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Hermán-Sánchez N, G-García ME, Jiménez-Vacas JM, Yubero-Serrano EM, López-Sánchez LM, Romero-Martín S, Raya-Povedano JL, Álvarez-Benito M, Castaño JP, Luque RM, Gahete MD. The splicing machinery is dysregulated and represents a therapeutic vulnerability in breast cancer. Cell Mol Life Sci 2024; 82:18. [PMID: 39725737 DOI: 10.1007/s00018-024-05515-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/27/2024] [Accepted: 11/15/2024] [Indexed: 12/28/2024]
Abstract
Breast cancer (BCa) is a highly prevalent pathological condition (̴30% in women) with limited and subtype-dependent prognosis and therapeutic options. Therefore, BCa management might benefit from the identification of novel molecular elements with clinical potential. Since splicing process is gaining a great relevance in cancer, this work analysed the expression of multiple Spliceosome Components (SCs = 17) and Splicing Factors (SFs = 26) and found a drastic dysregulation in BCa (n = 69) vs. control (negative biopsies; n = 50) samples. Among all the components analysed, we highlight the upregulation of ESRP1 and down-regulation of PRPF8 and NOVA1 in BCa vs. control samples. Indeed, ESRP1 was specially overexpressed in triple-negative BCa (TNBCa) and associated with worse prognosis (i.e., higher BCa grade and lower overall survival), suggesting an association of ESRP1 with BCa aggressiveness. On the other hand, PRPF8 expression was generally downregulated in BCa with no associations to clinical characteristics, while NOVA1 expression was lower in TNBCa patients and highly aggressive tumours. Consistently, NOVA1 overexpression in vitro reduced functional parameters of aggressiveness in ER-/PR- cell lines (MDA-MB-231 and BT-549) but not in ER+/PR+ cells (MCF7), suggesting a critical role of NOVA1 in subtype-specific BCa. Finally, the in vitro pharmacological inhibition of splicing machinery using pladienolide B decreased aggressiveness features in all the BCa cell lines, showing a subtype-independent inhibitory potential, but being relatively innocuous in normal-like breast cells. These results demonstrate the profound dysregulation of the splicing machinery in BCa and their potential as source of promising diagnosis/prognosis markers, as well as valuable therapeutic targets for BCa.
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Affiliation(s)
- Natalia Hermán-Sánchez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Miguel E G-García
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Juan M Jiménez-Vacas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Elena M Yubero-Serrano
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
- Lipids and Atherosclerosis Unit, Reina Sofía University Hospital, Córdoba, Spain
| | - Laura M López-Sánchez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Sara Romero-Martín
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- Mammary Gland Unit, Reina Sofía University Hospital, Córdoba, Spain
| | - Jose L Raya-Povedano
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- Mammary Gland Unit, Reina Sofía University Hospital, Córdoba, Spain
| | - Marina Álvarez-Benito
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain
- Reina Sofía University Hospital, Córdoba, 14004, Spain
- Mammary Gland Unit, Reina Sofía University Hospital, Córdoba, Spain
| | - Justo P Castaño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain.
- Reina Sofía University Hospital, Córdoba, 14004, Spain.
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
| | - Raúl M Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain.
- Reina Sofía University Hospital, Córdoba, 14004, Spain.
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
| | - Manuel D Gahete
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), IMIBIC building. Av. Menéndez Pidal s/n, Córdoba, 14004, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain.
- Reina Sofía University Hospital, Córdoba, 14004, Spain.
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
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He C, Chen Y, Zhang X, Feng H, Rao Y, Ji T, Wang W. Down-regulation of ESRP2 inhibits breast cancer cell proliferation via inhibiting cyclinD1. Sci Rep 2024; 14:28475. [PMID: 39557898 PMCID: PMC11574003 DOI: 10.1038/s41598-024-77980-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 10/28/2024] [Indexed: 11/20/2024] Open
Abstract
Epithelial splicing regulatory protein 2 (ESRP2),an important alternative splicing protein of mRNA, is reported to have a dual role in tumors, which can promote or inhibit the occurrence and development of tumors. However, the function and mechanism of ESRP2 in breast cancer (BC) remain unclear. The distribution of ESRP2 expression in breast cancer and the correlation between ESRP2 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene Ontology(GO)analysis, containing biological process, cellular components, and molecular function, was utilized to evaluate the potential mechanism of ESRP2 in breast cancer. The ESRP2 expression in breast cancer cell lines was detected by real-time quantitative PCR analysis (RT-qPCR) and western blotting. Cell clone was performed to examine the proliferation of ESRP2 knockdown in MCF-7 cells. The cell cycle was measured by flow cytometry assays. The role of ESRP2 knockdown in synergistic effect with chemotherapeutic agents was also determined by MTT assay. Bioinformatics analysis demonstrated that the ESRP2 gene was elevated in breast cancer cells and its overexpression was strongly correlated with shorter overall survival. GO analysis revealed that ESRP2 expression was related to cell proliferation. ESRP2 mRNA and protein expression were elevated in breast cancer cell lines, compared to the normal human breast cell line MCF-10 A. Dwon-regulation of ESRP2 inhibited cell proliferation and promoted the sensitivity of chemotherapy drug, Cisplatin(DDP) and Paclitaxel (TAXOL), in MCF-7 cells.Additionally, ESRP2 knockdown obstructed the cell cycle at the G1 phase and caused a decrease in cyclinD1 protein expression. These findings reveal that ESRP2 is highly expressed in breast cancer and is correlated with poor prognosis in breast cancer patients. ESRP2 knockdown can inhibit MCF-7 cell proliferation by arresting the cell cycle at the G1 phase and promoting the sensitivity of chemotherapy drugs (DDP and TAXOL)in MCF-7 cells. ESRP2 may be required for the regulation of breast cancer progression, as well as a critical target for the clinical treatment of breast cancer.
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Affiliation(s)
- Caiping He
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuting Chen
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong, China
| | - Ximin Zhang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Guangzhou Civil Aviation College, Guangzhou, Guangdong, China
| | - Huancun Feng
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Yuzhen Rao
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Tangyang Ji
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenya Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
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Wei L, Li Y, Chen J, Wang Y, Wu J, Yang H, Zhang Y. Alternative splicing in ovarian cancer. Cell Commun Signal 2024; 22:507. [PMID: 39425166 PMCID: PMC11488268 DOI: 10.1186/s12964-024-01880-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024] Open
Abstract
Ovarian cancer is the second leading cause of gynecologic cancer death worldwide, with only 20% of cases detected early due to its elusive nature, limiting successful treatment. Most deaths occur from the disease progressing to advanced stages. Despite advances in chemo- and immunotherapy, the 5-year survival remains below 50% due to high recurrence and chemoresistance. Therefore, leveraging new research perspectives to understand molecular signatures and identify novel therapeutic targets is crucial for improving the clinical outcomes of ovarian cancer. Alternative splicing, a fundamental mechanism of post-transcriptional gene regulation, significantly contributes to heightened genomic complexity and protein diversity. Increased awareness has emerged about the multifaceted roles of alternative splicing in ovarian cancer, including cell proliferation, metastasis, apoptosis, immune evasion, and chemoresistance. We begin with an overview of altered splicing machinery, highlighting increased expression of spliceosome components and associated splicing factors like BUD31, SF3B4, and CTNNBL1, and their relationships to ovarian cancer. Next, we summarize the impact of specific variants of CD44, ECM1, and KAI1 on tumorigenesis and drug resistance through diverse mechanisms. Recent genomic and bioinformatics advances have enhanced our understanding. By incorporating data from The Cancer Genome Atlas RNA-seq, along with clinical information, a series of prognostic models have been developed, which provided deeper insights into how the splicing influences prognosis, overall survival, the immune microenvironment, and drug sensitivity and resistance in ovarian cancer patients. Notably, novel splicing events, such as PIGV|1299|AP and FLT3LG|50,941|AP, have been identified in multiple prognostic models and are associated with poorer and improved prognosis, respectively. These novel splicing variants warrant further functional characterization to unlock the underlying molecular mechanisms. Additionally, experimental evidence has underscored the potential therapeutic utility of targeting alternative splicing events, exemplified by the observation that knockdown of splicing factor BUD31 or antisense oligonucleotide-induced BCL2L12 exon skipping promotes apoptosis of ovarian cancer cells. In clinical settings, bevacizumab, a humanized monoclonal antibody that specifically targets the VEGF-A isoform, has demonstrated beneficial effects in the treatment of patients with advanced epithelial ovarian cancer. In conclusion, this review constitutes the first comprehensive and detailed exposition of the intricate interplay between alternative splicing and ovarian cancer, underscoring the significance of alternative splicing events as pivotal determinants in cancer biology and as promising avenues for future diagnostic and therapeutic intervention.
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Affiliation(s)
- Liwei Wei
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, 300072, China
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310030, China
| | - Yisheng Li
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310030, China
| | - Jiawang Chen
- Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, 325101, China
| | - Yuanmei Wang
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310030, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianmin Wu
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310030, China
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Huanming Yang
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310030, China.
| | - Yi Zhang
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310030, China.
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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Shen J, Shentu J, Zhong C, Huang Q, Duan S. RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy. Clin Transl Med 2024; 14:e1788. [PMID: 39243148 PMCID: PMC11380049 DOI: 10.1002/ctm2.1788] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND Alternative splicing of pre-mRNA is a fundamental regulatory process in multicellular eukaryotes, significantly contributing to the diversification of the human proteome. RNA-binding fox-1 homologue 2 (RBFOX2), a member of the evolutionarily conserved RBFOX family, has emerged as a critical splicing regulator, playing a pivotal role in the alternative splicing of pre-mRNA. This review provides a comprehensive analysis of RBFOX2, elucidating its splicing activity through direct and indirect binding mechanisms. RBFOX2 exerts substantial influence over the alternative splicing of numerous transcripts, thereby shaping essential cellular processes such as differentiation and development. MAIN BODY OF THE ABSTRACT Dysregulation of RBFOX2-mediated alternative splicing has been closely linked to a spectrum of cardiovascular diseases and malignant tumours, underscoring its potential as a therapeutic target. Despite significant progress, current research faces notable challenges. The complete structural characterisation of RBFOX2 remains elusive, limiting in-depth exploration beyond its RNA-recognition motif. Furthermore, the scarcity of studies focusing on RBFOX2-targeting drugs poses a hindrance to translating research findings into clinical applications. CONCLUSION This review critically assesses the existing body of knowledge on RBFOX2, highlighting research gaps and limitations. By delineating these areas, this analysis not only serves as a foundational reference for future studies but also provides strategic insights for bridging these gaps. Addressing these challenges will be instrumental in unlocking the full therapeutic potential of RBFOX2, paving the way for innovative and effective treatments in various diseases.
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Affiliation(s)
- Jinze Shen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouChina
| | - Jianqiao Shentu
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouChina
| | - Chenming Zhong
- Medical Genetics Center, School of MedicineNingbo UniversityNingboChina
| | - Qiankai Huang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouChina
| | - Shiwei Duan
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouChina
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Zhang YE, Stuelten CH. Alternative splicing in EMT and TGF-β signaling during cancer progression. Semin Cancer Biol 2024; 101:1-11. [PMID: 38614376 PMCID: PMC11180579 DOI: 10.1016/j.semcancer.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 11/20/2023] [Accepted: 04/04/2024] [Indexed: 04/15/2024]
Abstract
Epithelial to mesenchymal transition (EMT) is a physiological process during development where epithelial cells transform to acquire mesenchymal characteristics, which allows them to migrate and colonize secondary tissues. Many cellular signaling pathways and master transcriptional factors exert a myriad of controls to fine tune this vital process to meet various developmental and physiological needs. Adding to the complexity of this network are post-transcriptional and post-translational regulations. Among them, alternative splicing has been shown to play important roles to drive EMT-associated phenotypic changes, including actin cytoskeleton remodeling, cell-cell junction changes, cell motility and invasiveness. In advanced cancers, transforming growth factor-β (TGF-β) is a major inducer of EMT and is associated with tumor cell metastasis, cancer stem cell self-renewal, and drug resistance. This review aims to provide an overview of recent discoveries regarding alternative splicing events and the involvement of splicing factors in the EMT and TGF-β signaling. It will emphasize the importance of various splicing factors involved in EMT and explore their regulatory mechanisms.
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Affiliation(s)
- Ying E Zhang
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
| | - Christina H Stuelten
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Underlying mechanisms of epithelial splicing regulatory proteins in cancer progression. J Mol Med (Berl) 2022; 100:1539-1556. [PMID: 36163376 DOI: 10.1007/s00109-022-02257-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/31/2022] [Accepted: 09/12/2022] [Indexed: 12/14/2022]
Abstract
Cancer is the second-leading disease-related cause of global mortality after cardiovascular disease. Despite significant advances in cancer therapeutic strategies, cancer remains one of the major obstacles to human life extension. Cancer pathogenesis is extremely complicated and not fully understood. Epithelial splicing regulatory proteins (ESRPs), including ESRP1 and ESRP2, belong to the heterogeneous nuclear ribonucleoprotein family of RNA-binding proteins and are crucial regulators of the alternative splicing of messenger RNAs (mRNAs). The expression and activity of ESRPs are modulated by various mechanisms, including post-translational modifications and non-coding RNAs. Although a growing body of evidence suggests that ESRP dysregulation is closely associated with cancer progression, the detailed mechanisms remain inconclusive. In this review, we summarize recent findings on the structures, functions, and regulatory mechanisms of ESRPs and focus on their underlying mechanisms in cancer progression. We also highlight the clinical implications of ESRPs as prognostic biomarkers and therapeutic targets in cancer treatment. The information reviewed herein could be extremely beneficial to the development of individualized therapeutic strategies for cancer patients.
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Gallerani G, Rossi T, Valgiusti M, Angeli D, Fici P, De Fanti S, Bandini E, Cocchi C, Frassineti GL, Bonafè M, Fabbri F. CNA Profiling of Single CTCs in Locally Advanced Esophageal Cancer Patients during Therapy Highlights Unexplored Molecular Pathways. Cancers (Basel) 2021; 13:6369. [PMID: 34944989 PMCID: PMC8699413 DOI: 10.3390/cancers13246369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Here, we monitored the evolution of CTCs spread in 11 patients affected by locally advanced EC who were undergoing therapy. METHODS In this perspective study, we designed multiple blood biopsies from individual patients: before and after neoadjuvant chemo-radio therapy and after surgery. We developed a multi-target array, named Grab-all assay, to estimate CTCs for their epithelial (EpCAM/E-Cadherin/Cytokeratins) and mesenchymal/stem (N-Cadherin/CD44v6/ABCG2) phenotypes. Identified CTCs were isolated as single cells by DEPArray, subjected to whole genome amplification, and copy number aberration (CNA) profiles were determined. Through bioinformatic analysis, we assessed the genomic imbalance of single CTCs, investigated specific focal copy number changes previously reported in EC and aberrant pathways using enrichment analysis. RESULTS Longitudinal monitoring allowed the identification of CTCs in at least one time-point per patient. Through single cell CNA analysis, we revealed that CTCs showed significantly dynamic genomic imbalance during treatment. Individual CTCs from relapsed patients displayed a higher degree of genomic imbalance relative to disease-free patients' groups. Genomic aberrations previously reported in EC occurred mostly in post-neoadjuvant therapy CTCs. In-depth analysis showed that networks enrichment in all time-point CTCs were inherent to innate immune system. Transcription/gene regulation, post-transcriptional and epigenetic modifications were uniquely affected in CTCs of relapsed patients. CONCLUSIONS Our data add clues to the comprehension of the role of CTCs in EC aggressiveness: chromosomal aberrations on genes related to innate immune system behave as relevant to the onset of CTC-status, whilst pathways of transcription/gene regulation, post-transcriptional and epigenetic modifications seem linked to patients' outcome.
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Affiliation(s)
- Giulia Gallerani
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (T.R.); (P.F.); (E.B.); (C.C.); (F.F.)
| | - Tania Rossi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (T.R.); (P.F.); (E.B.); (C.C.); (F.F.)
| | - Martina Valgiusti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.V.); (G.L.F.)
| | - Davide Angeli
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Pietro Fici
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (T.R.); (P.F.); (E.B.); (C.C.); (F.F.)
| | - Sara De Fanti
- Interdepartmental Centre “Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)”, University of Bologna, 40126 Bologna, Italy;
| | - Erika Bandini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (T.R.); (P.F.); (E.B.); (C.C.); (F.F.)
| | - Claudia Cocchi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (T.R.); (P.F.); (E.B.); (C.C.); (F.F.)
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.V.); (G.L.F.)
| | - Massimiliano Bonafè
- Department of Experimental and Diagnostic Medicine, University of Bologna, 40126 Bologna, Italy;
| | - Francesco Fabbri
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (T.R.); (P.F.); (E.B.); (C.C.); (F.F.)
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Ashok C, Ahuja N, Natua S, Mishra J, Samaiya A, Shukla S. E2F1 and epigenetic modifiers orchestrate breast cancer progression by regulating oxygen-dependent ESRP1 expression. Oncogenesis 2021; 10:58. [PMID: 34362878 PMCID: PMC8346533 DOI: 10.1038/s41389-021-00347-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 07/16/2021] [Accepted: 07/26/2021] [Indexed: 02/07/2023] Open
Abstract
Epithelial splicing regulatory protein 1 (ESRP1) is an RNA binding protein that governs the alternative splicing events related to epithelial phenotypes. ESRP1 contributes significantly at different stages of cancer progression. ESRP1 expression is substantially elevated in carcinoma in situ compared to the normal epithelium, whereas it is drastically ablated in cancer cells within hypoxic niches, which promotes epithelial to mesenchymal transition (EMT). Although a considerable body of research sought to understand the EMT-associated ESRP1 downregulation, the regulatory mechanisms underlying ESRP1 upregulation in primary tumors remained largely uncharted. This study seeks to unveil the regulatory mechanisms that spatiotemporally fine-tune the ESRP1 expression during breast carcinogenesis. Our results reveal that an elevated expression of transcription factor E2F1 and increased CpG hydroxymethylation of the E2F1 binding motif conjointly induce ESRP1 expression in breast carcinoma. However, E2F1 fails to upregulate ESRP1 despite its abundance in oxygen-deprived breast cancer cells. Mechanistically, impelled by the hypoxia-driven reduction of tet methylcytosine dioxygenase 3 (TET3) activity, CpG sites across the E2F1 binding motif lose the hydroxymethylation marks while gaining the de novo methyltransferase-elicited methylation marks. These two oxygen-sensitive epigenetic events work in concert to repel E2F1 from the ESRP1 promoter, thereby diminishing ESRP1 expression under hypoxia. Furthermore, E2F1 skews the cancer spliceome by upregulating splicing factor SRSF7 in hypoxic breast cancer cells. Our findings provide previously unreported mechanistic insights into the plastic nature of ESRP1 expression and insinuate important implications in therapeutics targeting breast cancer progression.
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Affiliation(s)
- Cheemala Ashok
- grid.462376.20000 0004 1763 8131Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh India
| | - Neha Ahuja
- grid.462376.20000 0004 1763 8131Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh India
| | - Subhashis Natua
- grid.462376.20000 0004 1763 8131Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh India
| | - Jharna Mishra
- Department of Pathology, Bansal Hospital, Bhopal, Madhya Pradesh India
| | - Atul Samaiya
- Department of Surgical Oncology, Bansal Hospital, Bhopal, Madhya Pradesh India
| | - Sanjeev Shukla
- grid.462376.20000 0004 1763 8131Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh India
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Chakraborty P, Chen EL, McMullen I, Armstrong AJ, Kumar Jolly M, Somarelli JA. Analysis of immune subtypes across the epithelial-mesenchymal plasticity spectrum. Comput Struct Biotechnol J 2021; 19:3842-3851. [PMID: 34306571 PMCID: PMC8283019 DOI: 10.1016/j.csbj.2021.06.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022] Open
Abstract
Epithelial-mesenchymal plasticity plays a critical role in many solid tumor types as a mediator of metastatic dissemination and treatment resistance. In addition, there is also a growing appreciation that the epithelial/mesenchymal status of a tumor plays a role in immune evasion and immune suppression. A deeper understanding of the immunological features of different tumor types has been facilitated by the availability of large gene expression datasets and the development of methods to deconvolute bulk RNA-Seq data. These resources have generated powerful new ways of characterizing tumors, including classification of immune subtypes based on differential expression of immunological genes. In the present work, we combine scoring algorithms to quantify epithelial-mesenchymal plasticity with immune subtype analysis to understand the relationship between epithelial plasticity and immune subtype across cancers. We find heterogeneity of epithelial-mesenchymal transition (EMT) status both within and between cancer types, with greater heterogeneity in the expression of EMT-related factors than of MET-related factors. We also find that specific immune subtypes have associated EMT scores and differential expression of immune checkpoint markers.
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Affiliation(s)
- Priyanka Chakraborty
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | | | | | - Andrew J. Armstrong
- Department of Medicine, Durham, NC, United Kingdom
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, United Kingdom
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, United Kingdom
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Jason A. Somarelli
- Department of Medicine, Durham, NC, United Kingdom
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, United Kingdom
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10
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Guan X, Li C, Li Y, Wang J, Yi Z, Liu B, Chen H, Xu J, Qian H, Xu B, Ma F. Epithelial-Mesenchymal-Transition-Like Circulating Tumor Cell-Associated White Blood Cell Clusters as a Prognostic Biomarker in HR-Positive/HER2-Negative Metastatic Breast Cancer. Front Oncol 2021; 11:602222. [PMID: 34150608 PMCID: PMC8208036 DOI: 10.3389/fonc.2021.602222] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
Background Although positive Circulating tumor cells (CTCs) status has been validated as a prognostic marker in breast cancer, the interaction between immune cells and CTCs during the progress of Epithelial-mesenchymal-transition (EMT), and the clinical implications of CTC-associated white blood cell clusters (CTC-WBC clusters) for metastatic breast cancer are largely uncharacterized. Methods We optimized a filter-based method combined with an RNA in situ hybridization technique according to the epithelial- and mesenchymal-markers to analyze EMT in CTC-WBC clusters. Serial peripheral blood samples from 135 patients with Hormone receptor (HR)-positive/HER2-negative metastatic breast cancer receiving first-line chemotherapy with docetaxel plus capecitabine were prospectively collected until disease progression from Nov 2013 to March 2019. Follow-up data collection was conducted until July 2020. Results A total of 452 blood samples at all time-points were collected and analyzed. Median age of the cohort was 51.0 years (range, 27 to 73 years), and most of them (76.3%) had visceral metastases. Median progression-free survival (PFS) was 10.6 months (95% CI, 8.8 to 12.3 months). The presence of EMT-like CTC-WBC clusters was more frequently evident among patients with simultaneous bone and lymph node metastases (87.5% vs 36.2%, P=0.006), whereas no associations were observed between CTC-WBC clusters and other clinicopathologic characteristics before chemotherapy. The patients with EMT-like CTC-WBC clusters tended to show a significantly increased number of total CTC count (median,19.0 vs 5.0, P<0.001). The patients with at least one detectable EMT-like CTC-WBC cluster at baseline were characterized by significantly worse PFS, when compared to the patients with no EMT-like CTC-WBC clusters detected (7.0 vs 10.7 months, P=0.023), and those with five or more epithelial-based CTCs detected per 5mL of peripheral blood (7.0 vs 12.7 months, P=0.014). However, the total CTC-WBC clusters were not correlated with patients' survival in the cohort (8.4 vs 10.6 months, P=0.561). Conclusions Our data provide evidence that the emergence of CTC-WBC clusters underwent EMT before treatment is associated with significantly poorer PFS in HR-positive/HER2-negative metastatic breast cancer patients receiving docetaxel plus capecitabine, which may be used as a parameter to predict the clinical outcomes and a potential target for individualized therapy.
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Affiliation(s)
- Xiuwen Guan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunxiao Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiqun Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiani Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zongbi Yi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Binliang Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongyan Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | - Haili Qian
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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11
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Stinnesbeck M, Kristiansen A, Ellinger J, Hauser S, Egevad L, Tolkach Y, Kristiansen G. Prognostic role of TSPAN1, KIAA1324 and ESRP1 in prostate cancer. APMIS 2021; 129:204-212. [PMID: 33455017 PMCID: PMC7986212 DOI: 10.1111/apm.13117] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 01/08/2021] [Indexed: 12/20/2022]
Abstract
The aim of this study was to validate prostate cancer‐associated genes on transcript level and to assess the prognostic value of the most promising markers by immunohistochemistry. Based on differentially expressed genes found in a previous study, 84 genes were further validated using mRNA expression data and follow‐up information from the Cancer Genome Atlas (TCGA) prostate cancer cohort (n = 497). Immunohistochemistry was used for validation of three genes in an independent, clinically annotated prostatectomy patient cohort (n = 175) with biochemical relapse as endpoint. Also, associations with clinicopathological variables were evaluated. Eleven protein‐coding genes from the list of 84 genes were associated with biochemical recurrence‐free survival on mRNA expression level in multivariate Cox‐analyses. Three of these genes (TSPAN1, ESRP1 and KIAA1324) were immunohistochemically validated using an independent cohort of prostatectomy patients. Both ESRP1 and KIAA1324 were independently associated with biochemical recurrence‐free survival. TSPAN1 was univariately prognostic but failed significance on multivariate analysis, probably due to its strong correlation with high Gleason scores. Multistep filtering using the publicly available TCGA cohort, data of an earlier expression profiling study which profiled 3023 cancer‐associated transcripts in 42 primary prostate cancer cases, identified two novel candidate prognostic markers (ESRP1 and KIAA1324) of primary prostate cancer for further study.
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Affiliation(s)
| | - Anna Kristiansen
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Jörg Ellinger
- Clinic of Urology, University Hospital Bonn, Bonn, Germany
| | - Stefan Hauser
- Clinic of Urology, University Hospital Bonn, Bonn, Germany
| | - Lars Egevad
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Yuri Tolkach
- Institute of Pathology, University Hospital Bonn, Bonn, Germany.,Institute of Pathology, University Hospital Cologne, Cologne, Germany
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12
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Alternative splicing modulates cancer aggressiveness: role in EMT/metastasis and chemoresistance. Mol Biol Rep 2021; 48:897-914. [PMID: 33400075 DOI: 10.1007/s11033-020-06094-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/15/2020] [Indexed: 12/11/2022]
Abstract
Enhanced metastasis and disease recurrence accounts for the high mortality rates associated with cancer. The process of Epithelial-Mesenchymal Transition (EMT) contributes towards the augmentation of cancer invasiveness along with the gain of stem-like and the subsequent drug-resistant behavior. Apart from the well-established transcriptional regulation, EMT is also controlled post-transcriptionally by virtue of alternative splicing (AS). Numerous genes including Fibroblast Growth Factor receptor (FGFR) as well as CD44 are differentially spliced during this trans-differentiation process which, in turn, governs cancer progression. These splicing alterations are controlled by various splicing factors including ESRP, RBFOX2 as well as hnRNPs. Here, we have depicted the mechanisms governing the splice isoform switching of FGFR and CD44. Moreover, the role of the splice variants generated by AS of these gene transcripts in modulating the metastatic potential and stem-like/chemoresistant behavior of cancer cells has also been highlighted. Additionally, the involvement of splicing factors in regulating EMT/invasiveness along with drug-resistance as well as the metabolic properties of the cells has been emphasized. Tumorigenesis is accompanied by a remodeling of the cellular splicing profile generating diverse protein isoforms which, in turn, control the cancer-associated hallmarks. Therefore, we have also briefly discussed about a wide variety of genes which are differentially spliced in the tumor cells and promote cancer progression. We have also outlined different strategies for targeting the tumor-associated splicing events which have shown promising results and therefore this approach might be useful in developing therapies to reduce cancer aggressiveness in a more specific manner.
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13
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Faux MC, King LE, Kane SR, Love C, Sieber OM, Burgess AW. APC regulation of ESRP1 and p120-catenin isoforms in colorectal cancer cells. Mol Biol Cell 2020; 32:120-130. [PMID: 33237836 PMCID: PMC8120691 DOI: 10.1091/mbc.e20-05-0321] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The adenomatous polyposis coli (APC) tumor suppressor protein is associated with the regulation of Wnt signaling; however, APC also controls other cellular processes including the regulation of cell adhesion and migration. The expression of full-length APC in SW480 colorectal cancer cells (SW480+APC) not only reduces Wnt signaling, but increases membrane E-cadherin and restores cell–cell adhesion. This report describes the effects of full-length, wild-type APC (fl-APC) on cell–cell adhesion genes and p120-catenin isoform switching in SW480 colon cancer cells: fl-APC increased the expression of genes implicated in cell–cell adhesion, whereas the expression of negative regulators of E-cadherin was decreased. Analysis of cell–cell adhesion-related proteins in SW480+APC cells revealed an increase in p120-catenin isoform 3A; similarly, depletion of APC altered the p120-catenin protein isoform profile. Expression of ESRP1 (epithelial splice regulatory protein 1) is increased in SW480+APC cells, and its depletion results in reversion to the p120-catenin isoform 1A phenotype and reduced cell–cell adhesion. The ESRP1 transcript is reduced in primary colorectal cancer, and its expression correlates with the level of APC. Pyrvinium pamoate, which inhibits Wnt signaling, promotes ESRP1 expression. We conclude that re-expression of APC restores the cell–cell adhesion gene and posttranscriptional regulatory programs leading to p120-catenin isoform switching and associated changes in cell–cell adhesion.
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Affiliation(s)
- Maree C Faux
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia
| | - Lauren E King
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia
| | - Serena R Kane
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia
| | - Christopher Love
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia
| | - Oliver M Sieber
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.,Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.,Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3052, Australia
| | - Antony W Burgess
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.,Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3052, Australia
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14
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LSM3, NDUFB3, and PTGS2 may be potential biomarkers for BRCA1-mutation positive breast cancer. REV ROMANA MED LAB 2020. [DOI: 10.2478/rrlm-2020-0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Purpose: We aimed to find critical biomakers associated with BRCA1-mutation positive breast cancer.
Methods: The data set E-MTAB-982 was downloaded from ArrayExpress database and the data were preprocessed using R package Oligo. Differential expression analysis between BRCA1-mutation positive breast cancer patients and BRCA1-mutation positive healthy subjects were performed using limma package. Then, gene set enrichment analysis was conducted. We constructed the network for BRCA1, its related differentially expressed genes (DEGs), and the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. After that, survival analysis was performed based on the clinical data of breast cancer in TCGA database. Finally, box diagram for key genes was drawn.
Results: The network showed that LSM3, NDUFB3, GNPDA2, and PTGS2 were BRCA1 related DEGs. Furthermore, LSM3 was mainly enriched in RNA degradation pathway and spliceosome pathway. PTGS2 was enriched in arachidonic acid metabolism and VEGF signaling pathway. Survival analysis indicated that high expression of LSM3 indicated a poor prognosis of BRCA1-mutant breast cancer. Besides, box diagram showed that LSM3 was down-regulated in BRCA1-mutation positive breast cancer patients compared with that in BRCA1-mutation positive healthy subjects.
Conclusions: LSM3, NDUFB3, and PTGS2 may be biomarkers in BRCA1-mutant breast cancer, and high expression of LSM3 may indicate a poor prognosis of BRCA1-mutant breast cancer.
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15
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Ahuja N, Ashok C, Natua S, Pant D, Cherian A, Pandkar MR, Yadav P, Vishnu NSS, Mishra J, Samaiya A, Shukla S. Hypoxia-induced TGF-β-RBFOX2-ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer. NAR Cancer 2020; 2:zcaa021. [PMID: 33089214 PMCID: PMC7116222 DOI: 10.1093/narcan/zcaa021] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hypoxic microenvironment heralds epithelial-mesenchymal transition (EMT), invasion and metastasis in solid tumors. Deregulation of alternative splicing (AS) of several cancer-associated genes has been instrumental in hypoxia-induced EMT. Our study in breast cancer unveils a previously unreported mechanism underlying hypoxia-mediated AS of hMENA, a crucial cytoskeleton remodeler during EMT. We report that the hypoxia-driven depletion of splicing regulator ESRP1 leads to skipping of hMENA exon 11a producing a pro-metastatic isoform, hMENAΔ11a. The transcriptional repression of ESRP1 is mediated by SLUG, which gets stimulated via hypoxia-driven TGF-β signaling. Interestingly, RBFOX2, an otherwise RNA-binding protein, is also found to transcriptionally repress ESRP1 while interacting with SLUG. Similar to SLUG, RBFOX2 gets upregulated under hypoxia via TGF-β signaling. Notably, we found that the exosomal delivery of TGF-β contributes to the elevation of TGF-β signaling under hypoxia. Moreover, our results show that in addition to hMENA, hypoxia-induced TGF-β signaling contributes to global changes in AS of genes associated with EMT. Overall, our findings reveal a new paradigm of hypoxia-driven AS regulation of hMENA and insinuate important implications in therapeutics targeting EMT.
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Affiliation(s)
- Neha Ahuja
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Cheemala Ashok
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Subhashis Natua
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Deepak Pant
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Anna Cherian
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Madhura R Pandkar
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Pooja Yadav
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Narayanan S S Vishnu
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
| | - Jharna Mishra
- Department of Pathology, Bansal Hospital, Bhopal, Madhya Pradesh 462016, India
| | - Atul Samaiya
- Department of Surgical Oncology, Bansal Hospital, Bhopal, Madhya Pradesh 462016, India
| | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India
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16
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Ancel J, Dewolf M, Deslée G, Nawrocky-Raby B, Dalstein V, Gilles C, Polette M. Clinical Impact of the Epithelial-Mesenchymal Transition in Lung Cancer as a Biomarker Assisting in Therapeutic Decisions. Cells Tissues Organs 2020; 211:91-109. [PMID: 32750701 DOI: 10.1159/000510103] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/11/2020] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is one of the most common solid cancers and represents the leading cause of cancer death worldwide. Over the last decade, research on the epithelial-mesenchymal transition (EMT) in lung cancer has gained increasing attention. Here, we review clinical and histological features of non-small-cell lung cancer associated with EMT. We then aimed to establish potential clinical implications of EMT in current therapeutic options, including surgery, radiation, targeted therapy against oncogenic drivers, and immunotherapy.
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Affiliation(s)
- Julien Ancel
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Service de Pneumologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Maxime Dewolf
- Service de Pneumologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Gaëtan Deslée
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Service de Pneumologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Béatrice Nawrocky-Raby
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France
| | - Véronique Dalstein
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Laboratoire de Pathologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Christine Gilles
- Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium,
| | - Myriam Polette
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Laboratoire de Pathologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
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17
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Genna A, Vanwynsberghe AM, Villard AV, Pottier C, Ancel J, Polette M, Gilles C. EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis. Cancers (Basel) 2020; 12:E1632. [PMID: 32575608 PMCID: PMC7352430 DOI: 10.3390/cancers12061632] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/11/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023] Open
Abstract
Epithelial-mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major EMT-driven properties that may help hybrid Epithelial/Mesenchymal CTCs to survive in the bloodstream and accomplish early phases of metastatic colonization. We then discuss how interrogating EMT in CTCs as a companion biomarker could help refine cancer patient management, further supporting the relevance of CTCs in personalized medicine.
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Affiliation(s)
- Anthony Genna
- GIGA-Cancer, Laboratory of Tumor and Development Biology, CHU Sart-Tilman, University of Liège, Pathology Tower, 4000 Liège, Belgium; (A.G.); (A.M.V.); (A.V.V.); (C.P.)
| | - Aline M. Vanwynsberghe
- GIGA-Cancer, Laboratory of Tumor and Development Biology, CHU Sart-Tilman, University of Liège, Pathology Tower, 4000 Liège, Belgium; (A.G.); (A.M.V.); (A.V.V.); (C.P.)
| | - Amélie V. Villard
- GIGA-Cancer, Laboratory of Tumor and Development Biology, CHU Sart-Tilman, University of Liège, Pathology Tower, 4000 Liège, Belgium; (A.G.); (A.M.V.); (A.V.V.); (C.P.)
| | - Charles Pottier
- GIGA-Cancer, Laboratory of Tumor and Development Biology, CHU Sart-Tilman, University of Liège, Pathology Tower, 4000 Liège, Belgium; (A.G.); (A.M.V.); (A.V.V.); (C.P.)
- Department of Medical Oncology, University Hospital of Liège, 4000 Liège, Belgium
| | - Julien Ancel
- CHU (Centre Hopitalier Universitaire) de Reims, Hôpital Maison Blanche, Service de Pneumologie, 51092 Reims, France;
- INSERM, UMR (Unité Mixte de Recherche)-S1250, SFR CAP-SANTE, Université de Reims Champagne-Ardenne, 51097 Reims, France;
| | - Myriam Polette
- INSERM, UMR (Unité Mixte de Recherche)-S1250, SFR CAP-SANTE, Université de Reims Champagne-Ardenne, 51097 Reims, France;
- CHU de Reims, Hôpital Maison Blanche, Laboratoire de Pathologie, 51092 Reims, France
| | - Christine Gilles
- GIGA-Cancer, Laboratory of Tumor and Development Biology, CHU Sart-Tilman, University of Liège, Pathology Tower, 4000 Liège, Belgium; (A.G.); (A.M.V.); (A.V.V.); (C.P.)
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18
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Splicing regulatory factors in breast cancer hallmarks and disease progression. Oncotarget 2019; 10:6021-6037. [PMID: 31666932 PMCID: PMC6800274 DOI: 10.18632/oncotarget.27215] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 08/29/2019] [Indexed: 12/31/2022] Open
Abstract
By regulating transcript isoform expression levels, alternative splicing provides an additional layer of protein control. Recent studies show evidence that cancer cells use different splicing events to fulfill their requirements in order to develop, progress and metastasize. However, there has been less attention for the role of the complex catalyzing the complicated multistep splicing reaction: the spliceosome. The spliceosome consists of multiple sub-complexes in total comprising 244 proteins or splice factors and 5 associated RNA molecules. Here we discuss the role of splice factors in the oncogenic processes tumors cells need to fulfill their oncogenic properties (the so-called the hallmarks of cancer). Despite the fact that splice factors have been investigated only recently, they seem to play a prominent role in already five hallmarks of cancer: angiogenesis, resisting cell death, sustaining proliferation, deregulating cellular energetics and invasion and metastasis formation by affecting major signaling pathways such as epithelial-to-mesenchymal transition, the Warburg effect, DNA damage response and hormone receptor dependent proliferation. Moreover, we could relate expression of representative genes of four other hallmarks (enabling replicative mortality, genomic instability, avoiding immune destruction and evading growth suppression) to splice factor levels in human breast cancer tumors, suggesting that also these hallmarks could be regulated by splice factors. Since many splice factors are involved in multiple hallmarks of cancer, inhibiting splice factors might provide a new layer of oncogenic control and a powerful method to combat breast cancer progression.
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19
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Su LL, Chang XJ, Zhou HD, Hou LB, Xue XY. Exosomes in esophageal cancer: A review on tumorigenesis, diagnosis and therapeutic potential. World J Clin Cases 2019; 7:908-916. [PMID: 31119136 PMCID: PMC6509264 DOI: 10.12998/wjcc.v7.i8.908] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/28/2019] [Accepted: 03/09/2019] [Indexed: 02/05/2023] Open
Abstract
Exosomes are nanovesicles secreted from various types of cells and can be isolated from various bodily fluids, such as blood and urine. The number and molecular contents, including proteins and RNA of exosomes, have been shown to reflect their parental cell origins, characteristics and biological behaviors. An increasing number of studies have demonstrated that exosomes play a role in the course of tumorigenesis, diagnosis, treatment and prognosis, although its precise functions in tumors are still unclear. Moreover, owing to a lack of a standard approach, exosomes and its contents have not yet been put into clinical practice successfully. This review aims to summarize the current knowledge on exosomes and its contents in esophageal cancer as well as the current limitations/challenges in its clinical application, which may provide a basis for an all-around understanding of the implementation of exosomes and exosomal contents in the surveillance and therapy of esophageal cancer.
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Affiliation(s)
- Lin-Lin Su
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Xiao-Jing Chang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Huan-Di Zhou
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Liu-Bing Hou
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Xiao-Ying Xue
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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20
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Meng X, Yang S, Zhang J, Yu H. Contribution of alternative splicing to breast cancer metastasis. JOURNAL OF CANCER METASTASIS AND TREATMENT 2019; 5:21. [PMID: 31737791 PMCID: PMC6857724 DOI: 10.20517/2394-4722.2018.96] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alternative splicing is a major contributor to transcriptome and proteome diversity in eukaryotes. Comparing to normal samples, about 30% more alternative splicing events were recently identified in 32 cancer types included in The Cancer Genome Atlas database. Some alternative splicing isoforms and their encoded proteins contribute to specific cancer hallmarks. In this review, we will discuss recent progress regarding the contributions of alternative splicing to breast cancer metastasis. We plan to dissect the role of MTDH, CD44 and their interaction with other mRNA splicing factors. We believe an in-depth understanding of the mechanism underlying the contribution of splicing to breast cancer metastasis will provide novel strategies to the management of breast cancer.
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Affiliation(s)
- Xiangbing Meng
- Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Shujie Yang
- Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Jun Zhang
- Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Huimin Yu
- Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Department of Pathogenic Biology, Shenzhen University School of medicine, Shenzhen 518060, China
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21
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Ju H, Li Y, Xing X, Miao X, Feng Y, Ren Y, Qin J, Liu D, Chen Z, Yang Z. Manganese-12 acetate suppresses the migration, invasion, and epithelial-mesenchymal transition by inhibiting Wnt/β-catenin and PI3K/AKT signaling pathways in breast cancer cells. Thorac Cancer 2018; 9:353-359. [PMID: 29316252 PMCID: PMC5832475 DOI: 10.1111/1759-7714.12584] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 11/29/2017] [Accepted: 12/01/2017] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Breast cancer is the leading cause of cancer-related death in the world, and it is of great value to reveal the molecular mechanisms of breast cancer progression and develop new therapeutic targets. METHODS Transwell assay is used to analyze the migration and invasion of breast cancer cells. Real-time PCR and western blotting assay are applied to detect the expression levels of epithelial-mesenchymal transition markers and the key members of Wnt/β-catenin and PI3K/AKT signaling pathways. RESULTS Manganese-12 acetate (Mn12Ac) significantly inhibited the migration and invasion of MCF7 and MDA-MB-231 breast cancer cells. Western blotting assay further showed that Mn12Ac significantly upregulated E-cadherin, and downregulated N-cadherin and vimentin. We further found that Mn12Ac reduced the mRNA expressions of epithelial-mesenchymal transition-associated transcription factors snail, slug, twist1, and ZEB1 using real-time PCR assay. Importantly, we further found that Mn12Ac significantly reduced the Wnt1 and β-catenin protein expressions, and suppressed the phosphorylation of PI3K and AKT in MCF7 and MDA-MB-231 breast cancer cells. Very interestingly, we also showed that Mn12Ac decreased the mRNA and protein expressions of programmed cell death ligand 1. CONCLUSION Taken together, our results suggested that Mn12Ac inhibited the migration, invasion, and epithelial-mesenchymal transition by regulating Wnt/β-catenin and PI3K/AKT signaling pathways in breast cancer.
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Affiliation(s)
- Hongping Ju
- School of MedicineKunming UniversityKunmingChina
| | - Yongxia Li
- The Department of Respiratory Medicine, Second WardThe Second Affiliated Hospital of Kunming Medical UniversityKunmingChina
| | - Xiqian Xing
- The First Department of Respiratory MedicineYan'an Hospital Affiliated to Kunming Medical UniversityKunmingChina
| | - Xisong Miao
- School of MedicineKunming UniversityKunmingChina
| | - Yunping Feng
- School of MedicineKunming UniversityKunmingChina
| | - Yunhui Ren
- School of MedicineKunming UniversityKunmingChina
| | - Jing Qin
- School of MedicineKunming UniversityKunmingChina
| | - Dian Liu
- School of MedicineKunming UniversityKunmingChina
| | - Zihao Chen
- The Graduate SchoolHebei Medical UniversityShijiazhuangChina
| | - Zhaoyu Yang
- School of MedicineKunming UniversityKunmingChina
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22
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Marques DS, Grativol J, Alves da Silva Peres R, da Rocha Matos A, Gimba ERP. Osteopontin-c isoform levels are associated with SR and hnRNP differential expression in ovarian cancer cell lines. Tumour Biol 2017; 39:1010428317725442. [PMID: 28936921 DOI: 10.1177/1010428317725442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Osteopontin-c splicing isoform activates ovarian cancer progression features. Imbalanced expression of splicing factors from serine/arginine -rich and heterogeneous ribonucleoproteins families has been correlated with the generation of oncogenic splicing isoforms. Our goal was to investigate whether there is any association between the transcriptional patterns of these splicing factors in ovarian cells and osteopontin-c expression levels. We also aimed to investigate the occurrence of these splicing factors binding sites inside osteopontin exon 4 and adjacent introns. To test associations between osteopontin-c and splicing factors expression patterns, we used an in vitro model in which OVCAR-3 cells overexpressing osteopontin-c (OVCAR-3/OPNc++) presented higher transcriptional levels of osteopontin-c than two other ovarian carcinoma cells (TOV-112D, SKOV-3) and ovarian non-tumoral cell lines (IOSE 364 and IOSE 385). The transcriptional levels of osteopontin-c, serine/arginine-rich, and hnRNP factors were evaluated using real-time polymerase chain reaction. Human Splice Finder software was used to search for putative splicing factor binding sites in osteopontin genomic regions. OVCAR-3/OPNc++ cells presented higher transcriptional levels of hnRNP than serine/arginine-rich when compared to TOV-112D, SKOV-3, and IOSE cells. TOV-112D and SKOV-3 cells also overexpressed hnRNP in relation to serine/arginine-rich transcripts. Putative binding sites for these splicing factors have been predicted on osteopontin exon 4 and their upstream and downstream intronic regions. Our data showed that higher osteopontin-c expression levels are associated with a predominance of hnRNP in relation to serine/arginine-rich transcripts and that osteopontin exon 4 and adjacent intronic sequences contain predicted binding sites for some of these tested splicing factors. In conclusion, differential expression of these splicing factors in ovarian cancer cells could be one of the putative mechanisms leading to aberrant splicing of the osteopontin primary transcript. Future work, aiming to control ovarian cancer progression by downregulating osteopontin-c levels, could include strategies that also regulate heterogeneous ribonucleoproteins and serine/arginine-rich expression levels in order to modulate osteopontin splicing.
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Affiliation(s)
- Durval Santos Marques
- 1 Programa de Pós Graduação em Ciências Biomédicas (Fisiologia e Farmacologia), Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - Jessica Grativol
- 2 Curso de Graduação em Enfermagem, Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | | | - Aline da Rocha Matos
- 3 Laboratório de Vírus Respiratórios e do Sarampo, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil
| | - Etel Rodrigues Pereira Gimba
- 4 Departamento de Ciências da Natureza (RCN), Instituto de Humanidades e Saúde (IHS), Universidade Federal Fluminense, Rio de Janeiro, Brazil.,5 Coordenação de Pesquisa, Programa de Pós Graduação Stricto Sensu em Oncologia do INCa, Instituto Nacional de Câncer (INCa), Rio de Janeiro, Brazil
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23
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Liang Z, Lu L, Mao J, Li X, Qian H, Xu W. Curcumin reversed chronic tobacco smoke exposure induced urocystic EMT and acquisition of cancer stem cells properties via Wnt/β-catenin. Cell Death Dis 2017; 8:e3066. [PMID: 28981096 PMCID: PMC5680574 DOI: 10.1038/cddis.2017.452] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/03/2017] [Accepted: 08/04/2017] [Indexed: 12/17/2022]
Abstract
Tobacco smoke (TS) is the most important single risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a transdifferentiation process, involved in the initiation of TS-related cancer. Cancer stem cells (CSCs) have an essential role in the progression of many tumors including TS-related cancer. However, the molecular mechanisms of TS exposure induced urocystic EMT and acquisition of CSCs properties remains undefined. Wnt/β-catenin pathway is critical for EMT and the maintenance of CSCs. The aim of our present study was to investigate the role of Wnt/β-catenin pathway in chronic TS exposure induced urocystic EMT, stemness acquisition and the preventive effect of curcumin. Long time TS exposure induced EMT changes and the levels of CSCs' markers were significant upregulated. Furthermore, we demonstrated that Wnt/β-catenin pathway modulated TS-triggered EMT and stemness, as evidenced by the findings that TS elevated Wnt/β-catenin activation, and that TS-mediated EMT and stemness were attenuated by Wnt/β-catenin inhibition. Treatment of curcumin reversed TS-elicited activation of Wnt/β-catenin, EMT and CSCs properties. Collectively, these data indicated the regulatory role of Wnt/β-catenin in TS-triggered urocystic EMT, acquisition of CSCs properties and the chemopreventive effect of curcumin.
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Affiliation(s)
- Zhaofeng Liang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ling Lu
- Department of Children's Health Care, Women and Children Health Hospital of Zhenjiang, Jiangsu Province, Zhenjiang, China
| | - Jiahui Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xia Li
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
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Wang Y, Geng H, Zhao L, Zhang Z, Xie D, Zhang T, Min J, Yu D, Zhong C. Role of AP-1 in the tobacco smoke-induced urocystic abnormal cell differentiation and epithelial-mesenchymal transition in vivo. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:8243-8252. [PMID: 31966675 PMCID: PMC6965368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 05/27/2017] [Indexed: 06/10/2023]
Abstract
Bladder cancer is believed to arise after a series of progressive pathological changes. Cell differentiation exists in almost all cells, when become aberrant, can initiate or promote diseases processes and tumorigenesis. Epithelial-mesenchymal transition (EMT) is a crucial pathophysiological process in cancer initiation and development. Tobacco smoke is an important risk factor of bladder cancer. However, the molecular mechanisms of tobacco smoke-triggered abnormal cell differentiation and EMT in bladder tissues have not been well defined. The current study was designed to investigate the regulatory role of AP-1 in tobacco smoke-triggered urocystic abnormal cell differentiation and EMT in vivo. Exposure of male BALB/c mice to tobacco smoke for 12 weeks altered the expression of cell differentiation and EMT markers in bladder tissues. Importantly, we demonstrated that AP-1 modulated tobacco smoke-induced abnormal cell differentiation and EMT, as evidenced by the findings that tobacco smoke elevated AP-1 activation, and tobacco smoke-mediated cell differentiation and EMT were reversed by AP-1 suppression. These data indicated that AP-1 play an important role in tobacco smoke-induced urocystic abnormal cell differentiation and EMT. These findings provide new insights into the mechanism of tobacco smoke associated urocystic tumorigenesis and may help to discover potential targets for novel therapies and chemoprevention.
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Affiliation(s)
- Yi Wang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Hao Geng
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Li Zhao
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Zhiqiang Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Dongdong Xie
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Tao Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Jie Min
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Dexin Yu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical UniversityHefei 230032, China
| | - Caiyun Zhong
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical UniversityNanjing 211166, China
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Santamaria PG, Moreno‐Bueno G, Portillo F, Cano A. EMT: Present and future in clinical oncology. Mol Oncol 2017; 11:718-738. [PMID: 28590039 PMCID: PMC5496494 DOI: 10.1002/1878-0261.12091] [Citation(s) in RCA: 189] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/31/2017] [Accepted: 06/02/2017] [Indexed: 12/12/2022] Open
Abstract
Epithelial/mesenchymal transition (EMT) has emerged as a key regulator of metastasis by facilitating tumor cell invasion and dissemination to distant organs. Recent evidences support that the reverse mesenchymal/epithelial transition (MET) is required for metastatic outgrowth; moreover, the existence of hybrid epithelial/mesenchymal (E/M) phenotypes is increasingly being reported in different tumor contexts. The accumulated data strongly support that plasticity between epithelial and mesenchymal states underlies the dissemination and metastatic potential of carcinoma cells. However, the translation into the clinics of EMT and epithelial plasticity processes presents enormous challenges and still remains a controversial issue. In this review, we will evaluate current evidences for translational applicability of EMT and depict an overview of the most recent EMT in vivo models, EMT marker analyses in human samples as well as potential EMT therapeutic approaches and ongoing clinical trials. We foresee that standardized analyses of EMT markers in solid and liquid tumor biopsies in addition to innovative tools targeting the E/M states will become promising strategies for future translation to the clinical setting.
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Affiliation(s)
- Patricia G. Santamaria
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
| | - Gema Moreno‐Bueno
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
- Fundación MD Anderson InternationalMadridSpain
| | - Francisco Portillo
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
| | - Amparo Cano
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
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26
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Xiping Z, Qingshan W, Shuai Z, Hongjian Y, Xiaowen D. A summary of relationships between alternative splicing and breast cancer. Oncotarget 2017; 8:51986-51993. [PMID: 28881705 PMCID: PMC5584306 DOI: 10.18632/oncotarget.17727] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/05/2017] [Indexed: 12/13/2022] Open
Abstract
Alternative splicing (AS) is the process of combinatorial rearrangement of parts of exons, and/or parts of introns into mature RNA to result in a multitude of transcripts. AS is a biological process through which organisms produce as many protein variants as possible by a limited genetic resource. It plays an important role in growth and development of the organisms. Over the past few years, alternative splicing has been discovered to be critical for genesis and development of malignant tumors, including breast cancer. If the relationships between AS and breast cancer can be discussed more deeply, it will be helpful for better diagnosis, judging prognosis and intervening with breast cancer. In this paper, the relationships between AS and breast cancer are elaborated from different angles, in hope that this summary is beneficial for readers to understand the roles of AS and breast cancer.
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Affiliation(s)
- Zhang Xiping
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, China
| | - Wei Qingshan
- Cataloging Department, Library of Xi'an Jiaotong University, Xi'an 710049, Shaanxi Province, China
| | - Zhao Shuai
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, China
| | - Yang Hongjian
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, China
| | - Ding Xiaowen
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, China
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