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Famta P, Shah S, Dey B, Kumar KC, Bagasariya D, Vambhurkar G, Pandey G, Sharma A, Srinivasarao DA, Kumar R, Guru SK, Raghuvanshi RS, Srivastava S. Despicable role of epithelial-mesenchymal transition in breast cancer metastasis: Exhibiting de novo restorative regimens. CANCER PATHOGENESIS AND THERAPY 2025; 3:30-47. [PMID: 39872366 PMCID: PMC11764040 DOI: 10.1016/j.cpt.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/03/2024] [Accepted: 01/10/2024] [Indexed: 01/30/2025]
Abstract
Breast cancer (BC) is the most prevalent cancer in women globally. Anti-cancer advancements have enabled the killing of BC cells through various therapies; however, cancer relapse is still a major limitation and decreases patient survival and quality of life. Epithelial-to-mesenchymal transition (EMT) is responsible for tumor relapse in several cancers. This highly regulated event causes phenotypic, genetic, and epigenetic changes in the tumor microenvironment (TME). This review summarizes the recent advancements regarding EMT using de-differentiation and partial EMT theories. We extensively review the mechanistic pathways, TME components, and various anti-cancer adjuvant and neo-adjuvant therapies responsible for triggering EMT in BC tumors. Information regarding essential clinical studies and trials is also discussed. Furthermore, we also highlight the recent strategies targeting various EMT pathways. This review provides a holistic picture of BC biology, molecular pathways, and recent advances in therapeutic strategies.
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Affiliation(s)
- Paras Famta
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Saurabh Shah
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Biswajit Dey
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Kondasingh Charan Kumar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Deepkumar Bagasariya
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Ganesh Vambhurkar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Giriraj Pandey
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Anamika Sharma
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Dadi A. Srinivasarao
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Rahul Kumar
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Santosh Kumar Guru
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | | | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
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Yang H, Gong C, Wu Y, Xie X, Chen Y, Li Z, Shi Q, Liu J, Gao N, He B, Wang C, Liao Q, Bai J, Xiao Y. LncRNA SNHG1 facilitates colorectal cancer cells metastasis by recruiting HNRNPD protein to stabilize SERPINA3 mRNA. Cancer Lett 2024; 604:217217. [PMID: 39233042 DOI: 10.1016/j.canlet.2024.217217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/20/2024] [Accepted: 08/31/2024] [Indexed: 09/06/2024]
Abstract
Metastasis continues to negatively impact individuals diagnosed with colorectal cancer (CRC). Research has revealed the important role of long noncoding RNAs (lncRNAs) in CRC metastasis, but the underlying mechanisms remain unclear. Here, we revealed that the lncRNA small nucleolar RNA host gene 1 (SNHG1) is expressed at higher levels in metastatic CRC tissues than in primary CRC tissues, and that high lncRNA SNHG1 expression indicates poor patient outcomes. We found that lncRNA SNHG1 promotes the migration and invasion of tumor cells both in vivo and in vitro. Moreover, lncRNA SNHG1 increases serpin family A member 3 (SERPINA3) mRNA stability by interacting with the heterogeneous nuclear ribonucleoprotein D (HNRNPD) protein, and subsequently upregulates SERPINA3 expression. Moreover, HNRNPD and SERPINA3 reversed the effects of lncRNA SNHG1 knockdown on CRC cell metastasis. In conclusion, we report that the lncRNA SNHG1 recruits HNRNPD, in turn upregulating SERPINA3 expression and ultimately facilitating CRC cell migration and invasion. Targeting the lncRNA SNHG1/HNRNPD/SERPINA3 signaling pathway might be a therapeutic option for preventing CRC metastasis.
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Affiliation(s)
- Huan Yang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Chunli Gong
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Yuyun Wu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Xia Xie
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Yang Chen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Zhibin Li
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Qiuyue Shi
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Guangxi, 530021, China
| | - Jiao Liu
- Department of Gastroenterology, General Hospital of Northern Theater Command, Liaoning, 110003, China
| | - Nannan Gao
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Bing He
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Chao Wang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Qiushi Liao
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Jianying Bai
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
| | - Yufeng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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Liu M, Song L, Lai Y, Gao F, Man J. LncRNA FEZF1-AS1 promotes pulmonary fibrosis via up-regulating EZH2 and targeting miR-200c-3p to regulate the ZEB1 pathway. Sci Rep 2024; 14:26044. [PMID: 39472569 PMCID: PMC11522518 DOI: 10.1038/s41598-024-74570-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 09/26/2024] [Indexed: 11/02/2024] Open
Abstract
The role and detailed mechanisms of lncRNAs in idiopathic pulmonary fibrosis (IPF) are not fully understood. qPCR was conducted to verify lncRNA FEZF1-AS1 expression in the transforming growth factor-beta 1 (TGF-β1)-stimulated human lung fibroblasts (HLF) and A549. The EMT-related proteins were performed by western blotting. Cell proliferation, migration, and transition were detected by CCK-8, colony formation, wound-healing and transwell assays. A dual-luciferase reporter assay was conducted to validate the target relationship of FEZF1-AS1 and miR-200c-3p. FEZF1-AS1 is highly expressed in the fibrotic A549 and HLF. in vitro experiments revealed that FEZF1-AS1 facilitates cell proliferation, migration and invasion. Knockdown of FEZF1-AS1 attenuated TGF-b1-induced fibrogenesis both in vitro. Moreover, silencing FEZF1-AS1 inhibited fibrogenesis through modulation of miR-200c-3p. In addition, inhibition of miR-200c-3p promoted fibrogenesis by regulation of Zinc finger E-box binding homeobox 1 (ZEB1). Mechanistically, FEZF1-AS1 promoted lung fibrosis by acting as a competing endogenous RNA (ceRNA) for miR-200c-3p. FEZF1-AS1 silencing increased the expression and activity of miR-200c-3p to inhibit ZEB1 and alleviate lung fibrogenesis in A549 and HLF. In addition, our study showed that FEZF1-AS1 can regulate enhancer of zeste homolog2 (EZH2) to upregulate fibrosis-related proteins and promote lung fibrosis. In summary, the results of our study revealed the pulmonary fibrogenic effect of FEZF1-AS1 in cellular experiments, demonstrating the potential roles and mechanisms of the FEZF1-AS1/miR-200c-3p/ZEB1 and FEZF1-AS1/EZH2 pathways, which provides a novel and potential therapeutic target to lung fibrosis.
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Affiliation(s)
- Mengmeng Liu
- Department of Clinical Laboratory, Affiliated Hospital of Shandong Second Medical University, No. 2428, Yuhe Road, Kuiwen District, Weifang City, 261041, Shandong Province, China
| | - Longfei Song
- Department of Rehabilitation Medicine, Affiliated Hospital of Shandong Second Medical University, No. 2428 Yuhe Road, Kuiwen District, Weifang City, 261041, Shandong Province, China
| | - Yuxin Lai
- Beijing University of Chinese Medicine, No. 11 on North 3rd Ring Road, Beijing, 100029, China
| | - Fusheng Gao
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Shandong Second Medical University, No. 2428, Yuhe Road, Kuiwen District, Weifang City, 261041, Shandong Province, China.
| | - Jun Man
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Shandong Second Medical University, No. 2428, Yuhe Road, Kuiwen District, Weifang City, 261041, Shandong Province, China.
- Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, No. 4948, Shengli East Street, Kuiwen District, Weifang City, 261041, Shandong Province, China.
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Gao L, Meng F, Yang Z, Lafuente-Merchan M, Fernández LM, Cao Y, Kusamori K, Nishikawa M, Itakura S, Chen J, Huang X, Ouyang D, Riester O, Deigner HP, Lai H, Pedraz JL, Ramalingam M, Cai Y. Nano-drug delivery system for the treatment of multidrug-resistant breast cancer: Current status and future perspectives. Biomed Pharmacother 2024; 179:117327. [PMID: 39216449 DOI: 10.1016/j.biopha.2024.117327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/11/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024] Open
Abstract
Breast cancer (BC) is one of the most frequently diagnosed cancers in women. Chemotherapy continues to be the treatment of choice for clinically combating it. Nevertheless, the chemotherapy process is frequently hindered by multidrug resistance, thereby impacting the effectiveness of the treatment. Multidrug resistance (MDR) refers to the phenomenon in which malignant tumour cells develop resistance to anticancer drugs after one single exposure. It can occur with a broad range of chemotherapeutic drugs with distinct chemical structures and mechanisms of action, and it is one of the major causes of treatment failure and disease relapse. Research has long been focused on overcoming MDR by using multiple drug combinations, but this approach is often associated with serious side effects. Therefore, there is a pressing need for in-depth research into the mechanisms of MDR, as well as the development of new drugs to reverse MDR and improve the efficacy of breast cancer chemotherapy. This article reviews the mechanisms of multidrug resistance and explores the application of nano-drug delivery system (NDDS) to overcome MDR in breast cancer. The aim is to offer a valuable reference for further research endeavours.
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Affiliation(s)
- Lanwen Gao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Lab of Traditional Chinese Medicine Information Technology / International Science and Technology Cooperation Base of Guangdong Province / School of Pharmacy, Jinan University, Guangdong, Guangzhou 510632, China.
| | - Fansu Meng
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China.
| | - Zhenjiang Yang
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China.
| | - Markel Lafuente-Merchan
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Laura Merino Fernández
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Ye Cao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Lab of Traditional Chinese Medicine Information Technology / International Science and Technology Cooperation Base of Guangdong Province / School of Pharmacy, Jinan University, Guangdong, Guangzhou 510632, China.
| | - Kosuke Kusamori
- Laboratory of Cellular Drug Discovery and Development, Faculty of Pharmaceutical Sciences Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
| | - Makiya Nishikawa
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
| | - Shoko Itakura
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
| | - Junqian Chen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
| | - Xiaoxun Huang
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China.
| | - Dongfang Ouyang
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston, MA 02129, USA.
| | - Oliver Riester
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Villingen-Schwenningen 78054, Germany.
| | - Hans-Peter Deigner
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Villingen-Schwenningen 78054, Germany.
| | - Haibiao Lai
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China.
| | - Jose Luis Pedraz
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain; Joint Research Laboratory (JRL) on Bioprinting and Advanced Pharma Development, A Joint Venture of TECNALIA (Basque Research and Technology Alliance), Centro de Investigación Lascaray Ikergunea, Avenida Miguel de Unamuno, Vitoria-Gasteiz 01006, Spain.
| | - Murugan Ramalingam
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain; Joint Research Laboratory (JRL) on Bioprinting and Advanced Pharma Development, A Joint Venture of TECNALIA (Basque Research and Technology Alliance), Centro de Investigación Lascaray Ikergunea, Avenida Miguel de Unamuno, Vitoria-Gasteiz 01006, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain; School of Basic Medical Sciences, Binzhou Medical University, Yantai 264003, China.
| | - Yu Cai
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Lab of Traditional Chinese Medicine Information Technology / International Science and Technology Cooperation Base of Guangdong Province / School of Pharmacy, Jinan University, Guangdong, Guangzhou 510632, China.
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5
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Lee G, Wong C, Cho A, West JJ, Crawford AJ, Russo GC, Si BR, Kim J, Hoffner L, Jang C, Jung M, Leone RD, Konstantopoulos K, Ewald AJ, Wirtz D, Jeong S. E-Cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer. Cancer Res 2024; 84:2820-2835. [PMID: 38959339 PMCID: PMC11374473 DOI: 10.1158/0008-5472.can-23-3082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 03/27/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
The loss of E-cadherin, an epithelial cell adhesion molecule, has been implicated in metastasis by mediating the epithelial-mesenchymal transition, which promotes invasion and migration of cancer cells. However, recent studies have demonstrated that E-cadherin supports the survival and proliferation of metastatic cancer cells. Here, we identified a metabolic role for E-cadherin in breast cancer by upregulating the de novo serine synthesis pathway (SSP). The upregulated SSP provided metabolic precursors for biosynthesis and resistance to oxidative stress, enabling E-cadherin+ breast cancer cells to achieve faster tumor growth and enhanced metastases. Inhibition of phosphoglycerate dehydrogenase, a rate-limiting enzyme in the SSP, significantly and specifically hampered proliferation of E-cadherin+ breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. These findings reveal that E-cadherin reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers. Significance: E-Cadherin promotes the progression and metastasis of breast cancer by upregulating the de novo serine synthesis pathway, offering promising targets for inhibiting tumor growth and metastasis in E-cadherin-expressing tumors.
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Affiliation(s)
- Geonhui Lee
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Claudia Wong
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Anna Cho
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Junior J. West
- Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Ashleigh J. Crawford
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Gabriella C. Russo
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Bishwa Ranjan Si
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Jungwoo Kim
- Division of Hematology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Lauren Hoffner
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Cholsoon Jang
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Moonjung Jung
- Division of Hematology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Robert D. Leone
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Konstantinos Konstantopoulos
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Research Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Andrew J. Ewald
- Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Research Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Denis Wirtz
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Research Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Sangmoo Jeong
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Research Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
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Srivastava A, Ahmad R, Yadav K, Siddiqui S, Trivedi A, Misra A, Mehrotra S, Ahmad B, Ali Khan M. An update on existing therapeutic options and status of novel anti-metastatic agents in breast cancer: Elucidating the molecular mechanisms underlying the pleiotropic action of Withania somnifera (Indian ginseng) in breast cancer attenuation. Int Immunopharmacol 2024; 136:112232. [PMID: 38815352 DOI: 10.1016/j.intimp.2024.112232] [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: 01/02/2024] [Revised: 04/14/2024] [Accepted: 05/07/2024] [Indexed: 06/01/2024]
Abstract
Major significant advancements in pharmacology and drug technology have been made to heighten the impact of cancer therapies, improving the life expectancy of subjects diagnosed with malignancy. Statistically, 99% of breast cancers occur in women while 0.5-1% occur in men, the female gender being the strongest breast cancer risk factor. Despite several breakthroughs, breast cancer continues to have a worldwide impact and is one of the leading causes of mortality. Additionally, resistance to therapy is a crucial factor enabling cancer cell persistence and resurgence. As a result, the search and discovery of novel modulatory agents and effective therapies capable of controlling tumor progression and cancer cell proliferation is critical. Withania somnifera (L.) Dunal (WS), commonly known as Indian ginseng, has long been used traditionally for the treatment of several ailments in the Indian context. Recently, WS and its phytoconstituents have shown promising anti-breast cancer properties and, as such, can be employed as prophylactic as well as therapeutic adjuncts to the main line of breast cancer treatment. The present review is an attempt to explore and provide experimental evidences in support of the prophylactic and therapeutic potential of WS in breast cancer, along with a deeper insight into the multiple molecular mechanisms and novel targets through which it acts against breast and other hormonally-induced cancers viz. ovarian, uterine and cervical. This exploration might prove crucial in providing better understanding of breast cancer progression and metastasis and its use as an adjunct in improving disease prognosis and therapeutic outcome.
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Affiliation(s)
- Aditi Srivastava
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Rumana Ahmad
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Kusum Yadav
- Dept. of Biochemistry, University of Lucknow, Lucknow 226007, UP., India.
| | - Sahabjada Siddiqui
- Dept. of Biotechnology, Era's Lucknow Medical College & Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Anchal Trivedi
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Aparna Misra
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Sudhir Mehrotra
- Dept. of Biochemistry, University of Lucknow, Lucknow 226007, UP., India.
| | - Bilal Ahmad
- Research Cell, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Mohsin Ali Khan
- Dept. of Research & Development, Era University, Lucknow 226003, UP., India.
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7
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Han Y, Shan TD, Huang HT, Song MQ, Chen L, Li Q. Activation of lncRNA DANCR by H3K27 acetylation regulates proliferation of colorectal cancer cells. Discov Oncol 2024; 15:249. [PMID: 38940959 PMCID: PMC11213841 DOI: 10.1007/s12672-024-01124-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/25/2024] [Indexed: 06/29/2024] Open
Abstract
The long noncoding DANCR functions as a tumor oncogene in many cancers, including colorectal cancer (CRC). However, the molecular mechanism of DANCR in CRC has not been explored. This study probed the function and potential mechanism by which DANCR contributes to the progression of CRC. The obtained data indicated that DANCR is overexpressed in CRC tissues and cell lines. Knockdown of DANCR hindered CRC cell proliferation, which was mediated by cyclin D1 and CDK4. Bioinformatic analysis, luciferase reporter assays and subcellular fractionation verified that DANCR directly binds to miR-508-5p. Moreover, DANCR acts as a miR-508-5p ceRNA to regulate expression of ATF1. In addition, upregulation of DANCR is attributed to H3K27 acetylation at the promoter region. In conclusion, our study confirmed that activation of lncRNA DANCR by H3K27 acetylation has an oncogenic role in CRC progression and provides a potential therapeutic target for CRC.
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Affiliation(s)
- Yue Han
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiang Su Road, Qingdao, 266000, Shandong, People's Republic of China
| | - Ti-Dong Shan
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiang Su Road, Qingdao, 266000, Shandong, People's Republic of China.
| | - Hai-Tao Huang
- The International Medical Department, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, 262000, People's Republic of China
| | - Ming-Quan Song
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiang Su Road, Qingdao, 266000, Shandong, People's Republic of China
| | - Li Chen
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiang Su Road, Qingdao, 266000, Shandong, People's Republic of China
| | - Qian Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiang Su Road, Qingdao, 266000, Shandong, People's Republic of China
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Thakur C, Qiu Y, Pawar A, Chen F. Epigenetic regulation of breast cancer metastasis. Cancer Metastasis Rev 2024; 43:597-619. [PMID: 37857941 DOI: 10.1007/s10555-023-10146-7] [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: 07/22/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer-related mortality among women worldwide. Recurrent metastasis is associated with poor patient outcomes and poses a significant challenge in breast cancer therapies. Cancer cells adapting to a new tissue microenvironment is the key event in distant metastasis development, where the disseminating tumor cells are likely to acquire genetic and epigenetic alterations during the process of metastatic colonization. Despite several decades of research in this field, the exact mechanisms governing metastasis are not fully understood. However, emerging body of evidence indicates that in addition to genetic changes, epigenetic reprogramming of cancer cells and the metastatic niche are paramount toward successful metastasis. Here, we review and discuss the latest knowledge about the salient attributes of metastasis and epigenetic regulation in breast cancer and crucial research domains that need further investigation.
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Affiliation(s)
- Chitra Thakur
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA.
| | - Yiran Qiu
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA
| | - Aashna Pawar
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA
| | - Fei Chen
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA.
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9
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Cai Y, Zheng H, Xu D, Xie J, Wang W, Liu Z, Zheng Z. M6A RNA Methylation-Mediated Dysregulation of AGAP2-AS1 Promotes Trastuzumab Resistance of Breast Cancer. Pharmacology 2024; 109:282-292. [PMID: 38744264 DOI: 10.1159/000539202] [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: 04/10/2023] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
INTRODUCTION Trastuzumab is commonly used to treat human epidermal growth factor receptor-2-positive (HER2+) breast cancer, but its efficacy is often limited by chemotherapy resistance. Recent studies have indicated that long non-coding RNAs (lncRNAs) play important roles in tumor progression and response to therapy. However, the regulatory mechanisms associating lncRNAs and trastuzumab resistance remain unknown. METHODS Quantitative polymerase chain reaction was performed to detect the expression of related genes. Western blot and immunofluorescence assays were used to evaluate protein expression levels. A series of gain- or loss-of-function assays confirmed the function of AGAP2-AS1 in trastuzumab resistance, both in vitro and in vivo. RNA immunoprecipitation and pull-down analyses were conducted to verify the interaction between METTL3/YTHDF2 and lncRNA AGAP2-AS1. RESULTS AGAP2-AS1 was upregulated in trastuzumab-resistant cells and SKBR-3R-generated xenografts in nude mice. Silencing AGAP2-AS1 significantly decreased trastuzumab-induced cytotoxicity both in vitro and in vivo. Furthermore, m6A methylation of AGAP2-AS1 was reduced in trastuzumab-resistant cells compared to that in parental cells. In addition, METTL3 increased m6A methylation of AGAP2-AS1, which finally induced the suppressed AGAP2-AS1 expression. Moreover, YTHDF2 was essential for METTL3-mediated m6A methylation of AGAP2-AS1. Functionally, AGAP2-AS1 regulated trastuzumab resistance by inducing autophagy and increasing ATG5 expression. CONCLUSION we demonstrated that METTL3/YTHDF2-mediated m6A methylation increased the expression of AGAP2-AS1, which could promote trastuzumab resistance in breast cancer. AGAP2-AS1 regulates trastuzumab resistance by inducing autophagy. Therefore, AGAP2-AS1 may be a promising predictive biomarker and therapeutic target in patients with breast cancer.
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MESH Headings
- Humans
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Trastuzumab/pharmacology
- Trastuzumab/therapeutic use
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Animals
- Female
- Mice, Nude
- Mice
- Methyltransferases/genetics
- Methyltransferases/metabolism
- Methylation/drug effects
- Cell Line, Tumor
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Adenosine/analogs & derivatives
- Adenosine/pharmacology
- Xenograft Model Antitumor Assays
- Mice, Inbred BALB C
- Up-Regulation/drug effects
- RNA Methylation
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Affiliation(s)
- Yangjun Cai
- Department of Thyroid and Breast Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Haihong Zheng
- Department of Pathology, Taizhou Hospital of Zhejiang Province, Linhai, China
| | - Dong Xu
- Department of Thyroid and Breast Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Jingjing Xie
- Department of Oncology and Hematology, Taizhou Hospital of Zhejiang Province, Linhai, China
| | - Weiwen Wang
- Department of Thyroid and Breast Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Zhiwei Liu
- Department of Pharmacy, Taizhou Hospital of Zhejiang Province, Linhai, China
| | - Zhongqiu Zheng
- Department of Thyroid and Breast Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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10
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Zhou YH, Huang JY. Expression and Significance of LINC02418 in Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2024; 16:233-243. [PMID: 38694704 PMCID: PMC11061563 DOI: 10.2147/bctt.s454054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 03/17/2024] [Indexed: 05/04/2024]
Abstract
Purpose The complicated pathogenesis and poor prognosis of breast cancer have become a major difficulty in medical research. This study aims to explore new lncRNA as prognostic markers for breast cancer and explore their roles and molecular mechanisms to lay a foundation for the treatment of cancer patients. Patients and Methods The expression of LINC02418 and miR-766-5p in breast cancer tissues and cells was first identified using polymerase chain reaction, and Pearson was used to examine the correlation between the two. The cancer cells activities under different transfection conditions were detected using the Transwell assay and CCK8 assay. The correlation between LINC02418 and patient prognosis was analyzed using multifactor Cox regression and Kaplan-Meier. Results It was shown that LINC02418 expression was upregulated in breast cancer tissues and cells. There are significant differences in lymph node metastasis and TNM stage between high and low LINC02418 expression groups. The higher the expression of LINC02418, the higher the mortality rate of breast cancer patients. miR-766-5p expression was downregulated and negatively correlated with LINC02418. There are binding sites between LINC02418 and miR-766-5p; Transfection with miR-766-5p inhibitor boosted LINC02418 luciferase activity, but transfection with miR-766-5p mimic decreased it. Knockdown of LINC02418 promoted miR-766-5p expression and inhibited cancer progression, which was alleviated to some extent by transfection with miR-766-5p inhibitors. Conclusion LINC02418 has the potential to serve as a poor prognostic marker for breast cancer and plays a pro-oncogenic role by targeting miR-766-5p.
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Affiliation(s)
- Yong-Hong Zhou
- Department of General Surgery (Thyroid Gland/Blood Vessel), The First People’s Hospital of Neijiang, Neijiang, 641099, People’s Republic of China
| | - Jian-Yuan Huang
- Department of General Surgery (Thyroid Gland/Blood Vessel), The First People’s Hospital of Neijiang, Neijiang, 641099, People’s Republic of China
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11
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Yang F, Yang Y, Qiu Y, Tang L, Xie L, Guan X. Long Non-Coding RNAs as Regulators for Targeting Breast Cancer Stem Cells and Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential. Cancers (Basel) 2024; 16:290. [PMID: 38254782 PMCID: PMC10814583 DOI: 10.3390/cancers16020290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/01/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Breast cancer stem cells (BCSCs) is a subpopulation of cancer cells with self-renewal and differentiation capacity, have been suggested to give rise to tumor heterogeneity and biologically aggressive behavior. Accumulating evidence has shown that BCSCs play a fundamental role in tumorigenesis, progression, and recurrence. The development of immunotherapy, primarily represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, has greatly changed the treatment landscape of multiple malignancies. Recent studies have identified pervasive negative associations between cancer stemness and anticancer immunity. Stemness seems to play a causative role in the formation of cold tumor immune microenvironment (TIME). The multiple functions of long non-coding RNAs (lncRNAs) in regulating stemness and immune responses has been recently highlighted in breast cancer. The review focus on lncRNAs and keys pathways involved in the regulation of BCSCs and TIME. Potential clinical applications using lncRNAs as biomarkers or therapies will be discussed.
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Affiliation(s)
- Fang Yang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Yiqi Yang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Yuling Qiu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Lin Tang
- Department of Rheumatology and Immunology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China;
| | - Li Xie
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Xiaoxiang Guan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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12
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Lin H, Hu S, Li Y, Li S, Teng D, Yang Y, Liu B, Du X. H3K27ac-activated LncRNA NUTM2A-AS1 Facilitated the Progression of Colorectal Cancer Cells via MicroRNA-126-5p/FAM3C Axis. Curr Cancer Drug Targets 2024; 24:1222-1234. [PMID: 38347779 DOI: 10.2174/0115680096277956240119065938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/04/2024] [Accepted: 01/10/2024] [Indexed: 09/25/2024]
Abstract
OBJECTIVE Long non-coding RNAs (lncRNAs) are of great importance in the process of colorectal cancer (CRC) tumorigenesis and progression. However, the functions and underlying molecular mechanisms of the majority of lncRNAs in CRC still lack clarity. METHODS A Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect lncRNA NUTM2A-AS1 expression in CRC cell lines. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to examine the biological functions of lncRNA NUTM2A-AS1 in the proliferation and apoptosis of CRC cells. RT-qPCR and western blot were implemented for the detection of cell proliferation-, apoptosis-related proteins, and FAM3C. Bioinformatics analysis and dual- luciferase reporter assays were utilized to identify the mutual regulatory mechanism of ceRNAs. RESULTS lncRNA NUTM2A-AS1 notably elevated in CRC cell lines and the silenced of NUTM2A- AS1 declined proliferation and facilitated apoptosis. Mechanistically, NUTM2A-AS1 was transcriptionally activated by histone H3 on lysine 27 acetylation (H3K27ac) enriched at its promoter region, and NUTM2A-AS1 acted as a sponge for miR-126-5p, leading to the upregulation of FAM3C expression in CRC cell lines. CONCLUSION Our research proposed NUTM2A-AS1 as an oncogenic lncRNA that facilitates CRC malignancy by upregulating FAM3C expression, which might provide new insight and a promising therapeutic target for the diagnosis and treatment of CRC.
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Affiliation(s)
- Haiguan Lin
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Department of General Surgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, China
| | - Shidong Hu
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yuxuan Li
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Songyan Li
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Da Teng
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yan Yang
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Boyan Liu
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xiaohui Du
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
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13
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Liu C, Lu C, Yixi L, Hong J, Dong F, Ruan S, Hu T, Zhao X. Exosomal Linc00969 induces trastuzumab resistance in breast cancer by increasing HER-2 protein expression and mRNA stability by binding to HUR. Breast Cancer Res 2023; 25:124. [PMID: 37848981 PMCID: PMC10580635 DOI: 10.1186/s13058-023-01720-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 09/25/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common malignant disease in female patients worldwide. In HER-2+ BC patients, trastuzumab therapy is associated with a better prognosis. However, many HER-2+ BC patients experience recurrence or metastasis because of trastuzumab resistance. The mechanisms underlying trastuzumab resistance remain unclear. Recently, substantial evidence has suggested that exosomes are associated with drug resistance, and lncRNAs have attracted increasing attention due to their potential role in the regulation of trastuzumab resistance. METHODS We collected the exosomes from the plasma of BC patients with and without trastuzumab resistance, sequenced the whole transcriptomes, identified differentially expressed lncRNAs, and identified lncRNA Linc00969, which was overexpressed in trastuzumab-resistant patients. Then, we established trastuzumab-resistant BC cell lines and explored the role of exosomal Linc00969 in trastuzumab resistance in vitro and in vivo by silencing or overexpressing Linc00969 and performing a series of functional analyses. Furthermore, to explore the mechanism by which exosomal Linc00969 contributes to trastuzumab resistance, we measured changes in HER-2, HUR and autophagy-related protein expression levels after regulating Linc00969 expression. In addition, we investigated the interaction between Linc00969 and HUR via pull-down and RIP assays and the effect of HUR on HER-2 expression and trastuzumab resistance after blocking HUR. RESULTS We first found that exosomal lncRNA Linc00969 was overexpressed in trastuzumab-resistant BC patients and that exosome-mediated Linc00969 transfer could disseminate trastuzumab resistance in BC. Then, we found that silencing Linc00969 could reduce trastuzumab resistance and that overexpressing Linc00969 could enhance trastuzumab resistance. Furthermore, our results showed that Linc00969 could upregulate HER-2 expression at the protein level and maintain the stability of HER-2 mRNA by binding to HUR. Additionally, we found that exosomal Linc00969 could regulate trastuzumab resistance by inducing autophagy. CONCLUSIONS In this study, we first identified that exosomal lncRNA Linc00969 could induce trastuzumab resistance by increasing HER-2 protein expression and mRNA stability by binding to HUR, and Linc00969 might also be involved in trastuzumab resistance by inducing autophagy. Our results elucidate a novel mechanism underlying trastuzumab resistance, and Linc00969 might be a new target for improving the treatment of HER-2+ BC patients.
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Affiliation(s)
- Cuiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chong Lu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lamu Yixi
- Tibet Shannan Maternal and Child Health Hospital, Shannan, 856000, Tibet, China
| | - Jiaxing Hong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Fang Dong
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shengnan Ruan
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ting Hu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China.
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Tibet Shannan Maternal and Child Health Hospital, Shannan, 856000, Tibet, China.
| | - Xiangwang Zhao
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Dou R, Han L, Yang C, Fang Y, Zheng J, Liang C, Song J, Wei C, Huang G, Zhong P, Liu K, Peng Q, Peng C, Xiong B, Wang S. Upregulation of LINC00501 by H3K27 acetylation facilitates gastric cancer metastasis through activating epithelial-mesenchymal transition and angiogenesis. Clin Transl Med 2023; 13:e1432. [PMID: 37867401 PMCID: PMC10591115 DOI: 10.1002/ctm2.1432] [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: 03/13/2023] [Revised: 09/11/2023] [Accepted: 09/30/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND The molecular mechanism of the significant role of long noncoding RNAs (lncRNAs) in the progression and metastasis of gastric cancer (GC) remains largely elusive. Our objective is to detect overexpressed lncRNA in GC and investigate its role in promoting epithelial-mesenchymal transition and tumour microenvironment remodel. METHODS LncRNA differential expression profile in GC was analysed using RNA microarrays. The level of LINC00501 was evaluated in both GC patient tissues and GC cell lines by quantitative reverse transcription PCR and large-scale (n = 304) tissue microarray. To explore the biological role and regulatory driver of LINC00501 in GC, various experimental techniques including Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) assay, dual luciferase assays were performed. RESULTS Clinically, it was observed that LINC00501 level was abnormal overexpression in GC tissue and was associated with GC progression and distant metastasis. Gain and loss molecular biological experiments suggested that LINC00501, promoted EMT process and angiogenesis of GC. Mechanically, the enrichment of H3K27 acetylation in LINC00501 promoter region contributed to the increase of LINC00501 in GC. LINC00501 transactivated transcription of SLUG, by recruiting hnRNPR to its promoter. The growth of GC was inhibited both in vitro and in vivo by suppressing the level of LINC00501 using pharmacological intervention from the histone acetyltransferase (HAT) inhibitor -C646. CONCLUSIONS This study suggests that LINC00501 promotes GC progression via hnRNPR/SLUG pathway, which indicates a promising biomarker and target for GC.
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Affiliation(s)
- Rongzhang Dou
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Lei Han
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Yan Fang
- Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China
| | - Jinsen Zheng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Chenxi Liang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Jialin Song
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Chen Wei
- Department of Internal Medicine, Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Guoquan Huang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Panyi Zhong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Keshu Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Qian Peng
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chunwei Peng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
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15
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Zhang M, Xiao Z, Xie Y, Li Z, Zhang L, Zhang Z. A cuproptosis-related lncRNA signature-based prognostic model featuring on metastasis and drug selection strategy for patients with lung adenocarcinoma. Front Pharmacol 2023; 14:1236655. [PMID: 37745054 PMCID: PMC10513172 DOI: 10.3389/fphar.2023.1236655] [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: 06/08/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction: Lung adenocarcinoma is a common cause of mortality in patients with cancer. Recent studies have indicated that copper-related cell death may not occur in the same way as previously described. Long non-coding RNAs (lncRNAs) play a key role in the occurrence and development of tumors; however, the relationship between cuproptosis and lncRNAs in tumorigenesis and lung adenocarcinoma (LUAD) treatment has not been well established. Our study aimed to construct a model to analyze the prognosis of lung adenocarcinoma in patients using a carcinogenesis-related lncRNA (CR) signature. Methods: The transcriptional profiles of 507 samples from The Cancer Genome Atlas were assessed. Cox regression and co-expression analyses, and the least absolute shrinkage and selection operator (LASSO) were used to filter the CR and develop the model. The expression status of the six prognostic CRs was used to classify all samples into high- and low-risk groups. The overall disease-free survival rate was compared between the two groups. The Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes were used to identify the pathways and mechanisms involved in this model. Subsequently, immunotherapy response, sensitivity, and correlation analyses for several anti-tumor medications were performed. In vitro experiments, including qPCR, were conducted in nine lung adenocarcinoma cell lines and 16 pairs of lung adenocarcinoma and para-carcinoma tissues. Results: After confirmation using the ROC curve, patients in the low-risk category benefited from both overall and disease-free survival. Gene Ontology analysis highlighted cell movement in the model. In the in vitro experiments, qPCR results showed the expression levels of six CRs in 16 pairs of carcinoma and para-carcinoma tissues, which were in accordance with the results of the model. AL138778.1 is a protective factor that can weaken the invasion and migration of A549 cells, and AL360270.1 is a hazardous factor that promotes the invasion and migration of A549 cells. According to this model, targeted treatments such as axitinib, gefitinib, linsitinib, pazopanib, and sorafenib may be more appropriate for low-risk patients. Conclusion: Six CR profiles (AL360270.1, AL138778.1, CDKN2A-DT, AP003778.1, LINC02718, and AC034102.8) with predictive values may be used to evaluate the prognosis of patients with lung adenocarcinoma undergoing therapy.
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Affiliation(s)
- Mengzhe Zhang
- Department of Lung Cancer Surgery, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Zengtuan Xiao
- Department of Lung Cancer Surgery, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Department of Immunology, Biochemistry and Molecular Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Yongjie Xie
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Zekun Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Lianmin Zhang
- Department of Lung Cancer Surgery, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Zhenfa Zhang
- Department of Lung Cancer Surgery, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
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16
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Lin W, Mo CQ, Kong LJ, Chen L, Wu KL, Wu X. FTO-mediated epigenetic upregulation of LINC01559 confers cell resistance to docetaxel in breast carcinoma by suppressing miR-1343-3p. Kaohsiung J Med Sci 2023; 39:873-882. [PMID: 37584416 DOI: 10.1002/kjm2.12728] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/27/2023] [Accepted: 06/04/2023] [Indexed: 08/17/2023] Open
Abstract
This study was to explore the regulatory effect of long non-coding RNA LINC01559 on Docetaxel resistance in breast carcinoma (BCa) and its underlying mechanism. In the present study, we found that LINC01559 expression was elevated and LINC01559 overexpression facilitated docetaxel resistance in BCa cells. Moreover, it was revealed that the upregulation of LINC01559 in BCa cells was induced by FTO-mediated demethylation in an m6A-YTHDF2-dependent manner. Additionally, Dual-luciferase reporter assay confirmed the binding ability between LINC01559 and miR-1343-3p, and Pearson correlation analysis showed a negative correlation between them. Particularly, miR-1343-3p inhibition partly abolished the suppression on docetaxel resistance in BCa cells caused by LINC01559 knockdown. To sum up, FTO-mediated epigenetic upregulation of LINC01559 promoted cell resistance to Docetaxel in BCa by negatively regulating miR-1343-3p.
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Affiliation(s)
- Wei Lin
- Department of Thyroid and Breast Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Cai-Qin Mo
- Department of Thyroid and Breast Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ling-Jun Kong
- Department of Thyroid and Breast Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ling Chen
- Department of Thyroid and Breast Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Kun-Lin Wu
- Department of Thyroid and Breast Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xian Wu
- Department of Thyroid and Breast Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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17
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Zhang Y, Zhao L, Bi Y, Zhao J, Gao C, Si X, Dai H, Asmamaw MD, Zhang Q, Chen W, Liu H. The role of lncRNAs and exosomal lncRNAs in cancer metastasis. Biomed Pharmacother 2023; 165:115207. [PMID: 37499455 DOI: 10.1016/j.biopha.2023.115207] [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: 06/09/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/29/2023] Open
Abstract
Tumor metastasis is the main reason for cancer-related death, but there is still a lack of effective therapeutic to inhibit tumor metastasis. Therefore, the discovery and study of new tumor metastasis regulators is a prominent measure for cancer diagnosis and treatment. Long non-coding RNA (lncRNA) is a type of non-coding RNAs over 200 bp in length. It has been shown that the abnormally expressed lncRNAs promote tumor metastasis by participating in the epithelial-to-mesenchymal transition (EMT) process, altering the metastatic tumor microenvironment, or changing the extracellular matrix. It is,thus, critical to explore the regulation of lncRNAs expression in cells and the molecular mechanism of lncRNA-mediated cancer metastasis. Simultaneously, it has been shown that lncRNA is one kind of the main components of exosomes, which protects lncRNAs from being rapidly degraded. Meanwhile, the components of exosomes are parent-specific, making exosomal lncRNAs to be potential tumor metastasis markers and therapeutic targets. In view of this, we also summarized the aberrant enrichment of lncRNAs in exosomes and their role in metastatic cancer. The aberrant lncRNAs and exosomal lncRNAs gradually become biomarkers and therapeutic targets for tumor metastatic, and the potential of lncRNAs in therapeutics are studied here. Besides, the lncRNA-related databases, which could greatly facilitate in the study of lncRNAs and exosomal lncRNAs in metastatic of cancer are included in this review.
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Affiliation(s)
- Yutong Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China; The People's Hospital of Zhang Dian District, Zibo, China
| | - Lijuan Zhao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Science, Zhengzhou University, Zhengzhou China
| | - Yaping Bi
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China
| | - Jinyuan Zhao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China
| | - Chao Gao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China
| | - Xiaojie Si
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China
| | - Honglin Dai
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China
| | - Moges Dessale Asmamaw
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China
| | - Qiurong Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China.
| | - Wenchao Chen
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital; Zhengzhou University People's Hospital; Henan University People's Hospital, Zhengzhou China.
| | - Hongmin Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou China.
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18
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Pospelov AD, Kutova OM, Efremov YM, Nekrasova AA, Trushina DB, Gefter SD, Cherkasova EI, Timofeeva LB, Timashev PS, Zvyagin AV, Balalaeva IV. Breast Cancer Cell Type and Biomechanical Properties of Decellularized Mouse Organs Drives Tumor Cell Colonization. Cells 2023; 12:2030. [PMID: 37626840 PMCID: PMC10453279 DOI: 10.3390/cells12162030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/03/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Tissue engineering has emerged as an indispensable tool for the reconstruction of organ-specific environments. Organ-derived extracellular matrices (ECM) and, especially, decellularized tissues (DCL) are recognized as the most successful biomaterials in regenerative medicine, as DCL preserves the most essential organ-specific ECM properties such as composition alongside biomechanics characterized by stiffness and porosity. Expansion of the DCL technology to cancer biology research, drug development, and nanomedicine is pending refinement of the existing DCL protocols whose reproducibility remains sub-optimal varying from organ to organ. We introduce a facile decellularization protocol universally applicable to murine organs, including liver, lungs, spleen, kidneys, and ovaries, with demonstrated robustness, reproducibility, high purification from cell debris, and architecture preservation, as confirmed by the histological and SEM analysis. The biomechanical properties of as-produced DCL organs expressed in terms of the local and total stiffness were measured using our facile methodology and were found well preserved in comparison with the intact organs. To demonstrate the utility of the developed DCL model to cancer research, we engineered three-dimensional tissue constructs by recellularization representative decellularized organs and collagenous hydrogel with human breast cancer cells of pronounced mesenchymal (MDA-MB-231) or epithelial (SKBR-3) phenotypes. The biomechanical properties of the DCL organs were found pivotal to determining the cancer cell fate and progression. Our histological and scanning electron microscopy (SEM) study revealed that the larger the ECM mean pore size and the smaller the total stiffness (as in lung and ovary), the more proliferative and invasive the mesenchymal cells became. At the same time, the low local stiffness ECMs (ranged 2.8-3.6 kPa) did support the epithelial-like SKBR-3 cells' viability (as in lung and spleen), while stiff ECMs did not. The total and local stiffness of the collagenous hydrogel was measured too low to sustain the proliferative potential of both cell lines. The observed cell proliferation patterns were easily interpretable in terms of the ECM biomechanical properties, such as binding sites, embedment facilities, and migration space. As such, our three-dimensional tissue engineering model is scalable and adaptable for pharmacological testing and cancer biology research of metastatic and primary tumors, including early metastatic colonization in native organ-specific ECM.
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Affiliation(s)
- Anton D. Pospelov
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., Nizhny Novgorod 603950, Russia; (A.D.P.); (O.M.K.); (S.D.G.); (E.I.C.); (L.B.T.); (A.V.Z.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya, 16/10, Moscow 117997, Russia;
| | - Olga M. Kutova
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., Nizhny Novgorod 603950, Russia; (A.D.P.); (O.M.K.); (S.D.G.); (E.I.C.); (L.B.T.); (A.V.Z.)
| | - Yuri M. Efremov
- Institute for Regenerative Medicine, Sechenov University, Moscow 117418, Russia; (Y.M.E.); (A.A.N.)
| | - Albina A. Nekrasova
- Institute for Regenerative Medicine, Sechenov University, Moscow 117418, Russia; (Y.M.E.); (A.A.N.)
- Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| | - Daria B. Trushina
- Federal Research Center Crystallography and Photonics, Russian Academy of Sciences, Moscow 119991, Russia;
- Institute of Molecular Theranostics, Sechenov First Moscow State Medical University, Moscow 119435, Russia
| | - Sofia D. Gefter
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., Nizhny Novgorod 603950, Russia; (A.D.P.); (O.M.K.); (S.D.G.); (E.I.C.); (L.B.T.); (A.V.Z.)
| | - Elena I. Cherkasova
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., Nizhny Novgorod 603950, Russia; (A.D.P.); (O.M.K.); (S.D.G.); (E.I.C.); (L.B.T.); (A.V.Z.)
| | - Lidia B. Timofeeva
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., Nizhny Novgorod 603950, Russia; (A.D.P.); (O.M.K.); (S.D.G.); (E.I.C.); (L.B.T.); (A.V.Z.)
- Privolzhsky Research Medical University, 10/1, Minin and Pozharsky Sq., Nizhny Novgorod 603950, Russia
| | - Peter S. Timashev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya, 16/10, Moscow 117997, Russia;
- Chemistry Department, Lomonosov Moscow State University, Leninskiye Gory 1–3, Moscow 119991, Russia
- Laboratory of Clinical Smart Nanotechnology, Sechenov University, Moscow 117418, Russia
| | - Andrei V. Zvyagin
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., Nizhny Novgorod 603950, Russia; (A.D.P.); (O.M.K.); (S.D.G.); (E.I.C.); (L.B.T.); (A.V.Z.)
- Institute of Molecular Theranostics, Sechenov First Moscow State Medical University, Moscow 119435, Russia
- Laboratory of Clinical Smart Nanotechnology, Sechenov University, Moscow 117418, Russia
| | - Irina V. Balalaeva
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., Nizhny Novgorod 603950, Russia; (A.D.P.); (O.M.K.); (S.D.G.); (E.I.C.); (L.B.T.); (A.V.Z.)
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19
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Kang Y. Landscape of NcRNAs involved in drug resistance of breast cancer. Clin Transl Oncol 2023; 25:1869-1892. [PMID: 37067729 PMCID: PMC10250522 DOI: 10.1007/s12094-023-03189-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 07/02/2022] [Indexed: 04/18/2023]
Abstract
Breast cancer (BC) leads to the most amounts of deaths among women. Chemo-, endocrine-, and targeted therapies are the mainstay drug treatments for BC in the clinic. However, drug resistance is a major obstacle for BC patients, and it leads to poor prognosis. Accumulating evidences suggested that noncoding RNAs (ncRNAs) are intricately linked to a wide range of pathological processes, including drug resistance. Till date, the correlation between drug resistance and ncRNAs is not completely understood in BC. Herein, we comprehensively summarized a dysregulated ncRNAs landscape that promotes or inhibits drug resistance in chemo-, endocrine-, and targeted BC therapies. Our review will pave way for the effective management of drug resistance by targeting oncogenic ncRNAs, which, in turn will promote drug sensitivity of BC in the future.
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Affiliation(s)
- Yujuan Kang
- Department of Breast Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
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20
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Chen W, Bai Z, Bai W, Wang W, Guo J, Guo M, Sai Y, Shi J, Wu J. LncTUG1 contributes to the progression of hepatocellular carcinoma via the miR-144-3p/RRAGD axis and mTOR/S6K pathway. Sci Rep 2023; 13:7500. [PMID: 37160972 PMCID: PMC10170139 DOI: 10.1038/s41598-023-33976-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 04/21/2023] [Indexed: 05/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a symptomatic disease involed multi-stage program. Here, we elucidated the molecular mechanism of LncTUG1 in the regulation of HCC evolvement. And that may in all likelyhood supply a innovative latent target for HCC's diagnoses and prognosis. LncRNA TUG1, miR-144-3p, RRAGD and mTOR signaling pathway were screened as target genes in the database, and their expression levels at the cytological level were verified utilized qRT-PCR, Western Blot and immunohistochemistry. Then, we adopted CCK-8, Transwell and flow cytometry assays to estimate cell proliferation, invasion and apoptosis. By use of luciferase reporter assay, the relationships of LncRNA TUG1, miR-144-3p and RRAGD was confirmed. In addition, the LncRNA TUG1-miR-144-3p-RRAGD-mTOR signaling pathway in HCC cells was verified adopted rescue experiment and confirmed by xenotransplantation animal experiment. LncTUG1 in HCC tissues from three databases were identified and further verified through qRT-PCR in HCC cells (Huh7, Hep3B). Knockdown the LncTUG1 could increase apoptosis and inhibite invasion and proliferation in HCC cells. Using inhibitors and activators of the mTOR/S6K pathway, LncTUG1 was confirmed to regulate HCC progression by the mTOR/S6K pathway. Luciferase reporter assay demonstrated that TUG1 negatively regulates miR-144-3p. Furthermore, miR-144-3p negativly regulates RRAGD by way of interacting with the 3'UTR of the RRAGD mRNA in HCC utilized luciferase reporter assay. In vivo, we also discovered that neoplasm weight and tumor volume reduced significantly in subcutaneous xenograft nude mouse models derived from sh-LncTUG1-expressing Huh7 cells. And the expressions of p-mTOR, p-S6K and RRAGD were decreased obviously while the miR144-3p increased in subcutaneous xenograft nude mouse models. In a word, the research suggests that LncTUG1 targets miR-144-3p while miR-144-3p binds to RRAGD mRNA, which induces mTOR/S6K pathway activation and promotes the progression of HCC.
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Affiliation(s)
- Weixi Chen
- Tangshan Maternal and Child Health Care Hospital, North China University of Science and Technology, Tangshan, 063000, China
| | - Zekun Bai
- Tangshan Maternal and Child Health Care Hospital, North China University of Science and Technology, Tangshan, 063000, China
| | - Wen Bai
- Tangshan Maternal and Child Health Care Hospital, North China University of Science and Technology, Tangshan, 063000, China
| | - Wei Wang
- Tangshan Maternal and Child Health Care Hospital, North China University of Science and Technology, Tangshan, 063000, China
| | - Jiapei Guo
- School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Mengnan Guo
- Tangshan Maternal and Child Health Care Hospital, North China University of Science and Technology, Tangshan, 063000, China
| | - Yingying Sai
- Tangshan Maternal and Child Health Care Hospital, North China University of Science and Technology, Tangshan, 063000, China
| | - Jun Shi
- Tangshan Nanhu Hospital, Tangshan, 063000, China
| | - Jinghua Wu
- Tangshan Maternal and Child Health Care Hospital, North China University of Science and Technology, Tangshan, 063000, China.
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21
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Schwarzenbach H, Gahan PB. Interplay between LncRNAs and microRNAs in Breast Cancer. Int J Mol Sci 2023; 24:ijms24098095. [PMID: 37175800 PMCID: PMC10179369 DOI: 10.3390/ijms24098095] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
(1) Although long noncoding RNAs (lncRNAs) are known to be precursors of microRNAs (miRNAs), they frequently act as competing endogoneous RNAs (ceRNAs), yet still their interplay with miRNA is not well known. However, their interaction with miRNAs may result in the modulation of miRNA action. (2) To determine the contribution of these RNA molecules in tumor resistance to chemotherapeutic drugs, it is essential to consider not only the oncogenic and tumor suppressive function of miRNAs but also the impact of lncRNAs on miRNAs. Therefore, we performed an extensive search in different databases including PubMed. (3) The present study concerns the interplay between lncRNAs and miRNAs in the regulatory post-transcriptional network and their impact on drugs used in the treatment of breast cancer. (4) Consideration of this interplay may improve the search for new drugs to circumvent chemoresistance.
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Affiliation(s)
- Heidi Schwarzenbach
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Peter B Gahan
- Fondazione "Enrico Puccinelli" Onlus, 06126 Perugia, Italy
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22
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Jiang T, Zhu J, Jiang S, Chen Z, Xu P, Gong R, Zhong C, Cheng Y, Sun X, Yi W, Yang J, Zhou W, Cheng Y. Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023:e2207257. [PMID: 37096846 DOI: 10.1002/advs.202207257] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 04/06/2023] [Indexed: 05/03/2023]
Abstract
In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self-activatable siRNA/drug core-shell nanoparticle system, which effectively deliver both DDIT4-AS1 siRNA and paclitaxel to the tumor-bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient-derived organoids. These findings indicate that lncRNA DDIT4-AS1-mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4-AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC.
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Affiliation(s)
- Ting Jiang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Jiaojiao Zhu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China
| | - Shilong Jiang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zonglin Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Ping Xu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Rong Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Changxin Zhong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yueying Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Xinyuan Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Wenjun Yi
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Jinming Yang
- Department of Cancer Biology and Toxicology, Department of Pharmacology, College of Medicine and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA
| | - Wenhu Zhou
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China
| | - Yan Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, 410011, China
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23
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Lu B, Nie XH, Yin R, Ding P, Su ZZ, Qiu S, Qian YF. PGAM4 silencing inhibited glycolysis and chemoresistance to temozolomide in glioma cells. Cell Biol Int 2023; 47:776-786. [PMID: 36576012 DOI: 10.1002/cbin.11983] [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: 06/02/2022] [Revised: 12/12/2022] [Accepted: 12/17/2022] [Indexed: 12/29/2022]
Abstract
Gliomas account for about 80% of malignant brain tumors. The incidence of a new brain tumor is 6.4 per 100,000 persons per year with an overall 5-year survival rate of 33.4%. Regardless of the great advances that have been made in recent years, the causes and pathogenesis of glioma remain unclear. Here we study how phosphoglycerate mutase 4 (PGAM4) contributes to glioma. Using a variety of methods to examine glioma cell viability, proliferation, apoptosis, glycolysis, as well as ChIP coanalysis with modified histone H3, we showed that PGAM4 was significantly upregulated in patients with glioma and associated with poor survival. Silencing PGAM4 attenuated cell viability, proliferation, and glycolysis in T98G cells and suppressed tumor growth in vivo, while overexpressing PGAM4 promoted cell viability, proliferation, and glycolysis in U251 cells via regulating glycolysis pathway. Study also revealed that PGAM4 was regulated by EP300-mediated modifications of H3K27ac. PGAM4 silencing inhibited cell viability and proliferation, suppressed tumor growth, and decreased chemoresistance to temozolomide in glioma cells through suppressing glycolysis.
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Affiliation(s)
- Bin Lu
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Xiao-Hu Nie
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Rui Yin
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Peng Ding
- Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhong-Zhou Su
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Sheng Qiu
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Ya-Fang Qian
- Department of orthopedics, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
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24
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Morgado-Palacin L, Brown JA, Martinez TF, Garcia-Pedrero JM, Forouhar F, Quinn SA, Reglero C, Vaughan J, Heydary YH, Donaldson C, Rodriguez-Perales S, Allonca E, Granda-Diaz R, Fernandez AF, Fraga MF, Kim AL, Santos-Juanes J, Owens DM, Rodrigo JP, Saghatelian A, Ferrando AA. The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma. Nat Commun 2023; 14:1328. [PMID: 36899004 PMCID: PMC10006087 DOI: 10.1038/s41467-023-36713-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 02/13/2023] [Indexed: 03/12/2023] Open
Abstract
The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.
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Affiliation(s)
| | - Jessie A Brown
- Institute for Cancer Genetics, Columbia University, New York, NY, USA
| | - Thomas F Martinez
- Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA
| | - Juana M Garcia-Pedrero
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
- Ciber de Cáncer, CIBERONC, Madrid, Spain
| | - Farhad Forouhar
- Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - S Aidan Quinn
- Institute for Cancer Genetics, Columbia University, New York, NY, USA
| | - Clara Reglero
- Institute for Cancer Genetics, Columbia University, New York, NY, USA
| | - Joan Vaughan
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Yasamin Hajy Heydary
- Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA
| | - Cynthia Donaldson
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Sandra Rodriguez-Perales
- Molecular Cytogenetics Group, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain
| | - Eva Allonca
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Rocio Granda-Diaz
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
- Ciber de Cáncer, CIBERONC, Madrid, Spain
| | - Agustin F Fernandez
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
- Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), El Entrego, Spain
- Department of Organisms and Systems Biology (B.O.S.), University of Oviedo, Oviedo, Spain
- Rare Diseases CIBER (ciberer) of the Carlos III Health Institute (ISCIII), Madrid, Spain
| | - Mario F Fraga
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
- Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), El Entrego, Spain
- Department of Organisms and Systems Biology (B.O.S.), University of Oviedo, Oviedo, Spain
- Rare Diseases CIBER (ciberer) of the Carlos III Health Institute (ISCIII), Madrid, Spain
| | - Arianna L Kim
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jorge Santos-Juanes
- Department of Dermatology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain
- Dermatology Area, University of Oviedo Medical School, Oviedo, Asturias, Spain
| | - David M Owens
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Juan P Rodrigo
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
- Ciber de Cáncer, CIBERONC, Madrid, Spain
| | - Alan Saghatelian
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Adolfo A Ferrando
- Institute for Cancer Genetics, Columbia University, New York, NY, USA.
- Dermatology Area, University of Oviedo Medical School, Oviedo, Asturias, Spain.
- Department of Systems Biology, Columbia University, New York, NY, USA.
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25
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Chen F, Wang Y, Zhang X, Fang J. Five hub genes contributing to the oncogenesis and trastuzumab-resistance in gastric cancer. Gene 2023; 851:146942. [DOI: 10.1016/j.gene.2022.146942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022]
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26
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Hu C, Zhang X, Fang K, Guo Z, Li L. LINC00536 Promotes Breast Cancer Progression by Regulating ROCK1 via Sponging of miR-214-5p. Biochem Genet 2022; 61:1163-1184. [PMID: 36513954 DOI: 10.1007/s10528-022-10304-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 11/10/2022] [Indexed: 12/14/2022]
Abstract
Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play a significant role in regulating gene expression and participating in the progression of various malignancies. In our study, by analyzing data from The Cancer Genome Atlas (TCGA), LINC00536 was found to be highly expressed in breast cancer (BC) tissues, but its function and clinical significance in BC are still unknown. Therefore, we aimed to explore the role and molecular mechanism of LINC00536 in BC. We collected human BC tissue specimens and validated that LINC00536 was overexpressed in BC tissues. Increased LINC00536 expression was associated with advanced TNM stage, larger tumor diameter, lymph node metastasis and poor prognosis in patients with BC. Univariate and multivariate Cox regression analyses showed that high LINC00536 expression was an independent prognostic risk factor for overall survival in BC patients. Furthermore, quantitative reverse transcription PCR (qRT-PCR) showed that LINC00536 was upregulated in BC cell lines. Then, we confirmed that LINC00536 silencing-inhibited BC cell proliferation, migration, and invasion and led to cell cycle arrest in vitro. Animal experiments showed that knockdown of LINC00536 expression suppressed tumorigenesis in vivo. Mechanistically, LINC00536 serves as a ceRNA for miR-214-5p, increasing the expression of ROCK1, which acts as a tumor promoter in BC. Rescue assays revealed that miR-214-5p inhibition or ROCK1 overexpression could neutralize the suppressive effects of LINC00536 knockdown on cell proliferation, migration and invasion. Our data indicated that LINC00536 accelerates BC progression by regulating the miR-214-5p/ROCK1 pathway, which might provide a new perspective to investigate the development process of BC.
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Affiliation(s)
- Caixia Hu
- Oncology Institute, The Affiliated Hospital of Jiangnan University, 200# Huihe Road, Wuxi, 214062, Jiangsu, China
| | - Xiufen Zhang
- Oncology Institute, The Affiliated Hospital of Jiangnan University, 200# Huihe Road, Wuxi, 214062, Jiangsu, China
| | - Kai Fang
- Oncology Institute, The Affiliated Hospital of Jiangnan University, 200# Huihe Road, Wuxi, 214062, Jiangsu, China
| | - Zijian Guo
- Department of Oncological Surgery, The Affiliated Hospital of Jiangnan University, Wuxi, 214062, China.
| | - Lihua Li
- Oncology Institute, The Affiliated Hospital of Jiangnan University, 200# Huihe Road, Wuxi, 214062, Jiangsu, China.
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27
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Wang B, Chen H, Yang R, Xing L, Chen C, Chen J. LncRNA RP11-551L14.4 suppresses breast cancer development by inhibiting the expression of miR-4472. PeerJ 2022; 10:e14482. [PMID: 36523479 PMCID: PMC9745927 DOI: 10.7717/peerj.14482] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 11/08/2022] [Indexed: 12/12/2022] Open
Abstract
Background Previous studies have been reported that long non-coding RNA (lncRNA) can regulate the expression of genes which are involved in many important cellular processes The potential role of lncRNA RP11-551L14.4 in the development of breast cancer and the possible regulatory mechanisms was investigated. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to analyze RP11-551L14.4 expression in 36 paired breast cancer tissues and adjacent tissues. The expression of RP11-551L14.4 in multiple breast cancer cell lines was detected by qRT-PCR. Meanwhile, overexpression of RP11-551L14.4 models was established using lentivirus in BT474 and T47D breast cancer cells. Cell counting kit-8 (CCK-8), cell colony formation and cell cycle assays were performed to detect the effects of RP11-551L14.4 on the biological function of breast cancer cells. Besides, bioinformatics techniques, dual luciferase reporter gene assay and rescue experiments were used to investigate the potential mechanisms. Results RP11-551L14.4 expression was negatively associated with the advanced tumor stage. Breast cancer patients with low RP11-551L14.4 expression manifested a poorer prognosis. The results of qRT-PCR showed that RP11-551L14.4 expression in breast cancer tissues was significantly lower than in adjacent tissues. Meanwhile, overexpression of RP11-551L14.4 significantly decreased the cell proliferation and cell cycle. Bioinformatics technology showed that RP11-551L14.4 could complementarily bind to miR-4472. qRT-PCR results indicated that the expression levels of miR-4472 and RP11-551L14.4 in breast cancer were negatively correlated. Luciferase reporter gene assay showed that miR-4472 remarkably decreased the relative luciferase activity of the wild-type RP11-551L14.4 vector. miR-4472 is a direct target gene of RP11-551L14.4. miR-4472 levels were reduced, and repulsive guidance molecule A (RGMA) mRNA or protein levels were increased after overexpression of RP11-551L14.4 in the breast cancer cells. miR-4472 reversed the effects caused by RP11-551L14.4 in breast cancer cells. Conclusion RP11-551L14.4 expression was remarkably decreased in breast cancer tissues and cells. RP11-551L14.4 may inhibit the malignant progression of breast cancer by regulating miR-4472 expression.
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Affiliation(s)
- Bin Wang
- Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, China,Department of Oncology, Daping Hospital, Army Medical University, Chongqing, China
| | - Hang Chen
- Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, China
| | - Rui Yang
- Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, China
| | - Lei Xing
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chuan Chen
- Department of Oncology, Daping Hospital, Army Medical University, Chongqing, China
| | - Junxia Chen
- Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, China
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28
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Hashemi M, Arani HZ, Orouei S, Fallah S, Ghorbani A, Khaledabadi M, Kakavand A, Tavakolpournegari A, Saebfar H, Heidari H, Salimimoghadam S, Entezari M, Taheriazam A, Hushmandi K. EMT mechanism in breast cancer metastasis and drug resistance: Revisiting molecular interactions and biological functions. Biomed Pharmacother 2022; 155:113774. [DOI: 10.1016/j.biopha.2022.113774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/20/2022] [Accepted: 09/28/2022] [Indexed: 12/24/2022] Open
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LINC00589-dominated ceRNA networks regulate multiple chemoresistance and cancer stem cell-like properties in HER2 + breast cancer. NPJ Breast Cancer 2022; 8:115. [PMID: 36309503 PMCID: PMC9617889 DOI: 10.1038/s41523-022-00484-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 10/12/2022] [Indexed: 11/29/2022] Open
Abstract
Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy (trastuzumab), cancer stem cell (CSC)-like properties and multiple chemoresistance often concur and intersect in breast cancer, but molecular links that may serve as effective therapeutic targets remain largely unknown. Here, we identified the long noncoding RNA, LINC00589 as a key regulatory node for concurrent intervention of these processes in breast cancer cells in vitro and in vivo. We demonstrated that the expression of LINC00589 is clinically valuable as an independent prognostic factor for discriminating trastuzumab responders. Mechanistically, LINC00589 serves as a ceRNA platform that simultaneously sponges miR-100 and miR-452 and relieves their repression of tumor suppressors, including discs large homolog 5 (DLG5) and PR/SET domain 16 (PRDM16, a transcription suppressor of mucin4), thereby exerting multiple cancer inhibitory functions and counteracting drug resistance. Collectively, our results disclose two LINC00589-initiated ceRNA networks, the LINC00589-miR-100-DLG5 and LINC00589-miR-452-PRDM16- mucin4 axes, which regulate trastuzumab resistance, CSC-like properties and multiple chemoresistance of breast cancer, thus providing potential diagnostic and prognostic markers and therapeutic targets for HER2-positive breast cancer.
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30
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Huang L, Li L, Cheng B, Xing T. SLC38A6, regulated by EP300-mediated modifications of H3K27ac, promotes cell proliferation, glutamine metabolism and mitochondrial respiration in hepatocellular carcinoma. Carcinogenesis 2022; 43:885-894. [PMID: 35901507 DOI: 10.1093/carcin/bgac061] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/08/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common form of liver cancer. The incidence of HCC is increasing and effective prevention methods are needed. The solute carrier family 38 member 6 (SLC38A6) plays an important role in the metabolism of glutamine, which is a central nutrient for many cancers. However, the regulation and function of SLC38A6 in HCC are unclear. SLC38A6 levels in human HCC tissue arrays and cells were determined. SLC38A6 was silenced or overexpressed to determine its role in regulating cell viability, colony formation, cell cycle progression, glutamine metabolism and mitochondrial respiration. A luminescence assay was used to study the interaction between SLC38A6 and EP300. The interactions between SLC38A6, H3K27ac and EP300 were determined using chromatin immunoprecipitation assays. Quantitative RT-PCR and immunoblots were performed to measure mRNAs and proteins, respectively. SLC38A6 expression was higher in HCC compared with expression in normal tissue. Silencing SLC38A6 inhibited cell viability, colony formation, cell cycle progression, glutamine metabolism and mitochondrial respiration, while SLC38A6 overexpression had the opposite effects. Silencing SLC38A6 also inhibited tumor growth in vivo. Silencing EP300 significantly suppressed the interaction between H3K27ac and the SLC38A6 promoter, leading to decreased SLC38A6. SLC38A6 is regulated by EP300-mediated modifications of H3K27ac and promotes viability, colony formation, cell cycle progression, glutamine metabolism and mitochondrial respiration in HCC cells.
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Affiliation(s)
- Li Huang
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lixing Li
- Department of General Surgery, Shanghai Xuhui District Central Hospital, Shanghai, China
| | - Bin Cheng
- Department of Nuclear Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tonghai Xing
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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31
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Hashemi M, Moosavi MS, Abed HM, Dehghani M, Aalipour M, Heydari EA, Behroozaghdam M, Entezari M, Salimimoghadam S, Gunduz ES, Taheriazam A, Mirzaei S, Samarghandian S. Long non-coding RNA (lncRNA) H19 in human cancer: From proliferation and metastasis to therapy. Pharmacol Res 2022; 184:106418. [PMID: 36038043 DOI: 10.1016/j.phrs.2022.106418] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 02/07/2023]
Abstract
Initiation and development of cancer depend on multiple factors that mutations in genes and epigenetic level can be considered as important drivers. Epigenetic factors include a large family of members and understanding their function in cancer has been a hot topic. LncRNAs are RNA molecules with no capacity in synthesis of proteins, and they have regulatory functions in cells. LncRNAs are localized in nucleus and cytoplasm, and their abnormal expression is related to development of tumor. This manuscript emphasizes on the role of lncRNA H19 in various cancers and its association with tumor hallmarks. The function of lncRNA H19 in most tumors is oncogenic and therefore, tumor cells increase its expression for promoting their progression. LncRNA H19 contributes to enhancing growth and cell cycle of cancers and by EMT induction, it is able to elevate metastasis rate. Silencing H19 induces apoptotic cell death and disrupts progression of tumors. LncRNA H19 triggers chemo- and radio-resistance in cancer cells. miRNAs are dually upregulated/down-regulated by lncRNA H19 in increasing tumor progression. Anti-cancer agents reduce lncRNA H19 in impairing tumor progression and increasing therapy sensitivity. A number of downstream targets and molecular pathways for lncRNA H19 have been detected in cancers including miRNAs, RUNX1, STAT3, β-catenin, Akt2 and FOXM1. Clinical studies have revealed potential of lncRNA H19 as biomarker and its association with poor prognosis. LncRNA H19 can be transferred to cancer cells via exosomes in enhancing their progression.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Marzieh Sadat Moosavi
- Department of Biochemistry, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Hedyeh Maghareh Abed
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Dehghani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Masoumeh Aalipour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Ali Heydari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Emine Selda Gunduz
- Vocational School of Health Services, Department of First and Emergency Aid, Akdeniz University, Antalya, Turkey.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Khanbabaei H, Ebrahimi S, García-Rodríguez JL, Ghasemi Z, Pourghadamyari H, Mohammadi M, Kristensen LS. Non-coding RNAs and epithelial mesenchymal transition in cancer: molecular mechanisms and clinical implications. J Exp Clin Cancer Res 2022; 41:278. [PMID: 36114510 PMCID: PMC9479306 DOI: 10.1186/s13046-022-02488-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/06/2022] [Indexed: 11/30/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a fundamental process for embryonic development during which epithelial cells acquire mesenchymal characteristics, and the underlying mechanisms confer malignant features to carcinoma cells such as dissemination throughout the organism and resistance to anticancer treatments. During the past decades, an entire class of molecules, called non-coding RNA (ncRNA), has been characterized as a key regulator of almost every cellular process, including EMT. Like protein-coding genes, ncRNAs can be deregulated in cancer, acting as oncogenes or tumor suppressors. The various forms of ncRNAs, including microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, transfer RNA-derived RNA fragments, long non-coding RNAs, and circular RNAs can orchestrate the complex regulatory networks of EMT at multiple levels. Understanding the molecular mechanism underlying ncRNAs in EMT can provide fundamental insights into cancer metastasis and may lead to novel therapeutic approaches. In this review, we describe recent advances in the understanding of ncRNAs in EMT and provide an overview of recent ncRNA applications in the clinic.
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33
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Thakur C, Qiu Y, Fu Y, Bi Z, Zhang W, Ji H, Chen F. Epigenetics and environment in breast cancer: New paradigms for anti-cancer therapies. Front Oncol 2022; 12:971288. [PMID: 36185256 PMCID: PMC9520778 DOI: 10.3389/fonc.2022.971288] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/26/2022] [Indexed: 11/27/2022] Open
Abstract
Breast cancer remains the most frequently diagnosed cancer in women worldwide. Delayed presentation of the disease, late stage at diagnosis, limited therapeutic options, metastasis, and relapse are the major factors contributing to breast cancer mortality. The development and progression of breast cancer is a complex and multi-step process that incorporates an accumulation of several genetic and epigenetic alterations. External environmental factors and internal cellular microenvironmental cues influence the occurrence of these alterations that drives tumorigenesis. Here, we discuss state-of-the-art information on the epigenetics of breast cancer and how environmental risk factors orchestrate major epigenetic events, emphasizing the necessity for a multidisciplinary approach toward a better understanding of the gene-environment interactions implicated in breast cancer. Since epigenetic modifications are reversible and are susceptible to extrinsic and intrinsic stimuli, they offer potential avenues that can be targeted for designing robust breast cancer therapies.
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Affiliation(s)
- Chitra Thakur
- Department of Pathology, Stony Brook Cancer Center, Stony Brook, NY, United States
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Yiran Qiu
- Department of Pathology, Stony Brook Cancer Center, Stony Brook, NY, United States
| | - Yao Fu
- Department of Pathology, Stony Brook Cancer Center, Stony Brook, NY, United States
| | - Zhuoyue Bi
- Department of Pathology, Stony Brook Cancer Center, Stony Brook, NY, United States
| | - Wenxuan Zhang
- Department of Pathology, Stony Brook Cancer Center, Stony Brook, NY, United States
| | - Haoyan Ji
- Department of Pathology, Stony Brook Cancer Center, Stony Brook, NY, United States
| | - Fei Chen
- Department of Pathology, Stony Brook Cancer Center, Stony Brook, NY, United States
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
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Fan Y, Gao Z, Xu J, Wang H, Guo Q, Xue H, Zhao R, Guo X, Li G. Identification and validation of SNHG gene signature to predict malignant behaviors and therapeutic responses in glioblastoma. Front Immunol 2022; 13:986615. [PMID: 36159816 PMCID: PMC9493242 DOI: 10.3389/fimmu.2022.986615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma (GBM) patients exhibit high mortality and recurrence rates despite multimodal therapy. Small nucleolar RNA host genes (SNHGs) are a group of long noncoding RNAs that perform a wide range of biological functions. We aimed to reveal the role of SNHGs in GBM subtypes, cell infiltration into the tumor microenvironment (TME), and stemness characteristics. SNHG interaction patterns were determined based on 25 SNHGs and systematically correlated with GBM subtypes, TME and stemness characteristics. The SNHG interaction score (SNHGscore) model was generated to quantify SNHG interaction patterns. The high SNHGscore group was characterized by a poor prognosis, the mesenchymal (MES) subtype, the infiltration of suppressive immune cells and a differentiated phenotype. Further analysis indicated that high SNHGscore was associated with a weaker response to anti-PD-1/L1 immunotherapy. Tumor cells with high SNHG scores were more sensitive to drugs targeting the EGFR and ERK-MAPK signaling pathways. Finally, we assessed SNHG interaction patterns in multiple cancers to verify their universality. This is a novel and comprehensive study that provides targeted therapeutic strategies based on SNHG interactions. Our work highlights the crosstalk and potential clinical utility of SNHG interactions in cancer therapy.
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Affiliation(s)
- Yang Fan
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Zijie Gao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Jianye Xu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Huizhi Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Qindong Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Hao Xue
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Rongrong Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Xing Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
- *Correspondence: Xing Guo, ; Gang Li,
| | - Gang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
- *Correspondence: Xing Guo, ; Gang Li,
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Liu YC, Lin YH, Chi HC, Huang PS, Liao CJ, Liou YS, Lin CC, Yu CJ, Yeh CT, Huang YH, Lin KH. CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance. Clin Epigenetics 2022; 14:106. [PMID: 35999564 PMCID: PMC9400329 DOI: 10.1186/s13148-022-01326-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 08/09/2022] [Indexed: 11/10/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies worldwide. The long-term prognosis for HCC remains extremely poor, with drug resistance being the major underlying cause of recurrence and mortality. The lncRNA colorectal neoplasia differentially expressed (CRNDE) is an epigenetic mediator and plays an important role to drive proliferation and drug resistance in HCC. However, CRNDE as an epigenetic regulator with influences sorafenib resistance in HCC is unclear. Thus, we explore the potential of targeting the CRNDE/p300/YY1 axis as a novel therapeutic strategy to overcome sorafenib resistance of HCC. Method Detection of the expression level of CRNDE and EGFR in clinical specimens of HCC. CRNDE, EGFR, p300, and YY1expression were altered in HCC cells through transfection with different plasmids, and cell proliferation, migration, invasion, and sorafenib resistance were subsequently observed. Immunoprecipitation, chromatin immunoprecipitation, re-chromatin immunoprecipitation, site-directed mutagenesis, RNA Immunoprecipitation, immune fluorescence, qRT-PCR, and western blotting were performed to uncover the mechanisms of CRNDE regulation. The xenograft nude mice model was used to investigate the tumor growth and sorafenib resistance. Results In this study, we showed that CRNDE expression is significantly positively correlated with that of epidermal growth factor receptor (EGFR) in clinical specimens of HCC and induces proliferation and sorafenib resistance of HCC via EGFR-mediated signaling. Mechanistically, CRNDE stabilized the p300/YY1 complex at the EGFR promoter and simultaneously enhanced histone H3K9 and H3K27 acetylation, which serve as markers of relaxed chromatin. EGFR was positively upregulated by the epigenetic complex, p300/YY1, in a manner dependent on CRNDE expression, leading to enhanced tumor cell proliferation and sorafenib resistance. Furthermore, C646, a p300 inhibitor, suppressed EGFR transcriptional activity by decreasing chromatin relaxation and YY1 binding, which effectively reduced proliferation/sorafenib resistance and prolonged overall survival. Conclusion Our collective findings support the potential of targeting the CRNDE/p300/YY1 axis as a novel therapeutic strategy to overcome sorafenib resistance of HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-022-01326-3.
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Affiliation(s)
- Yu-Chin Liu
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan, Republic of China.,Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Hsiang-Cheng Chi
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan, Republic of China
| | - Chia-Jung Liao
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan, Republic of China
| | - Yu-Syuan Liou
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan, Republic of China
| | - Chiao-Chun Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan, Republic of China
| | - Chia-Jung Yu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan, Republic of China.,Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.,Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan. .,Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1 Road, Taoyuan, Taiwan, Republic of China. .,Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. .,Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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Ning X, Zhao J, He F, Yuan Y, Li B, Ruan J. lncRNA NUTM2A-AS1 Targets the SRSF1/Trim37 Signaling Pathway to Promote the Proliferation and Invasion of Breast Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3299336. [PMID: 35959349 PMCID: PMC9363211 DOI: 10.1155/2022/3299336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/10/2022] [Accepted: 06/25/2022] [Indexed: 11/17/2022]
Abstract
Method Using the tumor database (TCGA) and analysis platform (GEPIA), NUTM2A-AS1 expression in breast cancer cases was compared with the normal cases. In addition, Kaplan-Meier curve of overall survival according to the various levels of NUTM2A-AS1 was assessed. Then, we constructed a knockdown plasmid of NUTM2A-AS1 and successfully reduced the expression function of NUTM2A-AS1 in BC cells. Results We found NUTM2A-AS1 could promote the malignant phenotype of proliferation and invasion of BC. In terms of mechanism research, NUTM2A-AS1 was mainly located in the cytoplasm of BC cells, which indicated that NUTM2A-AS1 may achieve its function through transcriptional or posttranscriptional regulation pathways. While knocking down NUTM2A-AS1, we detected several major molecules of the trim family. The results showed that only trim37 mRNA was significantly affected, and protein detection also showed that knockdown NUTM2A-AS1 expression could reduce the expression of trim37. The results of RIP experiments suggested that NUTM2A-AS1 played a key role by combining with SRSF1 and affecting the interaction between SRSF1 and trim37 mRNA. The stability test of mRNA also confirmed that during the knockdown of NUTM2A-AS1, the mRNA stability of trim37 decreased significantly, but this downward trend could be reversed by overexpressed SRSF1. The above results suggested that NUTM2A-AS1 could maintain the stability and expression of trim37 through SRSF1 pathway. The results of rescue experiment showed the overexpression of trim37, while knocking down NUTM2A-AS1 could reverse the decrease of proliferation and invasiveness of BC cells induced by NUTM2A-AS1 knockdown. Conclusion Therefore, trim37 is seen as a necessary target for NUTM2A-AS1 to exert the biological function of BC. Additionally, NUTM2A-AS1 is to regulate the malignant phenotype of BC through NUTM2A-AS1/trim37 pathway.
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Affiliation(s)
- Xiaojie Ning
- Department of Thyroid and Breast Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei Province, China
| | - Jianguo Zhao
- Department of Thyroid and Breast Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei Province, China
| | - Fan He
- Department of Thyroid and Breast Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei Province, China
| | - Yuan Yuan
- Department of Thyroid and Breast Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei Province, China
| | - Bin Li
- Department of Thyroid and Breast Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei Province, China
| | - Jian Ruan
- Department of Thyroid and Breast Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei Province, China
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Zhou M, Dong J, Huang J, Ye W, Zheng Z, Huang K, Pan Y, Cen J, Liang Y, Shu G, Ye S, Lu X, Zhang J. Chitosan-Gelatin-EGCG Nanoparticle-Meditated LncRNA TMEM44-AS1 Silencing to Activate the P53 Signaling Pathway for the Synergistic Reversal of 5-FU Resistance in Gastric Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2105077. [PMID: 35717675 PMCID: PMC9353463 DOI: 10.1002/advs.202105077] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/31/2022] [Indexed: 05/16/2023]
Abstract
Chemoresistance is one of the leading causes of therapeutic failure in gastric cancer (GC) treatment. Recent studies have shown lncRNAs play pivotal roles in regulating GC chemoresistance. Nanocarriers delivery of small interfering RNAs (siRNAs) to silence cancer-related genes has become a novel approach to cancer treatment research. However, finding target genes and developing nanosystems capable of selectively delivering siRNAs for disease treatment remains a challenge. In this study, a novel lncRNA TMEM44-AS1 that is related to 5-FU resistance is identified. TMEM44-AS1 has the ability to bind to and sponge miR-2355-5p, resulting in the upregulated PPP1R13L expression and P53 pathway inhibition. Next, a new nanocarrier called chitosan-gelatin-EGCG (CGE) is developed, which has a higher gene silencing efficiency than lipo2000, to aid in the delivery of a si-TMEM44-AS1 can efficiently silence TMEM44-AS1 expression to synergistically reverse 5-FU resistance in GC, leading to a markedly enhanced 5-FU therapeutic effect in a xenograft mouse model of GC. These findings indicate that TMEM44-AS1 may estimate 5-FU therapy outcome among GC cases, and that systemic si-TMEM44-AS1 delivery combined with 5-FU therapy is significant in the treatment of patients with recurrent GC.
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MESH Headings
- Animals
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Antineoplastic Agents/metabolism
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Catechin/analogs & derivatives
- Catechin/pharmacology
- Catechin/therapeutic use
- Cell Line, Tumor
- Chitosan/pharmacology
- Chitosan/therapeutic use
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/physiology
- Fluorouracil/pharmacology
- Fluorouracil/therapeutic use
- Gelatin/pharmacology
- Gelatin/therapeutic use
- Gene Expression Regulation, Neoplastic
- Gene Silencing/drug effects
- Gene Silencing/physiology
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- MicroRNAs/genetics
- Nanoparticles/therapeutic use
- RNA/genetics
- RNA/metabolism
- RNA, Antisense/genetics
- RNA, Antisense/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Signal Transduction/genetics
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
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Affiliation(s)
- Mi Zhou
- Department of OncologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Jiaqi Dong
- Department of OncologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Junqing Huang
- Guangzhou Key Laboratory of Formula‐Pattern of Traditional Chinese MedicineFormula‐Pattern Research CenterSchool of Traditional Chinese MedicineJinan UniversityGuangzhou510632P. R. China
| | - Wen Ye
- Department of OncologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Zhousan Zheng
- Department of OncologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Kangbo Huang
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Yihui Pan
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Junjie Cen
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Yanping Liang
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Guannan Shu
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Sheng Ye
- Department of OncologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
| | - Xuanxuan Lu
- Department of Food Science and EngineeringJinan UniversityGuangzhou510632P. R. China
| | - Jiaxing Zhang
- Department of OncologyThe First Affiliated Hospital of Sun Yat‐sen UniversityNo. 58, Zhongshan road IIGuangzhou510080P. R. China
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Non-coding RNAs in EMT regulation: Association with tumor progression and therapy response. Eur J Pharmacol 2022; 932:175212. [DOI: 10.1016/j.ejphar.2022.175212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/03/2022] [Accepted: 08/11/2022] [Indexed: 12/12/2022]
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Zhu K, Wang Q, Wang L. Analysis of Competitive Endogenous RNA Regulatory Network of Exosomal Breast Cancer Based on exoRBase. Evol Bioinform Online 2022; 18:11769343221113286. [PMID: 35898233 PMCID: PMC9309761 DOI: 10.1177/11769343221113286] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 06/03/2022] [Indexed: 12/24/2022] Open
Abstract
Objective: To construct a competitive endogenous RNA (ceRNA) regulatory network derived
from exosomes of human breast cancer (BC) by using the exoRbase database, to
explore the possible pathogenesis of BC, and to develop new targets for
future diagnosis and treatment. Methods: The exosomal gene sequencing data of BC patients and normal controls were
downloaded from the exoRbase database, and the expression profiles of
exosomal mRNA, long non-coding RNA (lncRNA), and circular RNA (circRNA) were
analyzed by using R language. Use Targetscan and miRanda database to jointly
predict and differentially express miRNA (microRNA), miRNA combined with
mRNA. The miRcode database was used to predict the miRNA combined with
differentially expressed lncRNA, and the starBase database was used to
predict the miRNA combined with circRNA in the difference table. The related
mRNA, circRNA, lncRNA, and their corresponding miRNA prediction data were
imported into Cytoscape software to visualize the ceRNA network. Enrichment
analysis and visualization of KEGG were carried out using KOBAS. Hub gene
was determined by Cytohubba plug-in. Results: Forty-two differentially expressed mRNA, 43 differentially expressed circRNA,
and 26 differentially expressed lncRNA were screened out. The ceRNA network
was constructed by using Cytoscape software, including 19 mRNA nodes, 2
lncRNA nodes, 8 circRNA nodes, and 41 miRNA nodes. KEGG enrichment analysis
showed that differentially expressed mRNA in the regulatory network mainly
enriched the p53 signaling pathway. Find the key Hub gene PTEN. Conclusion: The ceRNA regulatory network in blood exosomes of BC patients has been
successfully constructed in this study, which provides an exact target for
the diagnosis and treatment of BC.
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Affiliation(s)
- Kangle Zhu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Qingqing Wang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Lian Wang
- Department of Oncology, Xuyi People's Hospital, Huai An, Jiangsu, China
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DNMT3A Regulates miR-149 DNA Methylation to Activate NOTCH1/Hedgehog Pathway to Promote the Development of Junctional Osteosarcoma. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3261213. [PMID: 35909477 PMCID: PMC9334075 DOI: 10.1155/2022/3261213] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/24/2022] [Accepted: 05/27/2022] [Indexed: 11/17/2022]
Abstract
Purpose. To investigate the DNMT3A/miR-149/NOTCH1/Hedgehog axis regulating the development of osteosarcoma. Methods. First, microRNA and mRNA expression microarrays were downloaded from the GEO database for osteosarcoma and differentially expressed microRNAs were analyzed. Subsequently, we collected cancerous tissues and corresponding paracancerous tissues from 42 osteosarcoma patients and examined the expression levels of miR-149, DNMT3A, and NOTCH1 in the samples. Subsequently, miR-149 was overexpressed in osteosarcoma cells to detect cell proliferation and metastatic ability changes. We then queried the methylation level of the miR-149 promoter on the bioinformatics website and verified it by experiment. We further demonstrated the expression level of miR-149 with NOTCH1 using a dual luciferase assay and confirmed the role of NOTCH1 on osteosarcoma cell growth and metastasis by functional rescue assay. Finally, we detected the activation level of the Hedgehog/catenin signaling pathway by WB and immunofluorescence. Results. miR-149 was significantly low expressed in osteosarcoma tissues and cells, while DNMT3A and NOTCH1 were highly expressed in osteosarcoma tissues and cells, and negatively correlated with miR-149 expression levels. Overexpression of miR-149 significantly inhibited the growth and metastasis of osteosarcoma cells in vitro and in vivo, and we found that DNMT3A could promote the methylation modification of the miR-149 promoter, thereby inhibiting the expression of miR-149. Subsequently, the experimental results showed that miR-149 could target negative regulation of NOTCH1, and further overexpression of NOTCH1 in cells with high miR-149 expression could promote the growth and metastasis of osteosarcoma cells in vitro. Conclusion. The methyltransferase DNMT3A suppresses miR-149 expression by promoting methylation modification of the miR-149 promoter, resulting in elevated expression levels of NOTCH1 in cells, therefore exacerbating activation of the Hedgehog signaling pathway and therefore exacerbating the development and progression of osteosarcoma.
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hsa_circ_0084811 Regulates Cell Proliferation and Apoptosis in Retinoblastoma through miR-18a-5p/miR-18b-5p/E2F5 Axis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6918396. [PMID: 35909488 PMCID: PMC9325647 DOI: 10.1155/2022/6918396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/21/2022] [Accepted: 07/01/2022] [Indexed: 11/17/2022]
Abstract
Background Retinoblastoma (RB) is the commonest primary intraocular malignancy during childhood. Circular RNAs (circRNAs) act as regulators in RB development, and hsa_circ_E2F5 (circ_0084811 in this study) was found to be highly expressed in RB cells, so we wanted to identify its detailed molecular mechanism. Methods The expression level of circ_0084811 in RB cells was tested by RT-qPCR and its effects on RB cells were evaluated through functional assays. The regulatory mechanism that circ_0084811 may exert in RB progression was testified through mechanism experiments. Results High circ_0084811 expression in RB cells facilitated cell proliferation but inhibited cell apoptosis. The enrichment of acetylation of histone 3 lysine 27 (H3K27ac) in circ_0084811 promoter induced circ_0084811 upregulation. Moreover, circ_0084811 regulated E2F transcription factor 5 (E2F5) expression via sponging microRNA-18a-5p (miR-18a-5p) and microRNA-18b-5p (miR-18b-5p). Conclusion circ_0084811 modulated RB progression via the miR-18a-5p/miR-18b-5p/E2F5 axis.
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Han M, Gu Y, Lu P, Li J, Cao H, Li X, Qian X, Yu C, Yang Y, Yang X, Han N, Dou D, Hu J, Dong H. Retraction Note to: Exosome-mediated lncRNA AFAP1-AS1 promotes trastuzumab resistance through binding with AUF1 and activating ERBB2 translation. Mol Cancer 2022; 21:143. [PMID: 35820907 PMCID: PMC9275128 DOI: 10.1186/s12943-022-01610-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Mingli Han
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Yuanting Gu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pengwei Lu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jingyi Li
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hui Cao
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiangke Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xueke Qian
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Chao Yu
- Department of General Surgery, University-Town Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yunqing Yang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xue Yang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Na Han
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Dongwei Dou
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jianguo Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Huaying Dong
- Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, No.19 XiuHua Road, Xiuying District, Haikou, 570311, China.
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Early-stage colon cancer with high MALAT1 expression is associated with the 5-Fluorouracil resistance and future metastasis. Mol Biol Rep 2022; 49:11243-11253. [PMID: 35794508 DOI: 10.1007/s11033-022-07680-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 06/06/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND This study aimed to investigate the role of long noncoding RNA (LncRNA) expression profiles to predict relapse and 5-FU response in patients with stage I/II colon cancer (CC). METHODS AND RESULTS The expression level of 15 LncRNA was analyzed in stage I/II colon tumors of 126 CC patients. To confirm the findings in-vitro, 5FU-resistant HT29 cells were generated by subjecting HT-29 cells to the increasing concentrations of 5FU for 6 months. The 5FU resistance was observed in WST-1 and Annexin V analyses. The colony formation and wound healing assays were assessed to determine the metastatic properties of the cells. Expression levels of LncRNAs and mRNA of EMT-related genes were determined by RT-PCR. The role of LncRNA on metastasis and 5FU sensitivity were confirmed in pcDNA3.0-PTENP1 and si-MALAT1 expressed 5FU-resistant HT29 cell lineages. RESULTS High MALAT1 (p = 0.0002) and low PTENP1 (p = 0.0044) expressions were significantly associated with 5-FU resistance and tumor relapse in stage I/II CC. The invasiveness and colony-forming characteristics of 5-FU-resistant cell lineages were higher as compared to the parent HT-29. Moreover, the expression of MALAT1 (p = 0.0009) was increased while the expression of PTENP1 (p = 0.0158) decreased in 5FU-resistant-HT-29 cells. Si-MALAT1 treatment increased cell sensitivity to 5FU, whereas it decreased invasive behaviors of 5 FU-resistant-HT-29 cells. CONCLUSION MALAT1 may be a biomarker in predicting recurrence in early-stage CC. Our findings suggest that a cell-based therapy to target MALAT1 could be established for these patients to prevent metastasis and 5-FU resistance.
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Wanowska E, Samorowska K, Szcześniak MW. Emerging Roles of Long Noncoding RNAs in Breast Cancer Epigenetics and Epitranscriptomics. Front Cell Dev Biol 2022; 10:922351. [PMID: 35865634 PMCID: PMC9294602 DOI: 10.3389/fcell.2022.922351] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Breast carcinogenesis is a multistep process that involves both genetic and epigenetic changes. Epigenetics refers to reversible changes in gene expression that are not accompanied by changes in gene sequence. In breast cancer (BC), dysregulated epigenetic changes, such as DNA methylation and histone modifications, are accompanied by epitranscriptomic changes, in particular adenine to inosine modifications within RNA molecules. Factors that trigger these phenomena are largely unknown, but there is evidence for widespread participation of long noncoding RNAs (lncRNAs) that already have been linked to virtually any aspect of BC biology, making them promising biomarkers and therapeutic targets in BC patients. Here, we provide a systematic review of known and possible roles of lncRNAs in epigenetic and epitranscriptomic processes, along with methods and tools to study them, followed by a brief overview of current challenges regarding the use of lncRNAs in medical applications.
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Affiliation(s)
- Elżbieta Wanowska
- Department of Biological Sciences, Auburn University, Auburn, AL, United States
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University in Poznan, Poznań, Poland
- *Correspondence: Elżbieta Wanowska, ; Michał Wojciech Szcześniak,
| | - Klaudia Samorowska
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University in Poznan, Poznań, Poland
| | - Michał Wojciech Szcześniak
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University in Poznan, Poznań, Poland
- *Correspondence: Elżbieta Wanowska, ; Michał Wojciech Szcześniak,
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Singh D, Assaraf YG, Gacche RN. Long Non-coding RNA Mediated Drug Resistance in Breast Cancer. Drug Resist Updat 2022; 63:100851. [DOI: 10.1016/j.drup.2022.100851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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DRAIC promotes growth of breast cancer by sponging miR-432-5p to upregulate SLBP. Cancer Gene Ther 2022; 29:951-960. [PMID: 34645975 DOI: 10.1038/s41417-021-00388-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 04/30/2021] [Accepted: 09/09/2021] [Indexed: 11/08/2022]
Abstract
Mounting evidence suggests that lncRNAs can exert functions in cancer progression in multiple manners. In recent years, competing endogenous RNA (ceRNA) has been widely reported in human cancers as a lncRNA-dominant molecular pathway. The current study aimed at proving the role of lncRNA downregulated RNA in cancer (DRAIC) in breast cancer (BRCA) progression. To be specific, qRT-PCR assay was conducted to measure the expression of DRAIC and other downstream target genes. It was uncovered that DRAIC was expressed at a high level in BRCA cells. Functional analyses, including CCK-8, colony formation, and EdU assays demonstrated that DRAIC depletion suppressed BRCA cell proliferation. In addition, cell apoptosis was promoted due to DRAIC knockdown. The inhibitory effect of DRAIC reduction on BRCA cell migration and invasion was proven by transwell assays. Mechanistically, DRAIC was confirmed to predominantly distribute in the cytoplasm and could interact with miR-432-5p. In addition, stem-loop binding protein (SLBP) was verified to be a downstream target of miR-432-5p and was positively regulated by DRAIC. Taken together, DRAIC sponged miR-432-5p to enhance SLBP expression, by which malignant behaviors of BRCA cells were promoted. Our findings may help to provide a promising therapeutic target for BRCA patients.
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LncRNA FOXD3-AS1 promotes breast cancer progression by mediating ARF6. Breast Cancer 2022; 29:908-920. [PMID: 35678943 DOI: 10.1007/s12282-022-01373-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/11/2022] [Indexed: 11/02/2022]
Abstract
BACKGROUND Breast cancer is one of the most common malignant tumor in women. The high metastatic characteristics cause a high mortality rate of breast cancer. Increasing number of studies have indicated that long non-coding RNAs (lncRNAs) play key roles in the progression of human cancers including breast cancer. In this study, we studied the expression and molecular mechanisms of lncRNA FOXD3-AS1 in breast cancer. METHODS The expression of lncRNA FOXD3-AS1 was analyzed by TCGA database and RT-qPCR assay. CCK8 assay was used to measure cell proliferation ability. Cell migration and invasion capacities were detected by transwell assay. Potential targets of lncRNA and miRNA were predicted by bioinformatic tools. The targeting relationship between genes was verified by dual-luciferase reporter assay. The nude mice tumor model was performed to study the effect of FOXD3-AS1 on breast cancer in vivo. Protein expression was detected by western blot. RESULTS In the present study, we found that the FOXD3-AS1 expression was significantly increased in breast cancer tissues compared with normal tissues and involved in the poor prognosis of patients. Functionally, knockdown of FOXD3-AS1 suppressed cell proliferation and metastasis abilities in vitro, and tumor growth in vivo. Mechanistically, FOXD3-AS1 functioned as a competing endogenous RNA (ceRNA) to upregulate ARF6 expression by targeting miR-127-3p. In addition, the roles of FOXD3-AS1 on cell proliferation and metastasis were achieved through miR-127-3p/ARF6 axis. CONCLUSION In summary, our results reported the regulatory mechanism of FOXD3-AS1 in breast cancer progression by targeting miR-127-3p/ARF6 axis to affect cell proliferation, migration, invasion and tumor growth.
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Lu Y, Ying D, Tian Y, Ruan Y, Cheng G, Lv K, Zhou X, Han S. LncRNA LINC01857 drives pancreatic adenocarcinoma progression via modulating miR-19a-3p/SMOC2. Clinics (Sao Paulo) 2022; 77:100047. [PMID: 35662010 PMCID: PMC9168480 DOI: 10.1016/j.clinsp.2022.100047] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 02/23/2022] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVES Emerging evidence has demonstrated that LINC01857 exerts a pivotal function in many cancers. However, its function in Pancreatic Ductal Adenocarcinoma (PDAC) still remains unclear. This study was designed to investigate the regulatory character of LINC01857 in PDAC. METHODS Bioinformatic tools and databases were used to seek potential miRNAs and mRNAs. Gene expression was evaluated by Reverse Transcription quantitative real-time Polymerase Chain Reaction (RT-qPCR), and western blot was used for protein level detection. A subcellular fraction assay was done to ascertain the location of LINC01857 in PANC-1 and BxPC-3 human pancreatic cancer cells. CCK-8, EdU, wound healing and Transwell assays were performed to inquire into the influence of LINC01857, and SPARC -related Modular Calcium-binding protein-2 (SMOC2) on cell viability, proliferation, migration, and invasion, respectively. The interaction between LINC01857 and its downstream genes was explored by RNA immunoprecipitation and luciferase reporter assays. RESULTS LINC01857 levels were significantly elevated in PDAC. Knockdown of LINC01857 significantly restrained the proliferation, migration, invasion, and Epithelial-Mesenchymal Transition (EMT) process of PDAC cells. MiR-19a-3p was a downstream target of LINC01857, and miR-19a-3p levels were significantly decreased in PDAC cells. In addition, SMOC2 expression had a negative correlation with that of miR-19a-3p, and SMOC2 was a downstream target of miR-19a-3p. Furthermore, SMOC2 upregulation partially abolished the inhibitive influence of LINC01857 downregulation on cell proliferation, migration, invasion, and the EMT process. CONCLUSION LINC01857 promotes malignant phenotypes of PDAC cells via upregulation of SMOC2 by interacting with miR-19a-3p.
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Affiliation(s)
- Yeting Lu
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University(Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China
| | - Dongjian Ying
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University(Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China
| | - Yuan Tian
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University(Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China
| | - Yi Ruan
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University(Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China
| | - Gong Cheng
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University(Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China
| | - Kaiji Lv
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University(Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China
| | - Xinhua Zhou
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University(Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China
| | - Shuo Han
- Department of Healthcare Security and Price Management, The Affiliated Lihuili Hospital, Ningbo University (Ningbo Medical Center Lihuili Hospital), Ningbo 315100, Zhejiang, China.
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Mavingire N, Campbell P, Liu T, Wooten J, Khan S, Chen X, Matthews J, Wang C, Brantley E. Aminoflavone upregulates putative tumor suppressor miR-125b-2-3p to inhibit luminal A breast cancer stem cell-like properties. PRECISION CLINICAL MEDICINE 2022; 5:pbac008. [PMID: 35694715 PMCID: PMC9172653 DOI: 10.1093/pcmedi/pbac008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/21/2022] [Indexed: 11/18/2022] Open
Abstract
Metastatic breast cancer is incurable and often due to breast cancer stem cell (CSC)-mediated self-renewal. We previously determined that the aryl hydrocarbon receptor (AhR) agonist aminoflavone (AF) inhibits the expression of the CSC biomarker α6-integrin (ITGA6) to disrupt the formation of luminal (hormone receptor-positive) mammospheres (3D breast cancer spheroids). In this study, we performed miRNA-sequencing analysis of luminal A MCF-7 mammospheres treated with AF to gain further insight into the mechanism of AF-mediated anti-cancer and anti-breast CSC activity. AF significantly induced the expression of >70 microRNAs (miRNAs) including miR125b-2-3p, a predicted stemness gene regulator. AF-mediated miR125b-2-3p induction was validated in MCF-7 mammospheres and cells. miR125b-2-3p levels were low in breast cancer tissues irrespective of subtype compared to normal breast tissues. While miR125b-2-3p levels were low in MCF-7 cells, they were much lower in AHR100 cells (MCF-7 cells made unresponsive to AhR agonists). The miR125b-2-3p mimic decreased, while the antagomiR125b-2-3p increased the expression of stemness genes ITGA6 and SOX2 in MCF-7 cells. In MCF-7 mammospheres, the miR125b-2-3p mimic decreased only ITGA6 expression although the antagomiR125b-2-3p increased ITGA6, SOX2 and MYC expression. AntagomiR125b-2-3p reversed AF-mediated suppression of ITGA6. The miR125b-2-3p mimic decreased proliferation, migration, and mammosphere formation while the antagomiR125b-2-3p increased proliferation and mammosphere formation in MCF-7 cells. The miR125b-2-3p mimic also inhibited proliferation, mammosphere formation, and migration in AHR100 cells. AF induced AhR- and miR125b2-3p-dependent anti-proliferation, anti-migration, and mammosphere disruption in MCF-7 cells. Our findings suggest that miR125b-2-3p is a tumor suppressor and AF upregulates miR125b-2-3p to disrupt mammospheres via mechanisms that rely at least partially on AhR in luminal A breast cancer cells.
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Affiliation(s)
- Nicole Mavingire
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Petreena Campbell
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Current address: Frederick National Laboratory for Cancer Research, PO Box B, Bldg. 432, Room 232 Frederick, MD 21702-1201, USA
| | - Tiantian Liu
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Jonathan Wooten
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Salma Khan
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Xin Chen
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Jason Matthews
- Department of Nutrition, University of Oslo, Oslo 0372, Norway
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Charles Wang
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Eileen Brantley
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
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Chen SP, Zhu GQ, Xing XX, Wan JL, Cai JL, Du JX, Song LN, Dai Z, Zhou J. LncRNA USP2-AS1 Promotes Hepatocellular Carcinoma Growth by Enhancing YBX1-Mediated HIF1α Protein Translation Under Hypoxia. Front Oncol 2022; 12:882372. [PMID: 35692750 PMCID: PMC9174509 DOI: 10.3389/fonc.2022.882372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Abstract
Recently, the role of lncRNAs in tumorigenesis and development has received increasing attention, but the mechanism underlying lncRNAs-mediated tumor growth in the hypoxic microenvironment of solid tumors remains obscure. Using RNA sequencing, 25 hypoxia-related lncRNAs were found to be upregulated in HCC, of which lncRNA USP2-AS1 were significantly increased under hypoxia. We further confirmed that USP2-AS1 was significantly upregulated in liver cancer using FISH assay and that USP2-AS1 was associated with advanced liver cancer and increased tumor size. Furthermore, overexpression of USP2-AS1 under hypoxia dramatically increased HCC proliferation and clone formation, whereas the opposite results were observed after USP2-AS1 knockdown. We also found that overexpression of USP2-AS1 increased migration and invasion of HCC cells, while USP2-AS1 knockdown led to the opposite effect. In addition, USP2-AS1 knockdown can increase the efficacy of lenvatinib in our mice tumor xenograft model. Our findings also suggest that USP2-AS1 could increase the protein level of HIF1α by enhancing YBX1 protein binding to HIF1α mRNA under hypoxia and the therapeutic effect of lenvatinib can be enhanced by combination with HIF1α inhibitors in liver cancer.
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Affiliation(s)
- Shi-Ping Chen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Gui-Qi Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Xiao-Xia Xing
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jing-Lei Wan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Liang Cai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jun-Xian Du
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li-Na Song
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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