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Jin Y, Hu H, Tian Y, Xu H, Yu Q, Cheng L, Guo X, Wang Z, Huang X, Wang X, Wang G. The role of LncRNA-MANCR induced by HIF-1α drive the malignant progression of pancreatic cancer by targeting miRNA-494/SIRT1 signaling axis under hypoxic conditions. Cancer Gene Ther 2025:10.1038/s41417-025-00900-0. [PMID: 40195439 DOI: 10.1038/s41417-025-00900-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/08/2025] [Accepted: 03/25/2025] [Indexed: 04/09/2025]
Abstract
This study revealed the prospective biological role and fundamental mechanisms of hypoxia-induced lncRNA-MANCR (MANCR), which is notably upregulated in pancreatic cancer (PC). This work uncovered the potential biological function and underlying mechanisms of hypoxia-induced MANCR, which is significantly elevated in PC. Microarray assays confirmed MANCR expression in the tissues of patients with PC and patients with chronic pancreatitis (CP), which positively correlated with sirtuin-1 (SIRT1) mRNA levels. Chromatin immunoprecipitation and luciferase assays were employed to gauge binding within the hypoxia-inducible factor-1α (HIF-1α)/MANCR/miRNA-494/SIRT1 pathway. Additionally, the association between MANCR expression and the clinical outcomes of patients with PC was confirmed. MANCR is significantly upregulated in PC cells under hypoxic conditions, which is closely linked to poor prognosis in patients with PC. Depletion of MANCR repressed in vitro proliferation, migration, and invasion of PC cells and in vivo growth of PC xenograft tumours. We further demonstrated that MANCR is localised in the cytoplasm and competitively binds miR-494, which directly targets SIRT1. Mechanically, the overexpression of SIRT1 improved the stability of the HIF-1α protein through deacetylation, leading to enhanced HIF-1α assembly. Moreover, MANCR underwent transcriptional regulation by HIF-1α in a hypoxic setting. This modulation was ascribed to HIF-1α binding to hypoxia response elements present in the MANCR promoter sequence. Data revealed the potential possibility of feedback between MANCR and HIF-1α, which may be conducive to hypoxia-induced oncogenicity and PC tumorigenesis, thereby providing a suitable therapeutic target.
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Affiliation(s)
- Yan Jin
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
- Oncological and Laparoscopic Surgery Department, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hao Hu
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Yitong Tian
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Han Xu
- Department of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Qiao Yu
- Ultrasound medicine department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Long Cheng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Oncological and Laparoscopic Surgery Department, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoyu Guo
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Oncological and Laparoscopic Surgery Department, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zongwei Wang
- School of Medicine, Stanford University, San Francisco, CA, USA
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
- Oncological and Laparoscopic Surgery Department, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Singh SR, Bhaskar R, Ghosh S, Yarlagadda B, Singh KK, Verma P, Sengupta S, Mladenov M, Hadzi-Petrushev N, Stojchevski R, Sinha JK, Avtanski D. Exploring the Genetic Orchestra of Cancer: The Interplay Between Oncogenes and Tumor-Suppressor Genes. Cancers (Basel) 2025; 17:1082. [PMID: 40227591 PMCID: PMC11988167 DOI: 10.3390/cancers17071082] [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: 02/10/2025] [Revised: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
Cancer is complex because of the critical imbalance in genetic regulation as characterized by both the overexpression of oncogenes (OGs), mainly through mutations, amplifications, and translocations, and the inactivation of tumor-suppressor genes (TSGs), which entail the preservation of genomic integrity by inducing apoptosis to counter the malignant growth. Reviewing the intricate molecular interplay between OGs and TSGs draws attention to their cell cycle, apoptosis, and cancer metabolism regulation. In the present review, we discuss seminal discoveries, such as Knudson's two-hit hypothesis, which framed the field's understanding of cancer genetics, leading to the next breakthroughs with next-generation sequencing and epigenetic profiling, revealing novel insights into OG and TSG dysregulation with opportunities for targeted therapy. The key pathways, such as MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin, are presented in the context of tumor progression. Importantly, we further highlighted the advances in therapeutic strategies, including inhibitors of KRAS and MYC and restoration of TSG function, despite which mechanisms of resistance and tumor heterogeneity pose daunting challenges. A high-level understanding of interactions between OG-TSGs forms the basis for effective, personalized cancer treatment-something to strive for in better clinical outcomes. This synthesis should integrate foundational biology with translation and, in this case, contribute to the ongoing effort against cancer.
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Affiliation(s)
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeongsan-si 38541, Republic of Korea;
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan-si 38541, Republic of Korea
| | - Shampa Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, India
| | | | - Krishna Kumar Singh
- Symbiosis Centre for Information Technology (SCIT), Symbiosis International (Deemed University), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune 411057, India
| | - Prashant Verma
- School of Management, BML Munjal University, NH8, Sidhrawali, Gurugram 122413, India
| | - Sonali Sengupta
- Department of Gastroenterology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia
| | - Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | | | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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Wang C, Ma X. The role of acetylation and deacetylation in cancer metabolism. Clin Transl Med 2025; 15:e70145. [PMID: 39778006 PMCID: PMC11706801 DOI: 10.1002/ctm2.70145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
As a hallmark of cancer, metabolic reprogramming adjusts macromolecular synthesis, energy metabolism and redox homeostasis processes to adapt to and promote the complex biological processes of abnormal growth and proliferation. The complexity of metabolic reprogramming lies in its precise regulation by multiple levels and factors, including the interplay of multiple signalling pathways, precise regulation of transcription factors and dynamic adjustments in metabolic enzyme activity. In this complex regulatory network, acetylation and deacetylation, which are important post-translational modifications, regulate key molecules and processes related to metabolic reprogramming by affecting protein function and stability. Dysregulation of acetylation and deacetylation may alter cancer cell metabolic patterns by affecting signalling pathways, transcription factors and metabolic enzyme activity related to metabolic reprogramming, increasing the susceptibility to rapid proliferation and survival. In this review, we focus on discussing how acetylation and deacetylation regulate cancer metabolism, thereby highlighting the central role of these post-translational modifications in metabolic reprogramming, and hoping to provide strong support for the development of novel cancer treatment strategies. KEY POINTS: Protein acetylation and deacetylation are key regulators of metabolic reprogramming in tumour cells. These modifications influence signalling pathways critical for tumour metabolism. They modulate the activity of transcription factors that drive gene expression changes. Metabolic enzymes are also affected, altering cellular metabolism to support tumour growth.
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Affiliation(s)
- Cuicui Wang
- Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyang CityLiaoning ProvinceChina
- Key Laboratory of Gynecological Oncology of Liaoning ProvinceDepartment of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina
| | - Xiaoxin Ma
- Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyang CityLiaoning ProvinceChina
- Key Laboratory of Gynecological Oncology of Liaoning ProvinceDepartment of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina
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Zhang H, Sun X, Xiao H, Liu S, Guo N, Li Y, Shi J. miR-PC-3p-241582_34 Contributes to the Infection of Athetis lepigone by Regulating the Expression of HSWP4 in Nosema bombycis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024. [PMID: 39570147 DOI: 10.1021/acs.jafc.4c04093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Athetis lepigone is a recurring pest in the maize seedling stage under the wheat-maize no-tillage direct seeding system in China's summer maize region. Our previous research identified a highly pathogenic Nosema bombycis to A. lepigone, which spore wall protein plays an important role in the infection process. However, the regulatory mechanism of this spore wall protein is still unclear. In this study, we explored the regulatory mechanism of miRNAs on spore wall proteins. Transcriptome sequencing results showed that expression of the spore wall protein, HSWP4, significantly increased in the germination group compared to dormancy group. Silencing of HSWP4 reduced the number of microsporidian spores breaking through the midgut wall cells of A. lepigone. Association analysis of small RNA and mRNA revealed that the targeting site of miR-PC-3p-241582_34 on HSWP4 was located in the CDS region, and miR-PC-3p-241582_34 had a significant negative regulatory relationship with HSWP4. The dual luciferase reporter assay demonstrated that miR-PC-3p-241582_34 significantly affected the luciferase activity of the HSWP4-3'UTR expression vector (P < 0.05). Delivery of miRNA mimics decreased the expression of HSWP4 and inhibited the behavior of microsporidian spores breaking through the midgut wall of A. lepigone. On the other hand, delivery of inhibitors produced opposite results, indicating that the miR-HSWP4 pathway plays an important role in microsporidian infection of A. lepigone. This study provides a new theoretical basis for understanding the pathogenic mechanism and gene regulation of microsporidia, as well as for the green control of A. lepigone.
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Affiliation(s)
- Haijian Zhang
- Plant Protection Institute, Hebei Academy of Agriculture and Forestry Sciences, Key Laboratory of Integrated Pest Management on Crops in Northern Region of North China, Ministry of Agriculture and Rural Affairs, P. R. China, IPM Innovation Center of Hebei Province, International Science and Technology Joint Research Center on IPM of Hebei Province, Baoding, Hebei 071000, People's Republic of China
| | - Xuelian Sun
- Plant Protection Institute, Hebei Academy of Agriculture and Forestry Sciences, Key Laboratory of Integrated Pest Management on Crops in Northern Region of North China, Ministry of Agriculture and Rural Affairs, P. R. China, IPM Innovation Center of Hebei Province, International Science and Technology Joint Research Center on IPM of Hebei Province, Baoding, Hebei 071000, People's Republic of China
| | - Hongli Xiao
- Plant Protection Institute, Hebei Academy of Agriculture and Forestry Sciences, Key Laboratory of Integrated Pest Management on Crops in Northern Region of North China, Ministry of Agriculture and Rural Affairs, P. R. China, IPM Innovation Center of Hebei Province, International Science and Technology Joint Research Center on IPM of Hebei Province, Baoding, Hebei 071000, People's Republic of China
| | - Shusen Liu
- Plant Protection Institute, Hebei Academy of Agriculture and Forestry Sciences, Key Laboratory of Integrated Pest Management on Crops in Northern Region of North China, Ministry of Agriculture and Rural Affairs, P. R. China, IPM Innovation Center of Hebei Province, International Science and Technology Joint Research Center on IPM of Hebei Province, Baoding, Hebei 071000, People's Republic of China
| | - Ning Guo
- Plant Protection Institute, Hebei Academy of Agriculture and Forestry Sciences, Key Laboratory of Integrated Pest Management on Crops in Northern Region of North China, Ministry of Agriculture and Rural Affairs, P. R. China, IPM Innovation Center of Hebei Province, International Science and Technology Joint Research Center on IPM of Hebei Province, Baoding, Hebei 071000, People's Republic of China
| | - Yaofa Li
- Plant Protection Institute, Hebei Academy of Agriculture and Forestry Sciences, Key Laboratory of Integrated Pest Management on Crops in Northern Region of North China, Ministry of Agriculture and Rural Affairs, P. R. China, IPM Innovation Center of Hebei Province, International Science and Technology Joint Research Center on IPM of Hebei Province, Baoding, Hebei 071000, People's Republic of China
| | - Jie Shi
- Plant Protection Institute, Hebei Academy of Agriculture and Forestry Sciences, Key Laboratory of Integrated Pest Management on Crops in Northern Region of North China, Ministry of Agriculture and Rural Affairs, P. R. China, IPM Innovation Center of Hebei Province, International Science and Technology Joint Research Center on IPM of Hebei Province, Baoding, Hebei 071000, People's Republic of China
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Vahidi S, Agah S, Mirzajani E, Asghari Gharakhyli E, Norollahi SE, Rahbar Taramsari M, Babaei K, Samadani AA. microRNAs, oxidative stress, and genotoxicity as the main inducers in the pathobiology of cancer development. Horm Mol Biol Clin Investig 2024; 45:55-73. [PMID: 38507551 DOI: 10.1515/hmbci-2023-0012] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 03/06/2024] [Indexed: 03/22/2024]
Abstract
Cancer is one of the most serious leading causes of death in the world. Many eclectic factors are involved in cancer progression including genetic and epigenetic alongside environmental ones. In this account, the performance and fluctuations of microRNAs are significant in cancer diagnosis and treatment, particularly as diagnostic biomarkers in oncology. So, microRNAs manage and control the gene expression after transcription by mRNA degradation, or also they can inhibit their translation. Conspicuously, these molecular structures take part in controlling the cellular, physiological and pathological functions, which many of them can accomplish as tumor inhibitors or oncogenes. Relatively, Oxidative stress is defined as the inequality between the creation of reactive oxygen species (ROS) and the body's ability to detoxify the reactive mediators or repair the resulting injury. ROS and microRNAs have been recognized as main cancer promoters and possible treatment targets. Importantly, genotoxicity has been established as the primary reason for many diseases as well as several malignancies. The procedures have no obvious link with mutagenicity and influence the organization, accuracy of the information, or fragmentation of DNA. Conclusively, mutations in these patterns can lead to carcinogenesis. In this review article, we report the impressive and practical roles of microRNAs, oxidative stress, and genotoxicity in the pathobiology of cancer development in conjunction with their importance as reliable cancer biomarkers and their association with circulating miRNA, exosomes and exosomal miRNAs, RNA remodeling, DNA methylation, and other molecular elements in oncology.
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Affiliation(s)
- Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Mirzajani
- Department of Biochemistry and Biophysics, School of Medicine, 37554 Guilan University of Medical Sciences , Rasht, Iran
| | | | - Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Morteza Rahbar Taramsari
- Department of Forensic Medicine, School of Medicine, 37554 Guilan University of Medical Sciences , Rasht, Iran
| | - Kosar Babaei
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
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Guo Z, Ashrafizadeh M, Zhang W, Zou R, Sethi G, Zhang X. Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance. Cancer Metastasis Rev 2024; 43:29-53. [PMID: 37453022 DOI: 10.1007/s10555-023-10125-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
The metastasis is a multistep process in which a small proportion of cancer cells are detached from the colony to enter into blood cells for obtaining a new place for metastasis and proliferation. The metastasis and cell plasticity are considered major causes of cancer-related deaths since they improve the malignancy of cancer cells and provide poor prognosis for patients. Furthermore, enhancement in the aggressiveness of cancer cells has been related to the development of drug resistance. Metastasis of pancreatic cancer (PC) cells has been considered one of the major causes of death in patients and their undesirable prognosis. PC is among the most malignant tumors of the gastrointestinal tract and in addition to lifestyle, smoking, and other factors, genomic changes play a key role in its progression. The stimulation of EMT in PC cells occurs as a result of changes in molecular interaction, and in addition to increasing metastasis, EMT participates in the development of chemoresistance. The epithelial, mesenchymal, and acinar cell plasticity can occur and determines the progression of PC. The major molecular pathways including STAT3, PTEN, PI3K/Akt, and Wnt participate in regulating the metastasis of PC cells. The communication in tumor microenvironment can provide by exosomes in determining PC metastasis. The components of tumor microenvironment including macrophages, neutrophils, and cancer-associated fibroblasts can modulate PC progression and the response of cancer cells to chemotherapy.
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Affiliation(s)
- Zhenli Guo
- Department of Oncology, First Affiliated Hospital, Gannan Medical University, 128 Jinling Road, Ganzhou City, Jiangxi Province, 341000, China
| | - Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Wei Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Rongjun Zou
- Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, Guangdong, China
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Gautam Sethi
- Department of Pharmacology, National University of Singapore, 16 Medical Drive, Singapore, 117600, Singapore.
| | - Xianbin Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
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Hong Y, Chen B, Wang C, Gui R, Zhai X, Qian Q, Ren X, Xie X, Jiang C. circPPP2R4 promotes colorectal cancer progression and reduces ROS production through the miR-646/FOXK1 axis. Mol Carcinog 2024; 63:106-119. [PMID: 37750597 DOI: 10.1002/mc.23639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 08/25/2023] [Accepted: 09/13/2023] [Indexed: 09/27/2023]
Abstract
Circular RNAs (circRNAs) play important roles in colorectal cancer (CRC) development and progression. This study aimed to investigate the function and molecular mechanism of circPPP2R4 in CRC. Based on bioinformatic analyses and validation by qRT-PCR, we identified a novel circRNA, circPPP2R4, which was upregulated in CRC tissues. Receiver operating characteristic curve analysis implied a high diagnostic value of circPPP2R4 for CRC. Additionally, high circPPP2R4 levels were positively correlated with advanced clinical stage and lymph node metastasis. Functionally, circPPP2R4 overexpression facilitated CRC cells proliferation, migration and invasion, whereas circPPP2R4 knockdown attenuated the malignant behaviors. In mouse models, circPPP2R4 overexpression remarkably promoted tumor growth and lung metastasis. Mechanistically, a series of experiments containing RIP, RNA pull-down, and dual-luciferase reporter assays revealed the circPPP2R4/miR-646/FOXK1 axis in CRC. Further experiments were conducted to verify that circPPP2R4 reduced reactive oxygen species generation to exert its oncogenic function by sponging miR-646 to upregulate FOXK1 expression. For the first time, we identified the regulatory role of circPPP2R4 in CRC pathogenesis, providing a potential diagnostic biomarker and therapeutic strategy for CRC.
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Affiliation(s)
- Yuntian Hong
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
- Key Laboratory of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
| | - Baoxiang Chen
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
- Key Laboratory of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
| | - Chun Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Rui Gui
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiang Zhai
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
- Key Laboratory of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
| | - Qun Qian
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
- Key Laboratory of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
| | - Xianghai Ren
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
- Key Laboratory of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
| | - Xiaoyu Xie
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
- Key Laboratory of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
| | - Congqing Jiang
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
- Key Laboratory of Intestinal and Colorectal Diseases of Hubei Province, Wuhan, China
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Ye B, Duan Y, Zhou M, Wang Y, Lai Q, Yue K, Cao J, Wu Y, Wang X, Jing C. Hypoxic tumor-derived exosomal miR-21 induces cancer-associated fibroblast activation to promote head and neck squamous cell carcinoma metastasis. Cell Signal 2023; 108:110725. [PMID: 37230199 DOI: 10.1016/j.cellsig.2023.110725] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 04/30/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Both microRNA-21-5p (miR-21) and the tumor microenvironment, including hypoxia and cancer-associated fibroblasts (CAFs), play a vital role in head and neck squamous cell carcinoma (HNSCC), but whether there is an interaction and the specific regulatory mechanism between them in the process of metastasis is still unclear. In this study, we aimed to elucidate the connection and regulatory mechanism of miR-21, hypoxia, and CAFs in HNSCC metastasis. METHODS The underlying mechanisms of HIF1α regulating miR-21 transcription, promoting exosome secretion, CAFs activation, tumor invasion, and lymph node metastasis were determined through quantitative real-time PCR, immunoblotting, transwell, wound healing, immunofluorescence, ChIP, electron microscopy, nanoparticle tracking analysis, dual-luciferase reporter assay, co-culture model and xenografts experiments. RESULTS MiR-21 promoted the invasion and metastasis of HNSCC in vitro and in vivo, whereas HIF1α knockdown inhibited these processes. HIF1α upregulated transcription of miR-21 and promoted the release of exosomes from HNSCC cells. Exosomes derived from hypoxic tumor cells were rich in miR-21, which induced NFs activation towards CAFs by targeting YOD1. Knockdown the expression level of miR-21 in CAFs prevented lymph node metastasis in HNSCC. CONCLUSION Hypoxic tumor cell-derived exosomal miR-21 might be a therapeutic target to prevent or delay HNSCC invasion and metastasis.
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Affiliation(s)
- Beibei Ye
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Yuansheng Duan
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Mengqian Zhou
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui, China
| | - Yuxuan Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Qingchuan Lai
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Kai Yue
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Jiayan Cao
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Yansheng Wu
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
| | - Chao Jing
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
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Wang Y, Zhang M, Zhang L, Zhou M, Wang E. Nanoparticles loaded with circ_0086375 for suppressing the tumorigenesis of pancreatic cancer by targeting the miR-646/SLC4A4 axis. Clin Exp Metastasis 2023; 40:53-67. [PMID: 36479657 DOI: 10.1007/s10585-022-10197-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/12/2021] [Indexed: 12/12/2022]
Abstract
Nanoparticles possess the ability to adsorb and load other compounds. This study aimed to synthesize a gene carrier with polyethyleneimine (PEI), hyaluronic acid (HA) and mesoporous silica nanoparticles (MSNs) for circ_0086375 delivery to investigate the role and mechanism of circ_0086375 in pancreatic cancer (PC) progression. The expression of genes and proteins was detected by quantitative real-time polymerase chain reaction and Western blot. In vitro experiments were performed by cell counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, transwell assay, and wound healing assay, respectively. Dual-luciferase activity assay was used to investigate the target relationship between miR-646 and circ_0086375 or SLC4A4 (solute carrier family 4 member 4). Circ_0086375 loaded PEI/HA-based mesoporous silica nanoparticles (MSNs) were prepared, and in vivo assay was performed by using xenograft tumor model. Circ_0086375 expression was decreased in PC tissues and cells. Restoration of circ_0086375 suppressed PC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, circ_0086375 acted as a sponge for miR-646 to elevate SLC4A4 expression, which was confirmed to be a target of miR-646. The prepared circ_0086375/MSN/PEI/HA nanocomplexes showed excellent fluorescent properties and a higher cellular uptake of circ_0086375 in PC cells. Moreover, circ_0086375/MSN/PEI/HA showed relatively more anticancer effects in PC than that of circ_0086375 alone in vitro and in vivo. Delivery of circ_0086375 by nanoparticles suppresses the tumorigenicity of pancreatic cancer by miR-646/SLC4A4 axis, suggesting a new potential target for future pancreatic cancer treatment.
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Affiliation(s)
- Yunjian Wang
- Surgery Department of Hepatobiliary and Pancreatic, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, Henan Province, China.
| | - Min Zhang
- Surgery Department of Hepatobiliary and Pancreatic, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, Henan Province, China
| | - Luyang Zhang
- Surgery Department of Hepatobiliary and Pancreatic, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, Henan Province, China
| | - Minghe Zhou
- Surgery Department of Hepatobiliary and Pancreatic, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, Henan Province, China
| | - Enze Wang
- Surgery Department of Hepatobiliary and Pancreatic, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, Henan Province, China
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10
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Ray SK, Mukherjee S. Interaction Among Noncoding RNAs, DNA Damage Reactions, and Genomic Instability in the Hypoxic Tumor: Is it Therapeutically Exploitable Practice? Curr Mol Med 2023; 23:200-215. [PMID: 35048804 DOI: 10.2174/1566524022666220120123557] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/30/2021] [Accepted: 12/07/2021] [Indexed: 02/08/2023]
Abstract
Hypoxia is a classical function of the tumor's microenvironment with a substantial effect on the development and therapeutic response of cancer. When put in hypoxic environments, cells undergo several biological reactions, including activation of signaling pathways that control proliferation, angiogenesis, and death. These pathways have been adapted by cancer cells to allow tumors to survive and even develop in hypoxic conditions, and poor prognosis is associated with tumor hypoxia. The most relevant transcriptional regulator in response to hypoxia, Hypoxia-inducible factor-1 alpha (HIF-1α), has been shown to modulate hypoxic gene expression and signaling transduction networks significantly. The significance of non-coding RNAs in hypoxic tumor regions has been revealed in an increasing number of studies over the past few decades. In regulating hypoxic gene expression, these hypoxia-responsive ncRNAs play pivotal roles. Hypoxia, a general characteristic of the tumor's microenvironment, significantly affects the expression of genes and is closely associated with the development of cancer. Indeed, the number of known hypoxia-associated lncRNAs has increased dramatically, demonstrating the growing role of lncRNAs in cascades and responses to hypoxia signaling. Decades of research have helped us create an image of the shift in hypoxic cancer cells' DNA repair capabilities. Emerging evidence suggests that hypoxia can trigger genetic instability in cancer cells because of microenvironmental tumor stress. Researchers have found that critical genes' expression is coordinately repressed by hypoxia within the DNA damage and repair pathways. In this study, we include an update of current knowledge on the presentation, participation, and potential clinical effect of ncRNAs in tumor hypoxia, DNA damage reactions, and genomic instability, with a specific emphasis on their unusual cascade of molecular regulation and malignant progression induced by hypoxia.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry All India Institute of Medical Sciences. Bhopal, Madhya Pradesh-462020. India
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11
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Gao Y, Fang Y, Huang Y, Ma R, Chen X, Wang F, Pei X, Gao Y, Chen X, Liu X, Shan J, Li P. MIIP functions as a novel ligand for ITGB3 to inhibit angiogenesis and tumorigenesis of triple-negative breast cancer. Cell Death Dis 2022; 13:810. [PMID: 36130933 PMCID: PMC9492696 DOI: 10.1038/s41419-022-05255-0] [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: 06/06/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 01/23/2023]
Abstract
Migration and invasion inhibitory protein (MIIP) has been identified as a tumor suppressor in various cancer types. Although MIIP is reported to exert tumor suppressive functions by repressing proliferation and metastasis of cancer cells, the detailed mechanism is poorly understood. In the present study, we found MIIP is a favorable indicator of prognosis in triple-negative breast cancer. MIIP could inhibit tumor angiogenesis, proliferation, and metastasis of triple-negative breast cancer cells in vivo and in vitro. Mechanistically, MIIP directly interacted with ITGB3 and suppressed its downstream signaling. As a result, β-catenin was reduced due to elevated ubiquitin-mediated degradation, leading to downregulated VEGFA production and epithelial mesenchymal transition. More importantly, we found RGD motif is essential for MIIP binding with ITGB3 and executing efficient tumor-suppressing effect. Our findings unravel a novel mechanism by which MIIP suppresses tumorigenesis in triple-negative breast cancer, and MIIP is thus a promising molecular biomarker or therapeutic target for the disease.
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Affiliation(s)
- Yujing Gao
- grid.412194.b0000 0004 1761 9803National Health Commission Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China
| | - Yujie Fang
- grid.412194.b0000 0004 1761 9803National Health Commission Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yongli Huang
- grid.412194.b0000 0004 1761 9803National Health Commission Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Rui Ma
- grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xixi Chen
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Wang
- grid.413385.80000 0004 1799 1445Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xiuying Pei
- grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yuanqi Gao
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuehua Chen
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinrui Liu
- grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Jingxuan Shan
- grid.5386.8000000041936877XDepartment of Genetic Medicine, Weill Cornell Medicine, New York, NY USA
| | - Pu Li
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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12
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Gu W, Shen H, Xie L, Zhang X, Yang J. The Role of Feedback Loops in Targeted Therapy for Pancreatic Cancer. Front Oncol 2022; 12:800140. [PMID: 35651786 PMCID: PMC9148955 DOI: 10.3389/fonc.2022.800140] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 04/11/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic cancer is the leading cause of cancer-related deaths worldwide, with limited treatment options and low long-term survival rates. The complex and variable signal regulation networks are one of the important reasons why it is difficult for pancreatic cancer to develop precise targeted therapy drugs. Numerous studies have associated feedback loop regulation with the development and therapeutic response of cancers including pancreatic cancer. Therefore, we review researches on the role of feedback loops in the progression of pancreatic cancer, and summarize the connection between feedback loops and several signaling pathways in pancreatic cancer, as well as recent advances in the intervention of feedback loops in pancreatic cancer treatment, highlighting the potential of capitalizing on feedback loops modulation in targeted therapy for pancreatic cancer.
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Affiliation(s)
- Weigang Gu
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - HongZhang Shen
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lu Xie
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- *Correspondence: Xiaofeng Zhang, ; Jianfeng Yang,
| | - Jianfeng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xiaofeng Zhang, ; Jianfeng Yang,
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Sun G, Yuan W, Zhu W, Chen J. WZY-321 triggers glioma cell apoptosis via XAF1 up-regulation caused by MTM-mediated miR-873 down-regulation. J Cancer 2022; 13:2312-2321. [PMID: 35517406 PMCID: PMC9066199 DOI: 10.7150/jca.68775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 03/06/2022] [Indexed: 11/05/2022] Open
Abstract
Gliomas account for the majority of primary malignant brain tumors around the world and are highly aggressive. Evodiamine is one of the main effective components of Evodia rutaecarpa, which can inhibit proliferation and promote apoptosis of tumor cells including glioma cells. The derivative of Evodiamine named WZY-321 was successfully developed, and exhibited significant cytotoxicity and could efficiently induce glioma cell apoptosis; however, the mechanism of WZY-321-induced glioma cell apoptosis is not clear. Our current studies showed that WZY-321 increased X-linked inhibitor of apoptosis-associated factor 1 (XAF1) expression in glioma cells, and up-regulated XAF1 resulted in glioma cell apoptosis. Moreover, WZY-321 treatment decreased miR-873 expression and increased lncRNA MTM expression in glioma cells, and down-regulated miR-873 or up-regulated MTM lead to glioma cell apoptosis. Mechanically, WZY-321 up-regulated XAF1 gene expression via MTM-decreased miR-873 expression, that bound to XAF1 3' UTR and decreased XAF1 mRNA levels. Taken together, these data indicate that WZY-321 triggers glioma cell apoptosis via XAF1 up-regulation caused by MTM-mediated miR-873 down-regulation.
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Affiliation(s)
- Guan Sun
- Department of Neurosurgery, The Fourth Affiliated Hospital of Nantong University, The First People's Hospital of Yancheng, Yancheng, P.R. China.,Department of Neurosurgery, The Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Wei Yuan
- Department of Neurosurgery, The Fourth Affiliated Hospital of Nantong University, The First People's Hospital of Yancheng, Yancheng, P.R. China
| | - Weiye Zhu
- Department of Neurosurgery, The Fourth Affiliated Hospital of Nantong University, The First People's Hospital of Yancheng, Yancheng, P.R. China
| | - Jian Chen
- Department of Neurosurgery, The Affiliated Hospital of Nantong University, Nantong, P.R. China
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14
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Zhang D, Tao L, Xu N, Lu X, Wang J, He G, Tang Q, Huang K, Shen S, Chu J. CircRNA circTIAM1 promotes papillary thyroid cancer progression through the miR-646/HNRNPA1 signaling pathway. Cell Death Dis 2022; 8:21. [PMID: 35022405 PMCID: PMC8755710 DOI: 10.1038/s41420-021-00798-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 09/07/2021] [Accepted: 12/02/2021] [Indexed: 11/24/2022]
Abstract
Papillary thyroid cancer (PTC) is a common endocrine tumor with a rapidly increasing incidence in recent years. Although the majority of PTCs are relatively indolent and have a good prognosis, a certain proportion is highly aggressive with lymphatic metastasis, iodine resistance, and easy recurrence. Circular RNAs (circRNAs) are a class of noncoding RNAs that are linked to a variety of tumor processes in several cancers, including PTC. In the current study, circRNA high-throughput sequencing was performed to identify alterations in circRNA expression levels in PTC tissues. circTIAM1 was then selected because of its increased expression in PTC and association with apoptosis, proliferation, and migration of PTC cells in vitro and in vivo. Mechanistically, circTIAM1 acted as a sponge of microRNA-646 and functioned in PTC by targeting miR-646 and heterogeneous ribonucleoprotein A1. Fluorescence in situ hybridization and dual-luciferase reporter assays further confirmed these connections. Overall, our results reveal an important oncogenic role of circTIAM1 in PTC and may represent a potentially therapeutic target against PTC progression.
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Affiliation(s)
- Deguang Zhang
- Department of head and neck surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, People's Republic of China
| | - Li Tao
- Department of head and neck surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, People's Republic of China
| | - Nizheng Xu
- Department of head and neck surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, People's Republic of China
| | - Xiaoxiao Lu
- Department of head and neck surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, People's Republic of China
| | - Jianle Wang
- Department of orthopaedic surgery, Sir Run Run Shaw Hospital, Zhejiang University school of Medicine & Key laboratory of Musculoskeletal system Degeneration and regeneration Translational research of Zhejiang Province, 3 east Qingchun road, Hangzhou, 310016, People's Republic of China
| | - Gaofei He
- Department of head and neck surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, People's Republic of China
| | - Qinghu Tang
- Department of general surgery, People's Hospital of Linghu, Nanxun District, Huzhou, Zhejiang Province, People's Republic of China
| | - Kangmao Huang
- Department of orthopaedic surgery, Sir Run Run Shaw Hospital, Zhejiang University school of Medicine & Key laboratory of Musculoskeletal system Degeneration and regeneration Translational research of Zhejiang Province, 3 east Qingchun road, Hangzhou, 310016, People's Republic of China
| | - Shuying Shen
- Department of orthopaedic surgery, Sir Run Run Shaw Hospital, Zhejiang University school of Medicine & Key laboratory of Musculoskeletal system Degeneration and regeneration Translational research of Zhejiang Province, 3 east Qingchun road, Hangzhou, 310016, People's Republic of China.
| | - Junjie Chu
- Department of head and neck surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, People's Republic of China.
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15
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Jin Y, Zhang Z, Yu Q, Zeng Z, Song H, Huang X, Kong Q, Hu H, Xia Y. Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer. Front Oncol 2021; 11:761979. [PMID: 34881179 PMCID: PMC8645903 DOI: 10.3389/fonc.2021.761979] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022] Open
Abstract
Background Many studies have reported the roles of the extracellular hypoxia microenvironment in the tumorigenesis and metastasis of multiple cancers. However, long noncoding RNAs (lncRNAs) that induce cancer oncogenicity and metastasis of pancreatic cancer (PC) under hypoxia conditions remain unclear. Methods In PC cells, the expression levels of lncRNAs in different conditions (normoxia or hypoxia) were compared through RNA sequencing (RNA-seq). The effects of the zinc finger E-box-binding homeobox 1 (ZEB1-AS1) antisense lncRNA on PC cells cultured in normoxia/hypoxia medium were measured through gain and loss-of-function experiments. Fluorescence in situ hybridization and luciferase reporter assays in addition to in vivo studies were utilized to explore the adaptive mechanisms of ZEB1-AS1 in the hypoxia-promoted proliferation, migration, and invasion ability of PC cells. Moreover, the level of ZEB1-AS1 and its associated targets or pathways were investigated in both PC and pancreatic normal tissues. Results RNA-seq revealed that ZEB1-AS1 was significantly upregulated in PC cells under hypoxia conditions. The ZEB1-AS1 expression level was closely associated with poor prognosis of PC patients. Knockdown of ZEB1-AS1 suppressed the proliferation, migration, and invasion of PC cells in vitro as well as PC xenograft tumor growth in vivo. In PC cells, RNAi-mediated reduction of ZEB1-AS1 inhibited zinc finger E-box-binding homeobox 1 (ZEB1), while ZEB1-AS1 overexpression rescued ZEB1 expression, indicating that ZEB1-AS1 promotes ZEB1 expression. Moreover, hypoxia-inducible factor-1α (HIF-1α)induced the expression of ZEB1-AS1 by binding to the ZEB1-AS1 promoter, which contains a putative hypoxia response element (HRE). Mechanistically, ZEB1-AS1 scaffolded the interaction among HIF-1α, ZEB1, and histone deacetylase 1 (HDAC1), leading to deacetylation-mediated stabilization of HIF-1α. We further revealed that ZEB1 induced the deacetylase capacity of HDAC1 to suppress the acetylation or degradation of HIF-1α, improving HIF-1α assembly. Thus, hypoxia-induced ZEB1-AS1 facilitated ZEB1 transcription and the stability of HIF-1α, which promoted the metastasis of PC cells. Clinically, dysregulated ZEB1 and HIF-1α expression was significantly correlated with histological grade, lymphatic metastasis, and distant metastasis in PC patients. Conclusions Our results emphasized that the positive reciprocal loop of HIF-1α/ZEB1-AS1/ZEB1/HDAC1 contributes to hypoxia-promoted oncogenicity and PC metastasis, indicating that it might be a novel therapeutic target for PC.
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Affiliation(s)
- Yan Jin
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Zhengming Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Qiao Yu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhu Zeng
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Song
- Department of Pathology, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Qi Kong
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Hao Hu
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
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16
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Kim A, Ha J, Kim J, Cho Y, Ahn J, Cheon C, Kim SH, Ko SG, Kim B. Natural Products for Pancreatic Cancer Treatment: From Traditional Medicine to Modern Drug Discovery. Nutrients 2021; 13:nu13113801. [PMID: 34836055 PMCID: PMC8625071 DOI: 10.3390/nu13113801] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer, the seventh most lethal cancer around the world, is considered complicated cancer due to poor prognosis and difficulty in treatment. Despite all the conventional treatments, including surgical therapy and chemotherapy, the mortality rate is still high. Therefore, the possibility of using natural products for pancreatic cancer is increasing. In this study, 68 natural products that have anti-pancreatic cancer effects reported within five years were reviewed. The mechanisms of anti-cancer effects were divided into four types: apoptosis, anti-metastasis, anti-angiogenesis, and anti-resistance. Most of the studies were conducted for natural products that induce apoptosis in pancreatic cancer. Among them, plant extracts such as Eucalyptus microcorys account for the major portion. Some natural products, including Moringa, Coix seed, etc., showed multi-functional properties. Natural products could be beneficial candidates for treating pancreatic cancer.
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Affiliation(s)
- Ahyeon Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (A.K.); (J.H.); (J.K.)
| | - Jiwon Ha
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (A.K.); (J.H.); (J.K.)
| | - Jeongeun Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (A.K.); (J.H.); (J.K.)
| | - Yongmin Cho
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (Y.C.); (J.A.); (S.-H.K.)
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (C.C.); (S.-G.K.)
| | - Jimyung Ahn
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (Y.C.); (J.A.); (S.-H.K.)
| | - Chunhoo Cheon
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (C.C.); (S.-G.K.)
| | - Sung-Hoon Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (Y.C.); (J.A.); (S.-H.K.)
| | - Seong-Gyu Ko
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (C.C.); (S.-G.K.)
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (A.K.); (J.H.); (J.K.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (Y.C.); (J.A.); (S.-H.K.)
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (C.C.); (S.-G.K.)
- Correspondence: ; Tel.: +82-2-961-9217
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17
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Estaras M, Gonzalez A. Modulation of cell physiology under hypoxia in pancreatic cancer. World J Gastroenterol 2021; 27:4582-4602. [PMID: 34366624 PMCID: PMC8326256 DOI: 10.3748/wjg.v27.i28.4582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
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Affiliation(s)
- Matias Estaras
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
| | - Antonio Gonzalez
- Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
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18
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Duan KM, Fang C, Yang SQ, Yang ST, Xiao JD, Chang H, Lin GX, Zhang LB, Peng MC, Liu ZQ, Wang SY. Genetic Polymorphism of rs13306146 Affects α2AAR Expression and Associated With Postpartum Depressive Symptoms in Chinese Women Who Received Cesarean Section. Front Genet 2021; 12:675386. [PMID: 34306020 PMCID: PMC8294467 DOI: 10.3389/fgene.2021.675386] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 05/17/2021] [Indexed: 01/20/2023] Open
Abstract
Postpartum depressive symptom (PDS) is a common psychological and mental disorder after giving birth. Our previous studies showing the application of dexmedetomidine, an α2-AR agonist, can significantly improve maternal sleep, as well as relieve and reduce the incidence of PDS. This study investigated the association between α2 A AR gene polymorphisms and PDS. A total of 568 cesarean section patients were enrolled; the incidence of PDS is 18.13% (103 with PDS, 465 with non-PDS). The Edinburgh Postpartum Depression Scale score ≥10 was used to diagnose PDS at 42 days after delivery. The single-nucleotide polymorphisms of α2AR were sequenced by pyrosequencing. The effect of rs13306146 A > G polymorphism on α2AR transcription and the regulation of miR-646 on α2AR expression were assessed by dual luciferase reporter assays or gene transfection. Increased stress during pregnancy, poor relationship between mother-in-law and daughter-in-law, spousal relationship, domestic violence, antenatal depression, self-harm ideation, and stressful life events were all associated with increased PDS incidence (p < 0.05). The logistic regression analysis found that the α2AAR rs13306146 polymorphism was associated with PDS after adjusting confounding variables. The transcriptional function of the α2AAR rs13306146 A allele was decreased compared with the G allele, and the α2AAR expression level was correspondingly decreased (p < 0.05), as the strongest binding ability of miR-646 to the α2AAR rs13306146 AA genotype. The effect of α2AAR rs13306146 A > G polymorphism may change the binding ability of miR-646 at the 3'UTR of the α2AAR gene, affecting the expression of α2AAR. This study supports the involvement of the norepinephrine system in the pathogenesis of PDS. Genotypes of α2AAR may be novel and useful biomarkers for PDS.
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Affiliation(s)
- Kai Ming Duan
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Chao Fang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China.,Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Si Qi Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Shu Ting Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Ji Dong Xiao
- Department of Ultrasonography, Third Xiangya Hospital of Central South University, Changsha, China
| | - Huang Chang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Guo Xin Lin
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Liang Bin Zhang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Ming Chao Peng
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhao Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Sai Ying Wang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
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19
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Du T, Han J. Arginine Metabolism and Its Potential in Treatment of Colorectal Cancer. Front Cell Dev Biol 2021; 9:658861. [PMID: 34095122 PMCID: PMC8172978 DOI: 10.3389/fcell.2021.658861] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Colorectal cancer is the leading cause of death from cancer globally. The current treatment protocol still heavily relies on early detection and surgery. The molecular mechanisms underlying development of colorectal cancer are clinically important and determine the prognosis and treatment response. The arginine metabolism pathway is hyperactive in colorectal cancer and several molecules involved in the pathway are potential targets for chemoprevention and targeted colorectal cancer therapy. Endothelial nitric oxide synthase (eNOS), argininosuccinate synthetase and ornithine decarboxylase (ODC) are the main enzymes for arginine metabolism. Limiting arginine-rich meat consumption and inhibiting ODC activity largely reduces polyamine synthesis and the incidence of colorectal cancer. Arginine transporter CAT-1 and Human member 14 of the solute carrier family 6 (SLC6A14) are overexpressed in colorectal cancer cells and contributes to intracellular arginine levels. Human member 9 of the solute carrier family 38 (SLC38A9) serves as a component of the lysosomal arginine-sensing machinery. Pharmaceutical inhibition of single enzyme or arginine transporter is hard to meet requirement of restoring of abnormal arginine metabolic network. Apart from application in early screening for colorectal cancer, microRNA-based therapeutic strategy that simultaneously manipulating multiple targets involved in arginine metabolism brings promising future in the treatment of colorectal cancer.
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Affiliation(s)
- Tao Du
- Department of Colorectal Surgery, East Hospital, Tongji University School of Medicine, Pudong, China
| | - Junyi Han
- Department of Colorectal Surgery, East Hospital, Tongji University School of Medicine, Pudong, China
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20
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Guo HM, Liu ZP. Up-regulation of circRNA_0068481 promotes right ventricular hypertrophy in PAH patients via regulating miR-646/miR-570/miR-885. J Cell Mol Med 2021; 25:3735-3743. [PMID: 33710774 PMCID: PMC8051745 DOI: 10.1111/jcmm.16164] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023] Open
Abstract
CircRNA‐0068481 and several miRNAs are important in the pathogenesis of right ventricular hypertrophy (VH), while the inhibition of eye absent transcriptional coactivator and phosphatase 3 (EYA3) was proved to reverse vascular remodelling in rats. In this study, we tried to study the diagnostic value and mechanistic role of circRNA_0068481 in the diagnosis of RVH in PAH patients. qPCR was done to measure circRNA‐0068481, miR‐646, miR‐750, miR‐885 and EYA3 mRNA expression. Luciferase assay was done to explore the regulatory relationship between circRNA‐0068481/EYA3 and the miRNAs. Western blot was done to measure EYA3 expression in AC16 cells. The expression of circRNA‐0068481, miR‐646 and miR‐570 showed a considerable capability to diagnose RVH in PAH patients. The luciferase activity of circRNA‐0068481 was remarkably suppressed by miR‐646, miR‐570 or miR‐885. The luciferase signal of EYA3 was also inhibited by miR‐646, miR‐570 and miR‐885. Up‐regulation of circRNA‐0068481 expression in AC16 significantly decreased miR‐646, miR‐570 and miR‐885 expression, and up‐regulated EYA3 expression, whereas circRNA‐0068481 down‐regulation significantly increased miR‐646, miR‐570 and miR‐885 expression, and repressed EYA3 expression. CircRNA_0068481 sponged several miRNAs including miR‐646, miR‐570 and miR‐885. These miRNAs were all found to target the expression of EYA3 mRNA, which is involved in the onset of right ventricular hypertrophy. Therefore, it can be concluded that the up‐regulation of circRNA_0068481 can predict the diagnosis of right ventricular hypertrophy in pulmonary arterial hypertension patients.
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Affiliation(s)
- Hong-Mei Guo
- Ultrasonography Department, Weinan Maternal and Child Health Hospital, Weinan, China
| | - Zi-Peng Liu
- UItrasonic Diagnosis Department, Hanzhong Central Hospital, Hanzhong, China
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21
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He B, Chen J, Song W, Bai Y. miR-646/TET1 mediated demethylation of IRX1 promoter upregulates HIST2H2BE and promotes the progression of invasive ductal carcinoma. Genomics 2021; 113:1469-1481. [PMID: 33667646 DOI: 10.1016/j.ygeno.2020.12.044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 12/11/2020] [Accepted: 12/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND This study aimed to explore role of miR-646 in breast IDC. METHODS miR-646, TET1, IRX1, and HIST2H2BE expression was detected by RT-qPCR and/or Western blot analysis. The methylation status of IRX1 promoter region was evaluated by methylation specific PCR. ChIP assay was used to determine the enrichment of TET1 at IRX1 promoter region. Loss- and gain-of functions were performed to determine the roles of miR-646, TET1, IRX1, and HIST2H2BE in cell proliferation, migration, invasion, and apoptosis. The tumor growth, volume, weight, and apoptosis status were measured. RESULTS miR-646 was upregulated while TET1 was downregulated in IDC tissues. miR-646 targeted TET1. Downregulated TET1 impairs demethylation of IRX1 promoter region resulting in reduced expression of IRX1, which subsequently leads to upregulation of HIST2H2BE in IDC. Consequently, elevated HIST2H2BE promotes progression of IDC. CONCLUSION Our study has demonstrated that miR-646 facilitates the tumorigenesis of IDC via regulating TET1/IRX1/HIST2H2BE axis.
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Affiliation(s)
- Baoxia He
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450003, PR China.
| | - Jinhua Chen
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450003, PR China
| | - Wenping Song
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450003, PR China
| | - Yongtao Bai
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450003, PR China
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22
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Role of microRNAs in Lung Carcinogenesis Induced by Asbestos. J Pers Med 2021; 11:jpm11020097. [PMID: 33546236 PMCID: PMC7913345 DOI: 10.3390/jpm11020097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs are a class of small noncoding endogenous RNAs 19–25 nucleotides long, which play an important role in the post-transcriptional regulation of gene expression by targeting mRNA targets with subsequent repression of translation. MicroRNAs are involved in the pathogenesis of numerous diseases, including cancer. Lung cancer is the leading cause of cancer death in the world. Lung cancer is usually associated with tobacco smoking. However, about 25% of lung cancer cases occur in people who have never smoked. According to the International Agency for Research on Cancer, asbestos has been classified as one of the cancerogenic factors for lung cancer. The mechanism of malignant transformation under the influence of asbestos is associated with the genotoxic effect of reactive oxygen species, which initiate the processes of DNA damage in the cell. However, epigenetic mechanisms such as changes in the microRNA expression profile may also be implicated in the pathogenesis of asbestos-induced lung cancer. Numerous studies have shown that microRNAs can serve as a biomarker of the effects of various adverse environmental factors on the human body. This review examines the role of microRNAs, the expression profile of which changes upon exposure to asbestos, in key processes of carcinogenesis, such as proliferation, cell survival, metastasis, neo-angiogenesis, and immune response avoidance.
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23
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Zhu F, Li H, Long T, Zhou M, Wan J, Tian J, Zhou Z, Hu Z, Nie J. Tubular Numb promotes renal interstitial fibrosis via modulating HIF-1α protein stability. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166081. [PMID: 33486098 DOI: 10.1016/j.bbadis.2021.166081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/11/2021] [Accepted: 01/18/2021] [Indexed: 11/28/2022]
Abstract
Tubulointerstitial fibrosis is the ultimate common pathway of all manners of chronic kidney disease. We previously demonstrated that specific deletion of Numb in proximal tubular cells (PTCs) prevented G2/M arrest and attenuated renal fibrosis. However, how Numb modulates cell cycle arrest remains unclear. Here, we showed that Numb overexpression significantly increased the protein level of hypoxia-inducible factor-1α (HIF-1α). Numb overexpression-induced G2/M arrest was blocked by silencing endogenous HIF-1α, subsequently downregulated the expression of cyclin G1 which is an atypical cyclin to promote G2/M arrest of PTCs. Further analysis revealed that Numb-augmented HIF-1α protein was blocked by simultaneously overexpressing MDM2. Moreover, silencing Numb decreased TGF-β1-induceded HIF-1α protein expression. While endogenous MDM2 was knocked down this reduction was reversed, indicating that Numb stabilized HIF-1α protein via interfering MDM2-mediated HIF-1α protein degradation. Interestingly, HIF-1α overexpression significantly upregulated the expression of Numb and silencing endogenous HIF-1α blocked CoCl2 or TGF-β1-induced Numb expression. Chromatin immunoprecipitation (ChIP) assays demonstrated that HIF-1α binded to the promoter region of Numb. This binding was significantly increased by TGF-β1. Collectively, these data indicate that Numb and HIF-1α cooperates to promote G2/M arrest of PTCs, and thus aggravates tubulointerstitial fibrosis. Numb might be a potential target for the therapy of tubulointerstitial fibrosis.
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Affiliation(s)
- Fengxin Zhu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Hao Li
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Tantan Long
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Miaomiao Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiao Wan
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jianwei Tian
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhanmei Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zheng Hu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jing Nie
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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24
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Tao J, Yang G, Zhou W, Qiu J, Chen G, Luo W, Zhao F, You L, Zheng L, Zhang T, Zhao Y. Targeting hypoxic tumor microenvironment in pancreatic cancer. J Hematol Oncol 2021; 14:14. [PMID: 33436044 PMCID: PMC7805044 DOI: 10.1186/s13045-020-01030-w] [Citation(s) in RCA: 244] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/25/2020] [Indexed: 12/13/2022] Open
Abstract
Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.
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Affiliation(s)
- Jinxin Tao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenchuan Zhou
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. .,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.
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25
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Wang M, Zhao HY, Zhang JL, Wan DM, Li YM, Jiang ZX. Dysregulation of LncRNA ANRIL mediated by miR-411-3p inhibits the malignant proliferation and tumor stem cell like property of multiple myeloma via hypoxia-inducible factor 1α. Exp Cell Res 2020; 396:112280. [PMID: 32961145 DOI: 10.1016/j.yexcr.2020.112280] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 09/03/2020] [Accepted: 09/07/2020] [Indexed: 11/25/2022]
Abstract
Long non-coding RNA (lncRNA) ANRIL has been reported to be closely related to the relapse of multiple myeloma patients. However, the functional role and underlying mechanism of lncRNA ANRIL in multiple myeloma are not known. This study aims to investigate the biological function of lncRNA ANRIL in multiple myeloma. In this study, compared with normal tissues from healthy donors, lncRNA ANRIL and HIF-1α expressions were up-regulated in tumor tissues from multiple myeloma patients. miR-411-3p expression was down-regulated in tumor tissues from multiple myeloma patients. Besides, lncRNA ANRIL can interact with miR-411-3p. HIF-1α was confirmed to be a target of miR-411-3p. Correlation analysis showed that lncRNA ANRIL expression was negatively correlated with miR-411-3p expression. HIF-1α expression was negatively correlated with miR-411-3p expression. Further transfection experiments showed that knockdown of ANRIL or overexpression of miR-411-3p significantly inhibited cell proliferation, tumor formation ability and tumor stem cell like property, promoted cell apoptosis in vitro. Finally, miR-411-3p mimic reduced tumor volume, improved survival rate, suppressed malignant proliferation and tumor stem cell like property in U266 xenograft model. Our results demonstrate that lncRNA ANRIL mediated by miR-411-3p promotes the malignant proliferation and tumor stem cell like property of multiple myeloma through regulating HIF-1α.
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MESH Headings
- Animals
- Apoptosis/genetics
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Cell Line, Tumor
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Mice
- Mice, Nude
- MicroRNAs/agonists
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Multiple Myeloma/genetics
- Multiple Myeloma/metabolism
- Multiple Myeloma/mortality
- Multiple Myeloma/pathology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/pathology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Oligoribonucleotides/genetics
- Oligoribonucleotides/metabolism
- Plasma Cells/metabolism
- Plasma Cells/pathology
- RNA, Long Noncoding/antagonists & inhibitors
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Signal Transduction
- Survival Analysis
- Tumor Burden
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Meng Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Hua-Yan Zhao
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Jing-Lan Zhang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Ding-Ming Wan
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Ying-Mei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Zhong-Xing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China.
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26
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Li T, Mao C, Wang X, Shi Y, Tao Y. Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:224. [PMID: 33109235 PMCID: PMC7592369 DOI: 10.1186/s13046-020-01733-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023]
Abstract
Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.
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Affiliation(s)
- Tiansheng Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Chao Mao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Xiang Wang
- Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Ying Shi
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
| | - Yongguang Tao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China. .,Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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27
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Geismann C, Arlt A. Coming in the Air: Hypoxia Meets Epigenetics in Pancreatic Cancer. Cells 2020; 9:cells9112353. [PMID: 33113836 PMCID: PMC7694089 DOI: 10.3390/cells9112353] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/17/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
With a five-year survival rate under 9%, pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related death in 2020 in the US. In addition to a pronounced desmoplastic stroma reaction, pancreatic cancer is characterized by one of the lowest levels of oxygen availability within the tumor mass and these hypoxic conditions are known to contribute to tumor development and progression. In this context, the major hypoxia associated transcription factor family, HIF, regulates hundreds of genes involved in angiogenesis, metabolism, migration, invasion, immune escape and therapy resistance. Current research implications show, that hypoxia also modulates diverse areas of epigenetic mechanisms like non-coding RNAs, histone modifications or DNA methylation, which cooperate with the hypoxia-induced transcription factors as well as directly regulate the hypoxic response pathways. In this review, we will focus on hypoxia-mediated epigenetic alterations and their impact on pancreatic cancer.
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Affiliation(s)
- Claudia Geismann
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany;
| | - Alexander Arlt
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany;
- Department for Gastroenterology, European Medical School (EMS), Klinikum Oldenburg AöR, 26133 Oldenburg, Germany
- Correspondence: ; Tel.: +49-441-403-2581
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Liu Y, Qin P, Wu R, Du L, Li F. ERas regulates cell proliferation and epithelial-mesenchymal transition by affecting Erk/Akt signaling pathway in pancreatic cancer. Hum Cell 2020; 33:1186-1196. [PMID: 32700262 PMCID: PMC7505876 DOI: 10.1007/s13577-020-00401-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is the fourth most common lethal malignancy with an overall 5-year survival rate of less than 5%. ERas, a novel Ras family member, was first identified in murine embryonic stem cells and is upregulated in various cancers. However, the expression and potential role of ERas in pancreatic cancer have not been investigated. In this study, we found that ERas mRNA and protein were upregulated in pancreatic cancer tissues and cells compared with controls. Knockdown of ERas in pancreatic cancer cells by siRNA significantly decreased cell proliferation, colony formation, migration, and invasion and promoted cell apoptosis in vitro. Epithelial-mesenchymal transition (EMT) is closely related to tumor progression. We observed a significant decrease in N-cadherin expression in pancreatic cancer cells in response to ERas gene silencing by immunofluorescence assay and western blot. Furthermore, tumor growth and EMT were inhibited in xenografts derived from pancreatic cancer cells with ERas downregulation. We further investigated the regulatory mechanisms of ERas in pancreatic cancer and found that ERas may activate the Erk/Akt signaling pathway. Moreover, Erk inhibitor decreased pancreatic cancer cells proliferation and colony formation activities. Our data suggest that targeting ERas and its relevant signaling pathways might represent a novel therapeutic approach for the treatment of pancreatic cancer.
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Affiliation(s)
- Yang Liu
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China
| | - Peng Qin
- Department of Instrument Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Rong Wu
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China
| | - Lianfang Du
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China.
| | - Fan Li
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China.
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Tan Z, Xu J, Zhang B, Shi S, Yu X, Liang C. Hypoxia: a barricade to conquer the pancreatic cancer. Cell Mol Life Sci 2020; 77:3077-3083. [PMID: 31907561 PMCID: PMC11104901 DOI: 10.1007/s00018-019-03444-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/22/2019] [Accepted: 12/27/2019] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer (PC) remains one of the most extremely lethal malignancies worldwide due to late diagnosis and early metastasis, with a 1-year overall survival rate of approximately 20%. The hypoxic microenvironment, induced by intratumoral hypoxia, promotes tumor invasion and progression, leading to chemotherapy or radiotherapy resistance and eventual mortality after treatment of PC. However, the role of the hypoxic microenvironment in PC is complicated and requires further investigation. In this article, we review recent advances regarding the regulation of malignant behaviors in PC, which provide insight into the potential of hypoxic microenvironment activation therapy for the therapeutic agents.
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Affiliation(s)
- Zhen Tan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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microRNA-93-5p promotes hepatocellular carcinoma progression via a microRNA-93-5p/MAP3K2/c-Jun positive feedback circuit. Oncogene 2020; 39:5768-5781. [PMID: 32719439 DOI: 10.1038/s41388-020-01401-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/03/2020] [Accepted: 07/20/2020] [Indexed: 12/19/2022]
Abstract
Cumulative evidence suggests that microRNAs (miRNAs) promote gene expression in cancers. However, the pathophysiologic relevance of miRNA-mediated RNA activation in hepatocellular carcinoma (HCC) remains to be established. Our previous miRNA expression profiling in seven-paired HCC specimens revealed miR-93-5p as an HCC-related miRNA. In this study, miR-93-5p expression was assessed in HCC tissues and cell lines by quantitative real-time PCR and fluorescence in situ hybridization. The correlation of miR-93-5p expression with survival and clinicopathological features of HCC was determined by statistical analysis. The function and potential mechanism of miR-93-5p in HCC were further investigated by a series of gain- or loss-of-function experiments in vitro and in vivo. We identified that miR-93-5p, overexpressed in HCC specimens and cell lines, leads to poor outcomes in HCC cases and promotes proliferation, migration, and invasion in HCC cell lines. Mechanistically, rather than decreasing target mRNA levels as expected, miR-93-5p binds to the 3'-untranslated region (UTR) of mitogen-activated protein kinase kinase kinase 2 (MAP3K2) to directly upregulate its expression and downstream p38 and c-Jun N-terminal kinase (JNK) pathway, thereby leading to cell cycle progression in HCC. Notably, we also demonstrated that c-Jun, a downstream effector of the JNK pathway, enhances miR-93-5p transcription by targeting its promoter region. Besides, downregulation of miR-93-5p significantly retarded tumor growth, while overexpression of miR-93-5p accelerated tumor growth in the HCC xenograft mouse model. Altogether, we revealed a miR-93-5p/MAP3K2/c-Jun positive feedback loop to promote HCC progression in vivo and in vitro, representing an RNA-activating role of miR-93-5p in HCC development.
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Chen S, Xu M, Zhao J, Shen J, Li J, Liu Y, Cao G, Ma J, He W, Chen X, Shan T. MicroRNA-4516 suppresses pancreatic cancer development via negatively regulating orthodenticle homeobox 1. Int J Biol Sci 2020; 16:2159-2169. [PMID: 32549762 PMCID: PMC7294951 DOI: 10.7150/ijbs.45933] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/20/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer remains one of the most lethal human cancers without efficient therapeutic strategy. MicoRNAs (miRNAs) are a group of small non-coding RNAs involved in multiple biological processes including tumor development and progression. In this study, we investigated the expression and function of miR-4516 in pancreatic cancer. MiR-4516 was low-expressed in pancreatic cancer tissues and cell lines. Overexpression of miR-4516 inhibited pancreatic cancer cell proliferation, migration and invasion, while promoted cell apoptosis in vitro. Further, overexpression of miR-4516 suppressed xenograft pancreatic tumor growth in vivo. Bioinformatics analysis was performed and miR-4516 was predicted to negatively regulate orthodenticle homeobox 1 (OTX1) expression by binding to its 3'-UTR. Consistently, OTX1 was highly expressed in pancreatic cancer tissues and cell lines. Knockdown of OTX1 expression suppressed pancreatic cancer cell migration and invasion, with down-regulated MMP2 and MMP9 expression. Moreover, we demonstrated that miR-4516 regulated pancreatic cancer cell growth, migration, invasion and apoptosis via targeting OTX1. Overexpression of OTX1 could partially abrogate the inhibitory effect of miR-4516. Taken together, we conclude that miR-4516 could function as a tumor suppressor via targeting OTX1. These findings suggest that miR-4516/OTX1 axis might be a novel therapeutic target for miRNA-based therapy for pancreatic cancer patients.
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Affiliation(s)
- Shuo Chen
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Meng Xu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Jing Zhao
- School of Science, Xi'an Jiaotong University, PR China
| | - Jiaqi Shen
- School of Life Science, Xiamen University, PR China
| | - Junhui Li
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Yang Liu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Gang Cao
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Jiancang Ma
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Weizhou He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Xi Chen
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
| | - Tao Shan
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, PR China
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Liu Y, Chen S, Zong ZH, Guan X, Zhao Y. CircRNA WHSC1 targets the miR-646/NPM1 pathway to promote the development of endometrial cancer. J Cell Mol Med 2020; 24:6898-6907. [PMID: 32378344 PMCID: PMC7299690 DOI: 10.1111/jcmm.15346] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 12/25/2019] [Accepted: 04/12/2020] [Indexed: 12/16/2022] Open
Abstract
Circular RNAs (circRNAs) play important roles in human cancer progression. Their high stability and tissue specificity make circRNAs important molecular targets for clinical diagnosis, treatment and prognosis. However, the functions and molecular mechanisms of circRNA WHSC1 in endometrial cancer are unknown. CircWHSC1 expression in normal endometrial and endometrial cancer tissues was detected using PCR. Overexpression or knockdown of circWHSC1 in endometrial cancer cell lines HEC‐1B or Ishikawa, respectively, cell function experiments were used to detect the impact of circWHSC1 on endometrial cancer cells. A nude mouse xenograft model was used to detect changes in tumorigenesis of HEC‐1B cells after circWHSC1 overexpression. Bioinformatics and dual luciferase reporter gene technology were used to predict and validate the sponging ability of circWHSC1 on microRNAs. Gene expression changes were detected by using Western blotting. CircWHSC1 expression was increased in endometrial cancer tissues. CircWHSC1 overexpression promoted the proliferation, migration and invasion of endometrial cancer cells and decreased apoptosis. CircWHSC1 knockdown had the opposite effect. CircWHSC1 overexpressed nude mice showed increased tumorigenicity. Bioinformatics predicted that circWHSC1 binds to miR‐646, which was confirmed using luciferase reporter gene assays. High expression of miR‐646 could reverse the effect of circWHSC1 on endometrial cancer cells. Western blotting showed increased or decreased levels of nucleophosmin 1 (NPM1), an miR‐646 downstream target, after circWHSC1 overexpression or knockdown, respectively. CircWHSC1 promotes endometrial cancer development through sponging miR‐646 and targeting NPM1.
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Affiliation(s)
- Yao Liu
- Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institute in Guangdong Province, Guangzhou, China
| | - Shuo Chen
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhi-Hong Zong
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xue Guan
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yang Zhao
- Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institute in Guangdong Province, Guangzhou, China
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Wang J, Shu H, Guo S. MiR-646 suppresses proliferation and metastasis of non-small cell lung cancer by repressing FGF2 and CCND2. Cancer Med 2020; 9:4360-4370. [PMID: 32347652 PMCID: PMC7300416 DOI: 10.1002/cam4.3062] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 03/25/2020] [Accepted: 03/29/2020] [Indexed: 12/17/2022] Open
Abstract
MicroRNA‐646 (miR‐646) has been implicated in several other cancers; however, its functional mechanism in non‐small cell lung cancer (NSCLC) remains unclear. In this study, we observed the downregulation of miR‐646 expression in NSCLC tissues and cell lines. Low‐level expression of miR‐646 was associated with metastasis and stage of NSCLCs. Functional assays showed that overexpression of miR‐646 could suppress NSCLC cell proliferation, clonogenicity, invasion, and inhibit epithelial‐mesenchymal transition (EMT), whereas decreased miR‐646 expression showed the opposite effects. Importantly, miR‐646 overexpression attenuated in vivo tumor growth and metastasis in nude mice models. Mechanically, miR‐646 directly targeted and suppressed fibroblast growth factor 2 (FGF2) and cyclin D2 (CCND2) expression. Reintroduction of FGF2 and CCND2 attenuated miR‐646‐mediated suppression of proliferation and invasion in NSCLC. Collectively, these results demonstrate that miR‐646 acts as a tumor suppressor in NSCLC by targeting FGF2 and CCND2, and may serve as a therapeutic target for patients with NSCLC.
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Affiliation(s)
- Jing Wang
- Department of Respiratory Disease, Jinshan Hospital of Fudan University, Shanghai, China
| | - Huizhen Shu
- Xuanqiao Community Health Service Center, Shanghai, China
| | - Shuigen Guo
- Department of Respiratory Disease, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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Crosstalk of MicroRNAs and Oxidative Stress in the Pathogenesis of Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2415324. [PMID: 32411322 PMCID: PMC7204110 DOI: 10.1155/2020/2415324] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/02/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Abstract
Oxidative stress refers to an imbalance between reactive oxygen species (ROS) generation and body's capability to detoxify the reactive mediators or to fix the relating damage. MicroRNAs are considered to be important mediators that play essential roles in the regulation of diverse aspects of carcinogenesis. Growing studies have demonstrated that the ROS can regulate microRNA biogenesis and expression mainly through modulating biogenesis course, transcription factors, and epigenetic changes. On the other hand, microRNAs may in turn modulate the redox signaling pathways, altering their integrity, stability, and functionality, thus contributing to the pathogenesis of multiple diseases. Both ROS and microRNAs have been identified to be important regulators and potential therapeutic targets in cancers. However, the information about the interplay between oxidative stress and microRNA regulation is still limited. The present review is aimed at summarizing the current understanding of molecular crosstalk between microRNAs and the generation of ROS in the pathogenesis of cancer.
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Peng X, Gao H, Xu R, Wang H, Mei J, Liu C. The interplay between HIF-1α and noncoding RNAs in cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:27. [PMID: 32014012 PMCID: PMC6998277 DOI: 10.1186/s13046-020-1535-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/27/2020] [Indexed: 12/19/2022]
Abstract
Hypoxia is a classic characteristic of the tumor microenvironment with a significant impact on cancer progression and therapeutic response. Hypoxia-inducible factor-1 alpha (HIF-1α), the most important transcriptional regulator in the response to hypoxia, has been demonstrated to significantly modulate hypoxic gene expression and signaling transduction networks. In past few decades, growing numbers of studies have revealed the importance of noncoding RNAs (ncRNAs) in hypoxic tumor regions. These hypoxia-responsive ncRNAs (HRNs) play pivotal roles in regulating hypoxic gene expression at the transcriptional, posttranscriptional, translational and posttranslational levels. In addition, as a significant gene expression regulator, ncRNAs exhibit promising roles in regulating HIF-1α expression at multiple levels. In this review, we briefly elucidate the reciprocal regulation between HIF-1α and ncRNAs, as well as their effect on cancer cell behaviors. We also try to summarize the complex feedback loop existing between these two components. Moreover, we evaluated the biomarker potential of HRNs for the diagnosis and prognosis of cancer, as well as the potential clinical utility of shared regulatory mechanisms between HIF-1α and ncRNAs in cancer treatment, providing novel insights into tumorigenicity, which may lead to innovative clinical applications.
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Affiliation(s)
- Xiafeng Peng
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.,The First Clinical Medicine School, Nanjing Medical University, Nanjing, 211166, China
| | - Han Gao
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Rui Xu
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China
| | - Huiyu Wang
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China
| | - Jie Mei
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.
| | - Chaoying Liu
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.
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hsa_circ0021347 as a Potential Target Regulated by B7-H3 in Modulating the Malignant Characteristics of Osteosarcoma. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9301989. [PMID: 31950059 PMCID: PMC6948356 DOI: 10.1155/2019/9301989] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 10/15/2019] [Accepted: 11/09/2019] [Indexed: 12/20/2022]
Abstract
In our previous study, we showed that B7-H3 played crucial roles in osteosarcoma (OS) development and might serve as a negative regulator of in osteoimmunology and help tumor cells escape immune surveillance. However, little is known about B7-H3 deficiency and its corresponding circRNA alteration or their relationship with osteosarcoma progression. Therefore, we established stable silencing of B7-H3 in OS cells and validated our results with western blotting and real-time PCR detection. Then, we performed a circRNA array to analyze the differential expression of circRNAs between the control and B7-H3 knockdown cells. The association between target circRNA expression and the clinicopathological features of patients with OS was further analyzed. As a result, hsa_circ0021347 was selected and validated to be significantly downregulated in OS tissues and cell lines and showed a strong negative relationship with B7-H3 expression in OS. In addition, clinicopathological features showed that hsa_circ0021347 in OS tissues was negatively associated with Enneking stage and positively associated with patients' survival. Finally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and PANTHER pathway analyses were performed to predict a network of hsa_circ0021347/miRNAs interactions to help us develop potential biomarkers for clinical diagnosis and design therapeutic strategies for OS.
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Combined identification of three miRNAs in serum as effective diagnostic biomarkers for HNSCC. EBioMedicine 2019; 50:135-143. [PMID: 31780396 PMCID: PMC6921333 DOI: 10.1016/j.ebiom.2019.11.016] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 11/08/2019] [Accepted: 11/08/2019] [Indexed: 12/11/2022] Open
Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is a disastrous disease with substantial morbidity and mortality. This study aims to explore the effective diagnostic and prognostic biomarkers for HNSCC. Methods: MiRNA expression data and corresponding clinical information of HNSCC from The Cancer Genome Atlas (TCGA) database were analyzed comprehensively to identify the miRNAs with diagnostic and prognostic power. The predictive ability of different classifications was analyzed for the three-miRNA combinations. Diagnostic and prognostic value were then evaluated and verified in clinical patients. Findings: 128 differentially expressed miRNAs in HNSCC tissues were identified in the TCGA dataset, and 10 miRNAs were finally selected for further study. Classification analysis developed a three-miRNA signature of hsa-mir-383, hsa-mir-615, and hsa-mir-877 with the best diagnosis power, which was verified in validation patients. Survival analysis indicated that different expression levels of hsa-mir-383, rather than that of hsa-mir-615 or hsa-mir-877 led to significantly different survival rates in both cohorts. Furthermore, the multivariate Cox hazards analysis suggested that the microRNA signature yielded statistical significance to predict clinical outcome independently from other clinical variables in validation patients. Interpretation: A three-miRNA signature of hsa-mir-383, hsa-mir-615, and hsa-mir-877 may serve as an excellent diagnostic biomarker for HNSCC, and potential prognostic significance for HNSCC patients. Funding: This work was supported by the grants of the National Natural Science Foundation of China (81901021), Key Research and Development Program of Shandong (2019GSF108277), China postdoctoral Scinence Foundation Grant (2019M652380), Fundamental Research Funds of Shandong University (2018CJ047).
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Liu Y, Ding W, Ge H, Ponnusamy M, Wang Q, Hao X, Wu W, Zhang Y, Yu W, Ao X, Wang J. FOXK transcription factors: Regulation and critical role in cancer. Cancer Lett 2019; 458:1-12. [PMID: 31132431 DOI: 10.1016/j.canlet.2019.05.030] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/22/2019] [Accepted: 05/22/2019] [Indexed: 12/25/2022]
Abstract
Growing evidence suggests that alterations of gene expression including expression and activities of transcription factors are closely associated with carcinogenesis. Forkhead Box Class K (FOXK) proteins, FOXK1 and FOXK2, are a family of evolutionarily conserved transcriptional factors, which have recently been recognized as key transcriptional regulators involved in many types of cancer. Members of the FOXK family mediate a wide spectrum of biological processes, including cell proliferation, differentiation, apoptosis, autophagy, cell cycle progression, DNA damage and tumorigenesis. Therefore, the deregulation of FOXKs can affect the cell fate and they promote tumorigenesis as well as cancer progression. The mechanisms of FOXKs regulation including post-translational modifications (PTMs), microRNAs (miRNAs) and protein-protein interactions are well demonstrated. However, the detailed mechanisms of FOXKs activation and deregulation in cancer progression are still inconclusive. In this review, we summarize the regulatory mechanisms of FOXKs expression and activity, and their role in the development and progression of cancer. We have discussed whether FOXKs act as tumor suppressors/oncoproteins in tumor cells and their therapeutic applications in malignant diseases are also discussed. This review may assist in designing experimental studies involving FOXKs and it would strength the therapeutic potential of FOXKs as targets for cancers.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Wei Ding
- Department of Comprehensive Internal Medicine, Affiliated Hospital, Qingdao University, Qingdao 266003, China
| | - Hu Ge
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; Molecular Informatics Department, Hengrui Pharmaceutical Co., Ltd., Shanghai 200245, China
| | - Murugavel Ponnusamy
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Qiong Wang
- Molecular Informatics Department, Hengrui Pharmaceutical Co., Ltd., Shanghai 200245, China
| | - Xiaodan Hao
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Wei Wu
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yuan Zhang
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Wanpeng Yu
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xiang Ao
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Jianxun Wang
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; School of Basic Medical Sciences, Qingdao University, Qingdao 266071, China.
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Yan G, Ru Y, Yan F, Xiong X, Hu W, Pan T, Sun J, Zhang C, Wang Q, Li X. MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling. Cell Commun Signal 2019; 17:44. [PMID: 31092266 PMCID: PMC6521544 DOI: 10.1186/s12964-019-0355-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 04/17/2019] [Indexed: 12/09/2022] Open
Abstract
Background Over-activation of phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway is one of important mechanisms to promote castration resistant prostate cancer, the final stage of prostate cancer (PCa). Dysregulation of PP1-meditaed AKT dephosphorylation might contribute to such an event but is not fully understood. As a newly identified tumor suppressor, MIIP exerts its role in various types of cancer but has not been investigated in PCa. Results We first demonstrated that overexpression of migration and invasion inhibitory protein (MIIP) in human PCa cell lines suppresses their growth while knockdown of MIIP does the opposite in vitro. Although MIIP has no effect on the expression of AR and its target genes or the nuclear translocation of AR in AR-positive PCa cells, MIIP overexpression significantly inhibits activation of AKT-mTOR pathway in both AR- positive and negative PCa cells whereas knockdown of MIIP enhances AKT-mTOR signaling. Using Western blot, immunofluorescence co-localization and co-immunoprecipitation analysis, we found that MIIP interacts with PP1α via its C-terminal part but does not affect its protein level. Importantly, silence of PP1α reversed the inhibitory effect of MIIP on AKT phosphorylation and cell growth in PCa cell lines, while MIIP∆C, which is incapable of interacting with PP1α, loses MIIP’s effect, suggesting that MIIP exerts its roles via interaction with PP1α. Further, MIIP overexpression inhibits the growth of both AR- positive and negative PCa xenograft in nude mice. Finally, immunohistochemical staining of PCa tissue microarray showed that MIIP expression level is downregulated in PCa and negatively correlated with Gleason score of PCa. Conclusion We discovered that MIIP is a novel suppressor of oncogenic AKT-mTOR signaling in PCa by facilitating PP1-meditaed AKT dephosphorylation. Our study further emphasized the tumor suppressive role of MIIP and illustrated a novel mechanism. Electronic supplementary material The online version of this article (10.1186/s12964-019-0355-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guang Yan
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.,Andrology Department, Shanghai Seventh People's Hospital, Shanghai, 200137, China
| | - Yi Ru
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Fengqi Yan
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.,Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Xin Xiong
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Wei Hu
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Tao Pan
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jianming Sun
- Andrology Department, Shanghai Seventh People's Hospital, Shanghai, 200137, China
| | - Chi Zhang
- Rehabilitation Department, Gongli Hospital of Shanghai Pudong New Area, Shanghai, 200137, China
| | - Qinhao Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Xia Li
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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Upregulation of MIIP regulates human breast cancer proliferation, invasion and migration by mediated by IGFBP2. Pathol Res Pract 2019; 215:152440. [PMID: 31078343 DOI: 10.1016/j.prp.2019.152440] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/28/2019] [Accepted: 05/05/2019] [Indexed: 01/07/2023]
Abstract
AIMS The migration and invasion inhibitory protein (MIIP) was initially discovered in a yeast two-hybrid screen for proteins that interact and inhibit the migration and invasion-promoting protein insulin-like growth factor binding protein 2 (IGFBP2). This study aims to evaluate the biological effects of MIIP in breast cancer by targeting IGFBP2. MATERIALS AND METHODS Reverse transcription quantitative real-time polymerase chain reaction and Western blotting were used to evaluate the abnormal expression of MIIP and IGFBP2 in breast cancer tissue or breast cancer cell lines. Transfection assay was used to overexpress MIIP protein in breast cancer cells. MTT assay and colony formation assay were used to detect cell viability of breast cancer cells after MIIP overexpression. Transwell and wound-healing assays were used to detect cell invasion and migration after MIIP overexpression. RESULTS MIIP was significantly decreased and IGFBP2 was significantly increased in breast cancer tissues versus para cancerous. Breast cancer tissues of HER2 overexpression and Basal-like were more significant than Luminal A and Luminal B. MIIP was obviously downregulated and IGFBP2 was upregulated in MDA-MB-231, SKBR3 and MCF-7 versus MCF-10A especially in MDA-MB-231. Cell proliferation, cell migration and cell invasion were significantly inhibited after overexpression of MIIP. IGFBP2 was downregulated after overexpression of MIIP. The effects of MIIP on cell proliferation, cell migration and invasion were significantly reversed by IGFBP2. CONCLUSION The abnormal expression of MIIP in breast cancer affects the cell biological effects. IGFBP2 was regulated via MIIP which may be associated with these biological effects. These results reveal that MIIP can be a potential target for breast cancer treatment.
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Lin Y, Wu W, Sun Z, Shen L, Shen B. MiRNA-BD: an evidence-based bioinformatics model and software tool for microRNA biomarker discovery. RNA Biol 2018; 15:1093-1105. [PMID: 30081733 DOI: 10.1080/15476286.2018.1502590] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs with the potential as biomarkers for disease diagnosis, prognosis and therapy. In the era of big data and biomedical informatics, computer-aided biomarker discovery has become the current frontier. However, most of the computational models are highly dependent on specific prior knowledge and training-testing procedures, very few are mechanism-guided or evidence-based. To the best of our knowledge, untill now no general rules have been uncovered and applied to miRNA biomarker screening. In this study, we manually collected literature-reported cancer miRNA biomarkers and analyzed their regulatory patterns, including the regulatory modes, biological functions and evolutionary characteristics of their targets in the human miRNA-mRNA network. Two evidences were statistically detected and used to distinguish biomarker miRNAs from others. Based on these observations, we developed a novel bioinformatics model and software tool for miRNA biomarker discovery ( http://sysbio.suda.edu.cn/MiRNA-BD/ ). In contrast to routine methods that focus on miRNA synergic functions, our method searches for vulnerable sites in the miRNA-mRNA network and considers the independent regulatory power of miRNAs, i.e., single-line regulations between miRNAs and mRNAs. The performance comparison demonstrates the generality and precision of our model, which identifies miRNA biomarkers for cancers as well as other complex diseases without training or specific prior knowledge.
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Affiliation(s)
- Yuxin Lin
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China
| | - Wentao Wu
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China
| | - Zhandong Sun
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China
| | - Li Shen
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China.,b Department of Genetics & Systems Biology Institute , Yale University School of Medicine , West Haven , CT USA
| | - Bairong Shen
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China.,c Center for Translational Biomedical Informatics , Guizhou University School of Medicine , Guiyang , China.,d Institute for Systems Genetics, West China Hospital , Sichuan University , Chengdu , China
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Chen H, Xiao Z, Yu R, Wang Y, Xu R, Zhu X. miR-181d-5p-FOXP1 feedback loop modulates the progression of osteosarcoma. Biochem Biophys Res Commun 2018; 503:1434-1441. [DOI: 10.1016/j.bbrc.2018.07.060] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 07/11/2018] [Indexed: 12/22/2022]
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Li F, Liang J, Bai L. MicroRNA-449a functions as a tumor suppressor in pancreatic cancer by the epigenetic regulation of ATDC expression. Biomed Pharmacother 2018; 103:782-789. [DOI: 10.1016/j.biopha.2018.04.101] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/13/2018] [Accepted: 04/13/2018] [Indexed: 02/06/2023] Open
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