence has implicated microRNAs in regulating the production of multiple inflammatory mediators including cytokines and chemokines. We previously elucidated the dynamic activation of key signals that link colitis to colorectal cancer. In this study, we observed a sharp increase in the levels of matrix metalloproteinases (Mmps) that provided a basis for the inflammation-cancer link, and we questioned whether this was a consequence of the dysregulation of Mmp-specific microRNAs, at least partly. We assayed a panel of murine microRNAs that were predicted to target Mmps and found they were downregulated in the inflammation-cancer link. Furthermore, we demonstrated that three murine microRNAs, namely miR-128, -134, and -330, can target the three Mmps Mmp3, Mmp10, and Mmp13, respectively. We also found that the level of the microRNA-processing enzyme Dicer1 was decreased in the inflammation-cancer link. These microRNAs functioned as tumor suppressors in colon cancer cells, attenuating the proliferation, migration, and invasion potential of murine colon cancer cells as well as angiogenesis and the growth of tumors derived from these cells. Our results suggest that microRNAs modulate the production of key inflammatory mediators and that microRNA dysfunction may contribute to the non-resolving inflammation associated with cancer.
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Affiliation(s)
- Feiyan Ai
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Xuemei Zhang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Xiayu Li
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Zailong Qin
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Qiurong Ye
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Li Tian
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Anliu Tang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Nan Li
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Jian Ma
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Shourong Shen
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
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MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development. Genetics 2016; 202:1105-18. [PMID: 26773048 DOI: 10.1534/genetics.115.184176] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 01/10/2016] [Indexed: 12/20/2022] Open
Abstract
The Dicer1, Dcr-1 homolog (Drosophila) gene encodes a type III ribonuclease required for the canonical maturation and functioning of microRNAs (miRNAs). Subsets of miRNAs are known to regulate normal cerebellar granule cell development, in addition to the growth and progression of medulloblastoma, a neoplasm that often originates from granule cell precursors. Multiple independent studies have also demonstrated that deregulation of Sonic Hedgehog (Shh)-Patched (Ptch) signaling, through miRNAs, is causative of granule cell pathologies. In the present study, we investigated the genetic interplay between miRNA biogenesis and Shh-Ptch signaling in granule cells of the cerebellum by way of the Cre/lox recombination system in genetically engineered models of Mus musculus (mouse). We demonstrate that, although the miRNA biogenesis and Shh-Ptch-signaling pathways, respectively, regulate the opposing growth processes of cerebellar hypoplasia and hyperplasia leading to medulloblastoma, their concurrent deregulation was nonadditive and did not bring the growth phenotypes toward an expected equilibrium. Instead, mice developed either hypoplasia or medulloblastoma, but of a greater severity. Furthermore, some genotypes were bistable, whereby subsets of mice developed hypoplasia or medulloblastoma. This implies that miRNAs and Shh-Ptch signaling regulate an important developmental transition in granule cells of the cerebellum. We also conclusively show that the Dicer1 gene encodes a haploinsufficient tumor suppressor gene for Ptch1-induced medulloblastoma, with the monoallielic loss of Dicer1 more severe than biallelic loss. These findings exemplify how genetic interplay between pathways may produce nonadditive effects with a substantial and unpredictable impact on biology. Furthermore, these findings suggest that the functional dosage of Dicer1 may nonadditively influence a wide range of Shh-Ptch-dependent pathologies.
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Lo PK, Wolfson B, Zhou X, Duru N, Gernapudi R, Zhou Q. Noncoding RNAs in breast cancer. Brief Funct Genomics 2015; 15:200-21. [PMID: 26685283 DOI: 10.1093/bfgp/elv055] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The mammalian transcriptome has recently been revealed to encompass a large number of noncoding RNAs (ncRNAs) that play a variety of important regulatory roles in gene expression and other biological processes. MicroRNAs (miRNAs), the best studied of the short noncoding RNAs (sncRNAs), have been extensively characterized with regard to their biogenesis, function and importance in tumorigenesis. Another class of sncRNAs called piwi-interacting RNAs (piRNAs) has also gained attention recently in cancer research owing to their critical role in stem cell regulation. Long noncoding RNAs (lncRNAs) of >200 nucleotides in length have recently emerged as key regulators of developmental processes, including mammary gland development. lncRNA dysregulation has also been implicated in the development of various cancers, including breast cancer. In this review, we describe and discuss the roles of sncRNAs (including miRNAs and piRNAs) and lncRNAs in the initiation and progression of breast tumorigenesis, with a focus on outlining the molecular mechanisms of oncogenic and tumor-suppressor ncRNAs. Moreover, the current and potential future applications of ncRNAs to clinical breast cancer research are also discussed, with an emphasis on ncRNA-based diagnosis, prognosis and future therapeutics.
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Abstract
MicroRNAs (miRNAs) are integral to the gene regulatory network. A single miRNA is capable of controlling the expression of hundreds of protein coding genes and modulate a wide spectrum of biological functions, such as proliferation, differentiation, stress responses, DNA repair, cell adhesion, motility, inflammation, cell survival, senescence and apoptosis, all of which are fundamental to tumorigenesis. Overexpression, genetic amplification, and gain-of-function mutation of oncogenic miRNAs ("onco-miRs") as well as genetic deletion and loss-of-function mutation of tumor suppressor miRNAs ("suppressor-miRs") are linked to human cancer. In addition to the dysregulation of a specific onco-miR or suppressor-miRs, changes in global miRNA levels resulting from a defective miRNA biogenesis pathway play a role in tumorigenesis. The function of individual onco-miRs and suppressor-miRs and their target genes in cancer has been described in many different articles elsewhere. In this review, we primarily focus on the recent development regarding the dysregulation of the miRNA biogenesis pathway and its contribution to cancer.
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Affiliation(s)
- Akiko Hata
- a Cardiovascular Research Institute, University of California , San Francisco , CA , USA
| | - Risa Kashima
- a Cardiovascular Research Institute, University of California , San Francisco , CA , USA
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Chen L, Yang L, Qiao F, Hu X, Li S, Yao L, Yang XL, Shao ZM. High Levels of Nucleolar Spindle-Associated Protein and Reduced Levels of BRCA1 Expression Predict Poor Prognosis in Triple-Negative Breast Cancer. PLoS One 2015; 10:e0140572. [PMID: 26485712 PMCID: PMC4618922 DOI: 10.1371/journal.pone.0140572] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 09/26/2015] [Indexed: 12/13/2022] Open
Abstract
Purpose Nucleolar spindle-associated protein (NuSAP1) is an important mitosis-related protein, and aberrant NuSAP1 expression is associated with abnormal spindles and mitosis. This study investigated the prognostic value of NuSAP1 in breast cancer. Methods Two sets of tissue microarrays (TMAs) that included samples from 450 breast cancer patients were constructed, of which 250 patients were training set and the other 200 patients were validation set. Immunohistochemical staining was performed to determine the NuSAP1 levels. A Kaplan-Meier analysis was used to estimate the prognostic value of NuSAP1 in breast cancer. A stepwise Cox analysis was performed to construct a risk-prediction model for triple-negative breast cancer (TNBC). All statistical analysis was performed with SPSS software. Results There were 108 (43.5%) and 88 (44.0%) patients expressed NuSAP1 in the training set and validation set respectively. High levels of NuSAP1 expression were related to poor disease-free survival (DFS) in both training (P = 0.028) and validation (P = 0.006) cohorts, particularly in TNBC. With combination of two cohorts, both NuSAP1 (HR = 4.136, 95% CI: 1.956–8.747, P < 0.001) and BRCA1 (HR = 0.383, 95% CI: 0.160–0.915, P = 0.031) were independent prognostic indicators of DFS in TNBC. A receiver operating characteristic (ROC) analysis revealed that the combination of NuSAP1 and BRCA1 significantly improved the prognostic power compared with the traditional model (0.778 versus 0.612, P < 0.001). Conclusions Our study confirms the prognostic value of NuSAP1 in breast cancer. The combination of NuSAP1 and BRCA1 could improve the DFS prediction accuracy in TNBC.
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Affiliation(s)
- Li Chen
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Liu Yang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Feng Qiao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Xin Hu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Shan Li
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Ling Yao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- * E-mail: (ZMS); (L Yao)
| | - Xue-Li Yang
- Department of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- * E-mail: (ZMS); (L Yao)
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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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Bertoli G, Cava C, Castiglioni I. MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer. Theranostics 2015; 5:1122-43. [PMID: 26199650 PMCID: PMC4508501 DOI: 10.7150/thno.11543] [Citation(s) in RCA: 598] [Impact Index Per Article: 59.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 06/17/2015] [Indexed: 12/21/2022] Open
Abstract
Dysregulation of microRNAs (miRNAs) is involved in the initiation and progression of several human cancers, including breast cancer (BC), as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. This review presents the state of the art on the role of miRNAs in the diagnosis, prognosis, and therapy of BC. Based on the results obtained in the last decade, some miRNAs are emerging as biomarkers of BC for diagnosis (i.e., miR-9, miR-10b, and miR-17-5p), prognosis (i.e., miR-148a and miR-335), and prediction of therapeutic outcomes (i.e., miR-30c, miR-187, and miR-339-5p) and have important roles in the control of BC hallmark functions such as invasion, metastasis, proliferation, resting death, apoptosis, and genomic instability. Other miRNAs are of interest as new, easily accessible, affordable, non-invasive tools for the personalized management of patients with BC because they are circulating in body fluids (e.g., miR-155 and miR-210). In particular, circulating multiple miRNA profiles are showing better diagnostic and prognostic performance as well as better sensitivity than individual miRNAs in BC. New miRNA-based drugs are also promising therapy for BC (e.g., miR-9, miR-21, miR34a, miR145, and miR150), and other miRNAs are showing a fundamental role in modulation of the response to other non-miRNA treatments, being able to increase their efficacy (e.g., miR-21, miR34a, miR195, miR200c, and miR203 in combination with chemotherapy).
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Affiliation(s)
| | | | - Isabella Castiglioni
- Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan, Italy
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Lombard AP, Lim RM, Nakagawa RM, Vidallo KD, Libertini SJ, Platero AJ, Mudryj M. Dicer ablation promotes a mesenchymal and invasive phenotype in bladder cancer cells. Oncol Rep 2015; 34:1526-32. [PMID: 26166215 DOI: 10.3892/or.2015.4117] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 03/16/2015] [Indexed: 11/06/2022] Open
Abstract
Dicer expression is frequently altered in cancer and affects a wide array of cellular functions acting as an oncogene or tumor suppressor in varying contexts. It has been shown that Dicer expression is also deregulated in urothelial cell carcinoma of the bladder (UCCB) but the nature of this deregulation differs between reports. The aim of the present study was to gain a better understanding of the role of Dicer in bladder cancer to help determine its contribution to the disease. The results showed that Dicer transcript levels were decreased in UCCB tumor tissues as compared to normal tissues, suggesting that Dicer is a tumor suppressor. However, consistent with previous results, we demonstrated that knockdown of Dicer decreases cell viability and increases the induction of apoptosis, suggesting that Dicer is an oncogene. To resolve this discrepancy, we assessed the effects of decreased Dicer expression on epithelial-to‑mesenchymal transition, migration and invasion. We showed that decreased Dicer levels promoted a mesenchymal phenotype and increased migration. Additionally, the results showed that Dicer protein ablation leads to increased cell invasion, higher levels of matrix metalloproteinase-2, and decreased levels of key miRNAs shown to inhibit invasion. The results of this study suggest that decreased Dicer levels may portend a more malignant phenotype.
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Affiliation(s)
- Alan P Lombard
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
| | - Rebecca M Lim
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
| | - Rachel M Nakagawa
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
| | - Kathleen D Vidallo
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
| | - Stephen J Libertini
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
| | - Alexander J Platero
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
| | - Maria Mudryj
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
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Dysregulated expression of Dicer in invasive ductal breast carcinoma. Med Oncol 2015; 32:203. [PMID: 26076803 DOI: 10.1007/s12032-015-0643-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 05/19/2015] [Indexed: 12/21/2022]
Abstract
Several lines of evidence suggest that the global down-regulation of the microRNAome (miRNAome) involved in pathogenesis of various malignancies. Impaired microRNAs processing pathway is one possible mechanism for global down-regulation of the miRNAome. Dicer is a key enzyme in miRNA processing pathway, and dysregulation of its expression has been suggested as a possible cause of miRNAome alterations observed in various cancers. However, Dicer mRNA expression in invasive ductal breast carcinoma (IDC) has not been investigated in depth. Therefore, this study aimed to evaluate the mRNA expression of Dicer in IDC and also to assess the correlation of its expression with clinicopathological parameters including age, histological grade, tumor size and lymph node metastasis. We investigated the expression of the Dicer in seventy fresh invasive ductal breast carcinomas and matched adjacent non-neoplastic tissue by quantitative real-time PCR using validated reference genes. In addition, the possible impact of clinicopathological characteristics on Dicer expression levels was analyzed. Our results showed that Dicer mRNA expression is down-regulated in slightly more than half (51.43 %) of the tumor specimens when compared to adjacent non-neoplastic tissue. Comparison of the Dicer expression level between tumor and matched adjacent non-neoplastic tissue showed that there is no statistical significant differences between them (P = 0.425). We also found that Dicer mRNA expression in IDC samples was not correlated with clinicopathological features. In conclusion, our findings provide additional evidence to support the hypothesis that Dicer expression down-regulated in breast cancer. This study suggested that the decreased expression of Dicer may be potential underlying mechanism in pathogenesis of IDC.
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Abstract
MicroRNAs (miRNAs) are critical regulators of gene expression. Amplification and overexpression of individual 'oncomiRs' or genetic loss of tumour suppressor miRNAs are associated with human cancer and are sufficient to drive tumorigenesis in mouse models. Furthermore, global miRNA depletion caused by genetic and epigenetic alterations in components of the miRNA biogenesis machinery is oncogenic. This, together with the recent identification of novel miRNA regulatory factors and pathways, highlights the importance of miRNA dysregulation in cancer.
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Affiliation(s)
- Shuibin Lin
- 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Richard I Gregory
- 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA. [4] Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA
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Wampfler J, Federzoni EA, Torbett BE, Fey MF, Tschan MP. Low DICER1 expression is associated with attenuated neutrophil differentiation and autophagy of NB4 APL cells. J Leukoc Biol 2015; 98:357-63. [PMID: 25990244 DOI: 10.1189/jlb.1ab0514-258r] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 04/21/2015] [Indexed: 12/21/2022] Open
Abstract
Successful myeloid differentiation depends on the expression of a series of miRNAs. Thus, it is hardly surprising that miRNAs are globally repressed in AML, a disease mainly characterized by a block in cellular myeloid differentiation. Studies investigating the mechanisms for low miRNA expression in AML has mostly focused on altered transcriptional regulation or deletions, whereas defective miRNA processing has received less attention. In this study, we report that the expression of the key miRNA processing enzyme DICER1 is down-regulated in primary AML patient samples and healthy CD34(+) progenitor cells as compared with granulocytes. In line with these findings, Dicer1 expression was induced significantly in AML cell lines upon neutrophil differentiation. The knocking down of DICER1 in AML cells significantly attenuated neutrophil differentiation, which was paralleled by decreased expression of miRNAs involved in this process. Moreover, we found that inhibiting DICER1 attenuated the activation of autophagy, a cellular recycling process that is needed for proper neutrophil differentiation of AML cells. Our results clearly indicate that DICER1 plays a novel role in neutrophil differentiation as well as in myeloid autophagy of AML cells.
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Affiliation(s)
- Julian Wampfler
- *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Elena A Federzoni
- *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Bruce E Torbett
- *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Martin F Fey
- *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Mario P Tschan
- *Division of Experimental Pathology, Institute of Pathology, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
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