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1
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Du H, Wang H, Chen Y, Zhou X. A machine learning-derived angiogenesis signature for clinical prognosis and immunotherapy guidance in colon adenocarcinoma. Sci Rep 2025; 15:19126. [PMID: 40450107 DOI: 10.1038/s41598-025-03920-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 05/23/2025] [Indexed: 06/03/2025] Open
Abstract
Colon adenocarcinoma (COAD) is one of the most prevalent malignancies worldwide and its prognosis is extremely poor. Angiogenesis has been linked to clinical outcomes, tumor progression, and treatment sensitivity. However, the role of angiogenesis in the COAD microenvironment and its interaction with immunotherapy remains unclear. In this study, an integrative machine learning approach, including ten algorithms, was used to construct a prognostic consensus angiogenesis-related signature (CARS) for COAD. The optimal CARS constructed using the RSF + StepCox [forward] algorithm had superior performance for clinical prognostic prediction and served as an independent risk predictor for COAD. Patients in the low-CARS group, characterized by immune activation, elevated tumor mutation/neoantigen burden, and greater responsiveness to immunotherapy, had a superior prognosis. Patients in the high-CARS group exhibited a poor prognosis with higher angiogenesis activity and immunosuppressive status, indicating lower immunotherapy benefits. However, axitinib and olaparib may be promising treatment options for such patients. Taken together, we constructed a prognostic CARS that provides prognostic stratification and elucidates the characteristics of the tumor microenvironment, which might guide the selection of personalized treatments for patients with COAD.
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Affiliation(s)
- Hengrui Du
- Department of Gastrointestinal surgery, Tengzhou Central People's Hospital, Tengzhou, 277500, China
| | - Haochen Wang
- Department of Interventional Radiology, Jining First People's Hospital, Jining, 272000, China
| | - Yuxiang Chen
- Department of Otolaryngology, Tengzhou Central People's Hospital, Tengzhou, 277500, China.
| | - Xixi Zhou
- Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, 277500, China.
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2
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Nadukkandy AS, Blaize B, Kumar CD, Mori G, Cordani M, Kumar LD. Non-coding RNAs as mediators of epithelial to mesenchymal transition in metastatic colorectal cancers. Cell Signal 2025; 127:111605. [PMID: 39842529 DOI: 10.1016/j.cellsig.2025.111605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/06/2025] [Accepted: 01/12/2025] [Indexed: 01/24/2025]
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.
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Affiliation(s)
- Aisha Shigna Nadukkandy
- Cancer Biology, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India
| | - Britny Blaize
- Cancer Biology, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India
| | - Chethana D Kumar
- Department of Surgical ICU, Christian Medical College, IDA Scudder Road, Vellore 632004, Tamil Nadu, India
| | - Giulia Mori
- Department Of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Lekha Dinesh Kumar
- Cancer Biology, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India.
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3
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Fan X, Qi Z, Deng Y, Yang Z, Sun L, Li G, Liang J, Wu F, Yuan L. [LncRNA MAGI2-AS3 enhances cisplatin sensitivity of non-small cell lung cancer cells by regulating the miR-1269a/PTEN/AKT pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2024; 44:2033-2043. [PMID: 39523104 PMCID: PMC11526470 DOI: 10.12122/j.issn.1673-4254.2024.10.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE To investigate the mechanism mediating the regulatory effect of lncRNA MAGI2-AS3 on cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). METHODS MAGI2-AS3 and miR-1269a expression levels were detected by qRT-PCR in DDP-sensitive lung cancer cell lines (A549 and H1299) and their resistant counterparts (A549/DDP and H1299/DDP). In A549 and H1299 cells with MAGI2-AS3 silencing and A549/DDP and H1299/DDP cells overexpressing MAGI2-AS3, the effects of 20 μmol/L DDP on cell viability and apoptosis were examined with CCK-8 assay, colony formation assay, flow cytometry and Western blotting, and the changes in epithelial-mesenchymal transition (EMT) were assessed with wound healing and Transwell assays. The interaction between MAGI2-AS3, miR-1269a and PTEN was predicted using GEPIA, StarBase and miRDB and verified with luciferase reporter gene assay and radioimmunoprecipitation (RIP) assay. A miR-1269a mimic and pcDNA3.1-PTEN plasmid were used to perform the rescue assay. RESULTS MAGI2-AS3 expression was significantly downregulated in lung cancer tissues (P < 0.05) in association with a poor prognosis (P < 0.05). In the two DDP-resistant lung cancer cell lines, MAGI2-AS3 expression was significantly lowered as compared with the sensitive cells. Silencing MAGI2-AS3 significantly enhanced cell viability and promoted EMT of A549 and H1299 cells irrespective of DDP treatment, and also decreased DDP-induced apoptosis of the cells. In A549/DDP and H1299/DDP cells, MAGI2-AS3 overexpression strongly repressed cell viability and EMT irrespective of DDP treatment and promoted DDP-induced cell apoptosis. Luciferase reporter gene and RIP assays confirmed the binding of MAGI2-AS3 with miR-1269a and the binding of miR-1269a with 3 '-UTR domain of PTEN. The rescue assay demonstrated that MAGI2-AS3 acted as a sponge for miR-1269a to promote PTEN expression and downregulate AKT phosphorylation, thus inhibiting EMT and promoting DDP-induced apoptosis of A549/DDP cells. CONCLUSION MAGI2-AS3 enhances DDP sensitivity of NSCLC by targeted regulation of the miR-1269a/PTEN/AKT signaling axis.
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Affiliation(s)
- X Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wannan Medical College, Wuhu 241002, China
| | - Z Qi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wannan Medical College, Wuhu 241002, China
| | - Y Deng
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - Z Yang
- School of Clinical Medicine, Wannan Medical College, Wuhu 241002, China
| | - L Sun
- Department of Physiology, School of Basic Medical Sciences, Wannan Medical College, Wuhu 241002, China
| | - G Li
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - J Liang
- School of laboratory medicine, Wannan Medical College, Wuhu 241002, China
| | - F Wu
- School of Clinical Medicine, Wannan Medical College, Wuhu 241002, China
| | - L Yuan
- School of Anesthesia, Wannan Medical College, Wuhu 241002, China
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Liu X, Li D, Gao W, Chen P, Liu H, Zhao Y, Zhao W, Dong G. Molecular characterization, clinical value, and cancer-immune interactions of genes related to disulfidptosis and ferroptosis in colorectal cancer. Discov Oncol 2024; 15:183. [PMID: 38787520 PMCID: PMC11126553 DOI: 10.1007/s12672-024-01031-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND This research strived to construct a new signature utilizing disulfidptosis-related ferroptosis (SRF) genes to anticipate response to immunotherapy, prognosis, and drug sensitivity in individuals with colorectal cancer (CRC). METHODS The data for RNA sequencing as well as corresponding clinical information of individuals with CRC, were extracted from The Cancer Genome Atlas (TCGA) dataset. SRF were constructed with the help of the random forest (RF), least absolute shrinkage and selection operator (LASSO), and stepwise regression algorithms. To validate the SRF model, we applied it to an external cohort, GSE38832. Prognosis, immunotherapy response, drug sensitivity, molecular functions of genes, and somatic mutations of genes were compared across the high- and low-risk groups (categories). Following this, all statistical analyses were conducted with the aid of the R (version 4.23) software and various packages of the Cytoscape (version 3.8.0) tool. RESULTS SRF was developed based on five genes (ATG7, USP7, MMD, PLIN4, and THDC2). Both univariate and multivariate Cox regression analyses established SRF as an independent, prognosis-related risk factor. Individuals from the high-risk category had a more unfavorable prognosis, elevated tumor mutational burden (TMB), and significant immunosuppressive status. Hence, they might have better outcomes post-immunotherapy and might benefit from the administration of pazopanib, lapatinib, and sunitinib. CONCLUSION In conclusion, SRF can act as a new biomarker for prognosis assessment. Moreover, it is also a good predictor of drug sensitivity and immunotherapy response in CRC but should undergo optimization before implementation in clinical settings.
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Affiliation(s)
- Xianqiang Liu
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Dingchang Li
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Wenxing Gao
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Peng Chen
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Hao Liu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yingjie Zhao
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Wen Zhao
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- School of Medicine, Nankai University, Tianjin, 300071, China.
| | - Guanglong Dong
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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Xia X, Zhao S, Chen W, Xu C, Zhao D. CCT6A promotes esophageal squamous cell carcinoma cell proliferation, invasion and epithelial-mesenchymal transition by activating TGF-β/Smad/c-Myc pathway. Ir J Med Sci 2023; 192:2653-2660. [PMID: 37017854 DOI: 10.1007/s11845-023-03357-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/28/2023] [Indexed: 04/06/2023]
Abstract
OBJECTIVE Chaperonin-containing TCP1 subunit 6A (CCT6A) facilitates several malignant cancer behaviors, but its regulation of esophageal squamous cell carcinoma (ESCC) has not been reported. This study aimed to investigate the effect of CCT6A on cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) and its interaction with the TGF-β/Smad/c-Myc pathway in ESCC. METHODS CCT6A expression was detected in ESCC and normal esophageal epithelial cell lines by RT‒qPCR and western blotting. Furthermore, CCT6A siRNA, negative control (NC) siRNA, CCT6A encoding plasmid and NC encoding plasmid were transfected into OE21 and TE-1 cells. Subsequently, CCT6A siRNA- and NC siRNA-transfected cells were treated with TGF-β for rescue experiments. Cell proliferation, apoptosis, invasion, and E-cadherin/N-cadherin and p-Smad2/p-Smad3/c-Myc expression were detected. RESULTS CCT6A expression was increased in KYSE-180, TE-1, TE-4 and OE21 cells compared with HET-1A cells. In both OE21 and TE-1 cells, CCT6A knockdown inhibited cell proliferation, invasion and N-cadherin expression while promoting cell apoptosis and E-cadherin expression; meanwhile, CCT6A overexpression had the opposite effects. Furthermore, in both OE21 and TE-1 cells, CCT6A knockdown decreased p-Smad2/Smad2, p-Smad3/Smad3 and c-Myc/GAPDH expression; CCT6A overexpression had the opposite effects. Next, TGF-β facilitated cell proliferation, invasion, and N-cadherin, p-Smad2/Smad2, p-Smad3/Smad2 and c-Myc/GAPDH expression while repressing cell apoptosis and E-cadherin expression in OE21 and TE-1 cells; importantly, TGF-β could compensate for the regulation of CCT6A knockdown on these activities. CONCLUSION CCT6A facilitates ESCC malignant activities by activating the TGF-β/Smad/c-Myc pathway, which sheds light on the identification of a possible therapeutic target in the management of ESCC.
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Affiliation(s)
- Xiuli Xia
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Department of Gastroenterology, Handan Central Hospital, Handan, 056001, China
| | - Shushan Zhao
- Department of Gastroenterology, Handan Central Hospital, Handan, 056001, China
| | - Wenting Chen
- Department of Endoscopy Center, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China
| | - Chao Xu
- Department of Gastroenterology, Handan Central Hospital, Handan, 056001, China
| | - Dongqiang Zhao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
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Michas A, Michas V, Anagnostou E, Galanopoulos M, Tolia M, Tsoukalas N. The Clinical Significance of MicroRNAs in Colorectal Cancer Signaling Pathways: A Review. Glob Med Genet 2023; 10:315-323. [PMID: 38025193 PMCID: PMC10665125 DOI: 10.1055/s-0043-1777094] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023] Open
Abstract
Colorectal carcinoma (colon and rectum) is currently considered among the most prevalent malignancies of Western societies. The pathogenesis and etiological mechanisms underlying colorectal cancer (CRC) development remain complex and heterogeneous. The homeostasis and function of normal human intestinal cells is highly regulated by microRNAs. Therefore, it is not surprising that mutations and inactivation of these molecules appear to be linked with progression of colorectal tumors. Recent studies have reported significant alterations of microRNA expression in adenomas and CRCs compared with adjacent normal tissues. This observed deviation has been proposed to correlate with the progression and survival of disease as well as with choice of optimal treatment and drug resistance. MicroRNAs can adopt either oncogenic or tumor-suppressive roles during regulation of pathways that drive carcinogenesis. Typically, oncogenic microRNAs termed oncomirs, target and silence endogenous tumor-suppressor genes. On the other hand, tumor-suppressive microRNAs are critical in downregulating genes associated with cell growth and malignant capabilities. By extensively evaluating robust studies, we have emphasized and distinguished a discrete set of microRNAs that can modulate tumor progression by silencing specific driver genes crucial in signaling pathways including Wnt/b-catenin, epidermal growth factor receptor, P53, mismatch repair DNA repair, and transforming-growth factor beta.
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Affiliation(s)
- Athanasios Michas
- Department of Oncology, 401 General Military Hospital of Athens, Athens, Greece
| | - Vasileios Michas
- Department of Radiology, Achepa General Hospital Thessaloniki, Thessaloniki, Greece
| | - Evangelos Anagnostou
- Department of Neurosurgery, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | | | - Maria Tolia
- Department of Oncology, 401 General Military Hospital of Athens, Athens, Greece
| | - Nikolaos Tsoukalas
- Department of Oncology, 401 General Military Hospital of Athens, Athens, Greece
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7
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Fadaka AO, Akinsoji T, Klein A, Madiehe AM, Meyer M, Keyster M, Sikhwivhilu LM, Sibuyi NRS. Stage-specific treatment of colorectal cancer: A microRNA-nanocomposite approach. J Pharm Anal 2023; 13:1235-1251. [PMID: 38174117 PMCID: PMC10759263 DOI: 10.1016/j.jpha.2023.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 01/05/2024] Open
Abstract
Colorectal cancer (CRC) is among the leading causes of cancer mortality. The lifetime risk of developing CRC is about 5% in adult males and females. CRC is usually diagnosed at an advanced stage, and at this point therapy has a limited impact on cure rates and long-term survival. Novel and/or improved CRC therapeutic options are needed. The involvement of microRNAs (miRNAs) in cancer development has been reported, and their regulation in many oncogenic pathways suggests their potent tumor suppressor action. Although miRNAs provide a promising therapeutic approach for cancer, challenges such as biodegradation, specificity, stability and toxicity, impede their progression into clinical trials. Nanotechnology strategies offer diverse advantages for the use of miRNAs for CRC-targeted delivery and therapy. The merits of using nanocarriers for targeted delivery of miRNA-formulations are presented herein to highlight the role they can play in miRNA-based CRC therapy by targeting different stages of the disease.
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Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Taiwo Akinsoji
- School of Medicine, Southern Illinois University, Springfield, IL, 62702, USA
| | - Ashwil Klein
- Plant Omics Laboratory, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Abram Madimabe Madiehe
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
- Nanobiotechnology Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Mervin Meyer
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Marshall Keyster
- Environmental Biotechnology Laboratory, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
| | - Lucky Mashudu Sikhwivhilu
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Advanced Materials Division, Mintek, Johannesburg, 2125, South Africa
- Department of Chemistry, Faculty of Science, Engineering and Agriculture, University of Venda, Thohoyandou, 0950, South Africa
| | - Nicole Remaliah Samantha Sibuyi
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, 7535, South Africa
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Advanced Materials Division, Mintek, Johannesburg, 2125, South Africa
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Zhou J, Xu W, Wu Y, Wang M, Zhang N, Wang L, Feng Y, Zhang T, Wang L, Mao A. GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway. Oncogene 2023; 42:3319-3330. [PMID: 37749229 DOI: 10.1038/s41388-023-02841-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 09/04/2023] [Accepted: 09/13/2023] [Indexed: 09/27/2023]
Abstract
Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), unfortunately no effectively strategies for CRC liver metastasis (CRLM). In this study, we found GPR37 expression dramatically increased in human CRLM specimens and associated poor prognosis. GPR37 depletion greatly suppressed the liver metastasis in the mouse models of CRLM. Functional experiments showed that GPR37 knockdown inhibited the growth by reducing the glycolysis of CRC cells. Also, GPR37 knockdown in tumor cells produced decreased levels of two chemokines involved in neutrophil accumulation, which abrogated neutrophil recruitment in the tumor microenvironment of CRLM. Finally, the mechanism studies revealed that GPR37 could activate the hippo pathway, thereby promoting LDHA expression and glycolysis. This leads to increased lactylation of H3K18la, resulting in up-regulation of CXCL1 and CXCL5. These results support a role of the GPR37 in modulating the tumor metabolism and microenvironment in CRLM and GPR37 could be a potential therapeutic target.
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Affiliation(s)
- Jiamin Zhou
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Weiqi Xu
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Yibin Wu
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Miao Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Ning Zhang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Longrong Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Yun Feng
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Ti Zhang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Lu Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.
| | - Anrong Mao
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.
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9
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Xie Y, Ye J, Luo H. HOXC Cluster Antisense RNA 3, a Novel Long Non-Coding RNA as an Oncological Biomarker and Therapeutic Target in Human Malignancies. Onco Targets Ther 2023; 16:849-865. [PMID: 37899986 PMCID: PMC10612484 DOI: 10.2147/ott.s425523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 10/10/2023] [Indexed: 10/31/2023] Open
Abstract
HOXC cluster antisense RNA 3 (HOXC-AS3) is a novel long noncoding RNA (lncRNA) that exhibits aberrant expression patterns in various cancer types. Its expression is closely related to clinicopathological features, demonstrating significant clinical relevance across multiple tumors. And HOXC-AS3 plays multifaceted roles in tumor progression, impacting cell proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition (EMT), autophagy, senescence, tumor growth, and metastasis. In this review, we summarized and comprehensively analyzed the expression and clinical significance of HOXC-AS3 as a diagnostic and prognostic biomarker for malignancies. Additionally, we presented an in-depth update on HOXC-AS3's functions and regulatory mechanisms in cancer pathogenesis. This narrative review underscores the importance of HOXC-AS3 as a promising lncRNA candidate in cancer research and its potential as a predictive biomarker and therapeutic target in clinical applications.
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Affiliation(s)
- Yunhe Xie
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330008, People’s Republic of China
- Department of General Surgery, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332007, People’s Republic of China
| | - Jiarong Ye
- Queen Mary School, Nanchang University, Nanchang, Jiangxi, 330038, People’s Republic of China
| | - Hongliang Luo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330008, People’s Republic of China
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10
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Xiong B, Huang Q, Zheng H, Lin S, Xu J. Recent advances microRNAs and metabolic reprogramming in colorectal cancer research. Front Oncol 2023; 13:1165862. [PMID: 37576895 PMCID: PMC10415904 DOI: 10.3389/fonc.2023.1165862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/07/2023] [Indexed: 08/15/2023] Open
Abstract
Colorectal cancer (CRC) is a cancer with the highest incidence and mortality. Alteration of gene expression is the main pathophysiological mechanism of CRC, which results in disturbed signaling pathways and cellular metabolic processes. MicroRNAs are involved in almost all pathophysiological processes and are correlative with colorectal cancer metabolism, proliferation, and chemotherapy resistance. Metabolic reprogramming, an important feature of cancer, is strongly correlative with the development and prognosis of cancers, including colorectal cancer. MicroRNAs can target enzymes involved in metabolic processes, thus playing a regulatory role in tumor metabolism. The disorder of the signaling pathway is another characteristic of tumor, which induces the occurrence and proliferation of tumors, and is closely correlative with the prognosis and chemotherapy resistance of tumor patients. MicroRNAs can target the components of the signaling pathways to regulate their transduction. Understanding the function of microRNAs in the occurrence and proliferation of CRC provides novel insights into the optimal treatment strategies, prognosis, and development of diagnosis in CRC. This article reviews the relationship between CRC and microRNA expression and hopes to provide new options for the diagnosis and treatment of CRC.
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Affiliation(s)
- Bin Xiong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Qiaoyi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Huida Zheng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jianhua Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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11
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Ma Y, Xing X, Cheng C, Kong R, Sun L, Zhao F, Zhang D, Li J. Hsa-miR-1269a up-regulation fosters the malignant progression of esophageal squamous cell carcinoma via targeting FAM46C. Mutat Res 2023; 827:111832. [PMID: 37467675 DOI: 10.1016/j.mrfmmm.2023.111832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 06/20/2023] [Accepted: 07/04/2023] [Indexed: 07/21/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignancy of the alimentary tract resulting in death worldwide. The role and underlying mechanism of hsa-miR-1269a in the progression of ESCC remain unclear. In this study, hsa-miR-1269a was screened by differential expression analysis in TCGA, and its target gene FAM46C was predicted. qRT-PCR was conducted to assay the expression of hsa-miR-1269a and FAM46C in ESCC cells. The results showed that hsa-miR-1269a was upregulated in ESCC tissues and cell lines. Hsa-miR-1269a overexpression stimulated the proliferation, migration, and invasion capacities of ESCC cells, and FAM46C overexpression inhibited these phenotypes. Dual-luciferase assay verified that hsa-miR-1269a could target FAM46C. Next, qRT-PCR and western blot demonstrated that hsa-miR-1269a overexpression downregulated FAM46C. Rescue experiments revealed that hsa-miR-1269a accelerated the malignant progression of ESCC through FAM46C down-regulation. These results indicate that the interaction between hsa-miR-1269a and FAM46C plays a regulatory role in driving the malignant progression of ESCC cells, thereby providing a novel molecular mechanism for understanding ESCC.
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Affiliation(s)
- Yuefeng Ma
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China
| | - Xin Xing
- Department of Health Care for Cadres, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China
| | - Chuantao Cheng
- Department of Dermatology, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China
| | - Ranran Kong
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China
| | - Liangzhang Sun
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China
| | - Feng Zhao
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China
| | - Danjie Zhang
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China
| | - Jianzhong Li
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi' an 710004, Shaanxi Province, China.
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12
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Zhou B, Xue J, Wu R, Meng H, Li R, Mo Z, Zhai H, Chen X, Liu R, Lai G, Chen X, Li T, Zheng S. CREBZF mRNA nanoparticles suppress breast cancer progression through a positive feedback loop boosted by circPAPD4. J Exp Clin Cancer Res 2023; 42:138. [PMID: 37264406 DOI: 10.1186/s13046-023-02701-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/08/2023] [Indexed: 06/03/2023] Open
Abstract
BACKGROUND Breast cancer (BC) negatively impacts the health of women worldwide. Circular RNAs (circRNAs) are a group of endogenous RNAs considered essential regulatory factor in BC tumorigenesis and progression. However, the underlying molecular mechanisms of circRNAs remain unclear. METHODS Expression levels of circPAPD4, miR-1269a, CREBZF, and ADAR1 in BC cell lines and tissues were measured using bioinformatics analysis, RT-qPCR, ISH, and IHC. Cell proliferation and apoptosis were measured using CCK8, EdU staining, flow cytometry, and TUNEL assays. Pearson correlation analysis, RNA pull-down, dual-luciferase reporter, and co-immunoprecipitation assays were used to explore the correlation among circPAPD4, miR-1269a, CREBZF, STAT3, and ADAR1. Effects of circPAPD4 overexpression on tumor progression were investigated using in vivo assays. Moreover, CREBZF mRNA delivered by polymeric nanoparticles (CREBZF-mRNA-NPs) was used to examine application value of our findings. RESULTS CircPAPD4 expression was low in BC tissues and cells. Functionally, circPAPD4 inhibited proliferation and promoted apoptosis in vitro and in vivo. Mechanistically, circPAPD4 biogenesis was regulated by ADAR1. And circPAPD4 promoted CREBZF expression by competitively binding to miR-1269a. More importantly, CREBZF promoted circPAPD4 expression by suppressing STAT3 dimerization and ADAR1 expression, revealing a novel positive feedback loop that curbed BC progression. Systematic delivery of CREBZF-mRNA-NPs effectively induced CREBZF expression and activated the positive feedback loop of circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1, which might suppress BC progression in vitro and in vivo. CONCLUSION Our findings firstly illustrated that circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1 positive feedback loop mediated BC progression, and delivering CREBZF mRNA nanoparticles suppressed BC progression in vitro and in vivo, which might provide novel insights into therapeutic strategies for breast cancer.
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Affiliation(s)
- Boxuan Zhou
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Department of Breast Surgery, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, 341000, China
| | - Jinhua Xue
- Department of Physiology, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, 341000, China
| | - Runxin Wu
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hongyu Meng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Ruixi Li
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Zhaohong Mo
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Hang Zhai
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Xianyu Chen
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Rongqiang Liu
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Guie Lai
- Department of Breast Surgery, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, 341000, China
| | - Xiaohong Chen
- Department of Laboratory, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
| | - Taiyuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
| | - Shiyang Zheng
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
- Department of Head and Neck surgery, Cancer Center of Guangzhou Medical University, Guangzhou, 510060, China.
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13
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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14
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Horak J, Kubecek O, Siskova A, Honkova K, Chvojkova I, Krupova M, Manethova M, Vodenkova S, García-Mulero S, John S, Cecka F, Vodickova L, Petera J, Filip S, Vymetalkova V. Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer. Front Oncol 2023; 13:1133598. [PMID: 37182133 PMCID: PMC10172672 DOI: 10.3389/fonc.2023.1133598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 03/20/2023] [Indexed: 05/16/2023] Open
Abstract
Despite distant metastases being the critical factor affecting patients' survival, they remain poorly understood. Our study thus aimed to molecularly characterize colorectal cancer liver metastases (CRCLMs) and explore whether molecular profiles differ between Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. This characterization was performed by whole exome sequencing, whole transcriptome, whole methylome, and miRNAome. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. Among the differently methylated and expressed genes were those involved in cell adhesion, extracellular matrix organization and degradation, neuroactive ligand-receptor interaction. The top up-regulated microRNAs were hsa-miR-135b-3p and -5p, and the hsa-miR-200-family while the hsa-miR-548-family belonged to the top down-regulated. MmCRC patients evinced higher tumor mutational burden, a wider median of duplications and deletions, and a heterogeneous mutational signature than SmCRC. Regarding chronicity, a significant down-regulation of SMOC2 and PPP1R9A genes in SmCRC compared to MmCRC was observed. Two miRNAs were deregulated between SmCRC and MmCRC, hsa-miR-625-3p and has-miR-1269-3p. The combined data identified the IPO5 gene. Regardless of miRNA expression levels, the combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signaling pathways, and intracellular second messenger signaling. The intersection between our and validation sets confirmed the validity of our results. We have identified genes and pathways that may be considered as actionable targets in CRCLMs. Our data also provide a valuable resource for understanding molecular distinctions between SmCRC and MmCRC. They have the potential to enhance the diagnosis, prognostication, and management of CRCLMs by a molecularly targeted approach.
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Affiliation(s)
- Josef Horak
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Ondrej Kubecek
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Katerina Honkova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
| | - Irena Chvojkova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
| | - Marketa Krupova
- The Fingerland Department of Pathology, University Hospital in Hradec Kralove, Hradec Kralove, Czechia
| | - Monika Manethova
- The Fingerland Department of Pathology, University Hospital in Hradec Kralove, Hradec Kralove, Czechia
| | - Sona Vodenkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Sandra García-Mulero
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO)-Oncobell Programme, Bellvitge Biomedical Research Institute Oncobell Programme, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Oncobell Programme, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
| | - Stanislav John
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Filip Cecka
- Department of Surgery, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Jiri Petera
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Stanislav Filip
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
- *Correspondence: Veronika Vymetalkova, ; Stanislav Filip,
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- *Correspondence: Veronika Vymetalkova, ; Stanislav Filip,
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15
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Villegas-Mirón P, Gallego A, Bertranpetit J, Laayouni H, Espinosa-Parrilla Y. Signatures of genetic variation in human microRNAs point to processes of positive selection and population-specific disease risks. Hum Genet 2022; 141:1673-1693. [PMID: 35249174 PMCID: PMC9522702 DOI: 10.1007/s00439-021-02423-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 12/19/2021] [Indexed: 12/11/2022]
Abstract
The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last 20 years. Most of them have been focused on the role of specific mutations in disease, while a minor proportion seek to analyse microRNA diversity in the genomes of human populations. We analyse the latest human microRNA annotations in the light of the most updated catalogue of genetic variation provided by the 1000 Genomes Project. By means of the in silico analysis of microRNA genetic variation we show that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or genomic location. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants implicated in gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their SNPs in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk.
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Affiliation(s)
- Pablo Villegas-Mirón
- Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
| | - Alicia Gallego
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
| | - Jaume Bertranpetit
- Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
| | - Hafid Laayouni
- Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
- Bioinformatics Studies, ESCI-UPF, Pg. Pujades 1, 08003, Barcelona, Spain.
| | - Yolanda Espinosa-Parrilla
- Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile.
- Laboratorio de Medicina Molecular-LMM, Centro Asistencial, Docente Y de Investigación-CADI, Universidad de Magallanes, Punta Arenas, Chile.
- Interuniversity Center on Healthy Aging, Punta Arenas, Chile.
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16
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Wang L, Qiao C, Cao L, Cai S, Ma X, Song X, Jiang Q, Huang C, Wang J. Significance of HOXD transcription factors family in progression, migration and angiogenesis of cancer. Crit Rev Oncol Hematol 2022; 179:103809. [PMID: 36108961 DOI: 10.1016/j.critrevonc.2022.103809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 10/31/2022] Open
Abstract
The transcription factors (TFs) of the HOX family play significant roles during early embryonic development and cellular processes. They also play a key role in tumorigenesis as tumor oncogenes or suppressors. Furthermore, TFs of the HOXD geFIne cluster affect proliferation, migration, and invasion of tumors. Consequently, dysregulated activity of HOXD TFs has been linked to clinicopathological characteristics of cancer. HOXD TFs are regulated by non-coding RNAs and methylation of DNA on promoter and enhancer regions. In addition, HOXD genes modulate the biological function of cancer cells via the MEK and AKT signaling pathways, thus, making HOXD TFs, a suitable molecular marker for cancer prognosis and therapy. In this review, we summarized the roles of HOXD TFs in different cancers and highlighted its potential as a diagnostic and therapeutic target.
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Affiliation(s)
- Lumin Wang
- Gastroenterology department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China; Institute of precision medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China
| | - Chenyang Qiao
- Gastroenterology department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China
| | - Li Cao
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Shuang Cai
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Xiaoping Ma
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Xinqiu Song
- Department of Cell Biology and Genetics, Medical College of Yan'an University, Yan'an, Shaanxi, PR China
| | - Qiuyu Jiang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Chen Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China.
| | - Jinhai Wang
- Gastroenterology department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China; Institute of precision medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.
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17
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Yang F, Xuan G, Chen Y, Cao L, Zhao M, Wang C, Chen E. MicroRNAs Are Key Molecules Involved in the Gene Regulation Network of Colorectal Cancer. Front Cell Dev Biol 2022; 10:828128. [PMID: 35465317 PMCID: PMC9023807 DOI: 10.3389/fcell.2022.828128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common types of cancer and one of the leading causes of mortality worldwide. MicroRNAs (miRNAs) play central roles in normal cell maintenance, development, and other physiological processes. Growing evidence has illustrated that dysregulated miRNAs can participate in the initiation, progression, metastasis, and therapeutic resistance that confer miRNAs to serve as clinical biomarkers and therapeutic targets for CRC. Through binding to the 3′-untranslated region (3′-UTR) of target genes, miRNAs can lead to target mRNA degradation or inhibition at a post-transcriptional level. During the last decade, studies have found numerous miRNAs and their potential targets, but the complex network of miRNA/Targets in CRC remains unclear. In this review, we sought to summarize the complicated roles of the miRNA-target regulation network (Wnt, TGF-β, PI3K-AKT, MAPK, and EMT related pathways) in CRC with up-to-date, high-quality published data. In particular, we aimed to discuss the downstream miRNAs of specific pathways. We hope these data can be a potent supplement for the canonical miRNA-target regulation network.
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Affiliation(s)
- Fangfang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Guoyun Xuan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi’an, China
| | - Yixin Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Lichao Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Min Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Chen Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
- *Correspondence: Erfei Chen,
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18
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Xie Z, Zhong C, Duan S. miR-1269a and miR-1269b: Emerging Carcinogenic Genes of the miR-1269 Family. Front Cell Dev Biol 2022; 10:809132. [PMID: 35252180 PMCID: PMC8894702 DOI: 10.3389/fcell.2022.809132] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/20/2022] [Indexed: 01/15/2023] Open
Abstract
miRNAs play an important role in the occurrence and development of human cancer. Among them, hsa-mir-1269a and hsa-mir-1269b are located on human chromosomes 4 and 17, respectively, and their mature miRNAs (miR-1269a and miR-1269b) have the same sequence. miR-1269a is overexpressed in 9 cancers. The high expression of miR-1269a not only has diagnostic significance in hepatocellular carcinoma and non-small cell lung cancer but also is related to the poor prognosis of cancer patients such as esophageal cancer, hepatocellular carcinoma, and glioma. miR-1269a can target 8 downstream genes (CXCL9, SOX6, FOXO1, ATRX, RASSF9, SMAD7, HOXD10, and VASH1). The expression of miR-1269a is regulated by three non-coding RNAs (RP11-1094M14.8, LINC00261, and circASS1). miR-1269a participates in the regulation of the TGF-β signaling pathway, PI3K/AKT signaling pathway, p53 signaling pathway, and caspase-9-mediated apoptotic pathway, thereby affecting the occurrence and development of cancer. There are fewer studies on miR-1269b compared to miR-1269a. miR-1269b is highly expressed in hepatocellular carcinoma, non-small cell lung cancer, oral squamous cell carcinoma, and pharyngeal squamous cell carcinoma, but miR-1269b is low expressed in gastric cancer. miR-1269b can target downstream genes (METTL3, CDC40, SVEP1, and PTEN) and regulate the PI3K/AKT signaling pathway. In addition, sequence mutations on miR-1269a and miR-1269b can affect their regulation of cancer. The current studies have shown that miR-1269a and miR-1269b have the potential to be diagnostic and prognostic markers for cancer. Future research on miR-1269a and miR-1269b can focus on elucidating more of their upstream and downstream genes and exploring the clinical application value of miR-1269a and miR-1269b.At present, there is no systematic summary of the research on miR-1269a and miR-1269b. This paper aims to comprehensively analyze the abnormal expression, diagnostic and prognostic value, and molecular regulatory pathways of miR-1269a and miR-1269b in multiple cancers. The overview in our work can provide useful clues and directions for future related research.
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Affiliation(s)
- Zijun Xie
- School of Medicine, Zhejiang University City College, Hangzhou, China
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Chenming Zhong
- School of Medicine, Zhejiang University City College, Hangzhou, China
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Shiwei Duan
- School of Medicine, Zhejiang University City College, Hangzhou, China
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, China
- *Correspondence: Shiwei Duan,
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19
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Li B, Kang H, Xiao Y, Du Y, Xiao Y, Song G, Zhang Y, Guo Y, Yang F, He F, Yang S. LncRNA GAL promotes colorectal cancer liver metastasis through stabilizing GLUT1. Oncogene 2022; 41:1882-1894. [PMID: 35149838 DOI: 10.1038/s41388-022-02230-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/20/2022] [Accepted: 02/02/2022] [Indexed: 12/12/2022]
Abstract
Colorectal cancer liver metastasis (CRLM) is the leading cause of colorectal cancer-related deaths and remains a clinical challenge. Enhancement of glucose uptake is involved in CRLM; however, whether long noncoding RNAs (lncRNAs) participate in these molecular events remains largely unclear. Here, we report an lncRNA, GAL (glucose transporter 1 (GLUT1) associated lncRNA), that was upregulated in CRLM tissues compared with primary colorectal cancer (CRC) tissues or matched normal tissues and was associated with the overall survival rates of CRLM patients. Functionally, GAL served as an oncogene because it promoted CRC cell migration and invasion in vitro and enhanced the ability of CRC cells to metastasize from the intestine to the liver in vivo. Mechanistically, GAL interacted with the GLUT1 protein to increase GLUT1 SUMOylation, inhibiting the effect of the ubiquitin-proteasome system on the GLUT1 protein. GLUT1-knockout (-/+) repressed the GAL-mediated increase in CRC cell uptake of glucose, migrate, and invade in vitro, as well as metastasis from the intestine to the liver in vivo, and enforced expression of GLUT1 rescued GAL knockout-induced biological functions in CRC cells. Taken together, our findings demonstrated that GAL promotes CRLM by stabilizing GLUT1, suggesting that the GAL-GLUT1 complex may act as a potential therapeutic target for CRLM.
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Affiliation(s)
- Bosheng Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China.,Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Houyi Kang
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Yufeng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Yexiang Du
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Yunhua Xiao
- Department of Radiology, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Guojing Song
- Department of Urology, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yan Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Yu Guo
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Fan Yang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China.
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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20
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Xie Y, Wang Y, Xue W, Zou H, Li K, Liu K, Zhao W, Zhu C, Cao J. Profiling and Integrated Analysis of Differentially Expressed MicroRNAs as Novel Biomarkers of Hepatocellular Carcinoma. Front Oncol 2022; 11:770918. [PMID: 35174066 PMCID: PMC8841844 DOI: 10.3389/fonc.2021.770918] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/29/2021] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous disease that has multiple etiologies. It is the most common primary liver cancer, the sixth highest cause of cancer incidences, and the fourth highest cause of cancer-related deaths. The discovery of new biomarkers for the early detection, treatment, and prognosis of HCC would therefore be extremely useful. This study investigated differentially expressed ribonucleic acid (RNA) profiles by constructing a genome-wide profile of clinical samples. Differential expression analysis identified 1,280 differentially expressed messenger RNAs (dif-mRNAs), 99 differentially expressed microRNAs (dif-miRNAs), 181 differentially expressed long non-coding RNAs (dif-lncRNAs), and 31 differentially expressed circular RNAs (dif-circRNAs). Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) path analysis were then conducted on these differentially expressed RNAs, revealing that they were clearly related to cell division, foreign body metabolism, and ribosome assembly. A competing endogenous RNA (ceRNA) network was then constructed based on the regulatory dif-miRNA-dif-mRNA and dif-miRNA-dif-lncRNA relationships. These results were also verified using HCC data from the Cancer Genome Atlas (TCGA); seven dif-miRNAs were verified in clinical samples by real-time quantitative polymerase chain reaction (RT-qPCR). Kaplan-Meier survival analysis revealed that the expression levels of Hsa-miR-1269a, Hsa-miR-421, and Hsa-miR-190b were correlated with overall survival. (P <0.05). Survival analysis of clinical samples showed that hsa-mir-1269a, hsa-mir-421 were associated with prognosis (p<0.05).This study revealed the general expression characteristics of specific differentially expressed miRNAs using a ceRNA network constructed from HCC samples. Hsa-mir-1269a, hsa-mir-421 may be promising candidates.
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Affiliation(s)
- Yuwei Xie
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yixiu Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weijie Xue
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hao Zou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kun Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chengzhan Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Chengzhan Zhu, ; Jingyu Cao,
| | - Jingyu Cao
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Chengzhan Zhu, ; Jingyu Cao,
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21
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Elevated P-Element-Induced Wimpy-Testis-Like Protein 1 Expression Predicts Unfavorable Prognosis for Patients with Various Cancers. JOURNAL OF ONCOLOGY 2022; 2021:9982192. [PMID: 35003260 PMCID: PMC8741353 DOI: 10.1155/2021/9982192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 12/24/2022]
Abstract
Increasing evidence has shown that overexpression of P-element-induced wimpy-testis (PIWI)-like protein 1 (PIWIL1) was associated with unfavorable prognosis of patients with various types of cancers. Herein, we conducted this meta-analysis to identify the clinicopathological and prognostic value of the PIWIL1 expression in cancers. Three electronic databases (PubMed, Web of Science, and Embase) were comprehensively retrieved for relevant studies up to August 4th, 2019. RevMan 5.3 and STATA 12.0 statistical software programs were used to explore the relationships between PIWIL1 expression and the prognosis and clinicopathological features in cancer patients. A total of 13 studies recruiting 2179 patients with 9 types of solid tumors were finally included in the meta-analysis. The results indicated that patients with high PIWIL1 expression tended to have a shorter survival, and additionally deeper tumor invasion, higher clinical stage, and more lymph node metastasis. PIWIL1 could serve as a biomarker for prognosis and clinicopathological characteristics in various cancers.
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22
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Zhang TT, Chen HP, Yu SY, Zhao SP. LncRNA HOXC-AS3 overexpression inhibits TGF-β2-induced colorectal cancer cell migration and invasion by sponging miR-1269. Hum Exp Toxicol 2022; 41:9603271221093630. [PMID: 35537198 DOI: 10.1177/09603271221093630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Long non-coding RNA (lncRNA) HOXC-AS3 has been characterized as a cancer-related lncRNA in many types of cancer, while its role in colorectal cancer (CRC) is unknown. METHODS The expression of HOXC-AS3 and TGF-β2 were detected by RT-qPCR. Overexpression assays were performed to explore the interaction between HOXC-AS3 and TGF-β2. A follow-up study was performed to explore the prognostic value of HOXC-AS3 for CRC. The direct interaction between HOXC-AS3 and miR-1269 was assessed with RNA-RNA pulldown assay. Transwell assays were performed to determine the role of HOXC-AS3 and TGF-β2 in regulating CRC cell invasion and migration. RESULTS HOXC-AS3 was significantly downregulated in CRC tissues, while TGF-β2 was significantly upregulated in CRC tissues compared to that in adjacent non-cancer tissues of CRC patients. The follow-up study showed that low expression levels of HOXC-AS3 in CRC tissues were closely correlated with poor survival. Correlation analysis showed that HOXC-AS3 and TGF-β2 were inversely correlated across CRC tissues but not non-cancer tissues. Overexpression of HOXC-AS3 in the two cell lines resulted in downregulation of TGF-β2, while the expression of HOXC-AS3 was not affected by TGF-β2. Transwell migration and invasion assay showed that overexpression of TGF-β2 increased cell invasion and migration, while overexpression of HOXC-AS3 decreased cell migration and invasion. In addition, overexpression of HOXC-AS3 attenuated the effects of overexpression of TGF-β2. MiR-1269 increased the expression of TGF-β2. HOXC-AS3 directly interacted with miR-1269 in CRC cells. CONCLUSIONS Upregulation of HOXC-AS3 inhibited TGF-β2-induced colorectal cancer (CRC) cell migration and invasion possibly by sponging miR-1269.
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Affiliation(s)
- Tong-Tong Zhang
- Department of Gastrointestinal Surgery, 74725The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Hai-Peng Chen
- Department of Colorectal Surgery, 70317National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Beijing City, China
| | - Su-Yang Yu
- Department of Gastrointestinal Surgery, 74725The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Shi-Peng Zhao
- Department of Gastrointestinal Surgery, 74725The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
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23
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Czajka-Francuz P, Cisoń-Jurek S, Czajka A, Kozaczka M, Wojnar J, Chudek J, Francuz T. Systemic Interleukins' Profile in Early and Advanced Colorectal Cancer. Int J Mol Sci 2021; 23:124. [PMID: 35008550 PMCID: PMC8745135 DOI: 10.3390/ijms23010124] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 02/05/2023] Open
Abstract
Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients' prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells.
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Affiliation(s)
- Paulina Czajka-Francuz
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Sylwia Cisoń-Jurek
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Aleksander Czajka
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland;
| | - Maciej Kozaczka
- Department of Radiotherapy and Chemotherapy, National Institute of Oncology, Public Research Institute in Gliwice, 44-101 Gliwice, Poland;
| | - Jerzy Wojnar
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Jerzy Chudek
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Tomasz Francuz
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland
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24
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Malakoti F, Targhazeh N, Karimzadeh H, Mohammadi E, Asadi M, Asemi Z, Alemi F. The Multiple Function of lncRNA MALAT1 in Cancer Occurrence and Progression. Chem Biol Drug Des 2021; 101:1113-1137. [PMID: 34918470 DOI: 10.1111/cbdd.14006] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/29/2021] [Accepted: 12/09/2021] [Indexed: 11/28/2022]
Abstract
Long non-coding RNAs (lncRNAs) have received particular attention in the last decade due to its engaging in carcinogenesis and tumorigenesis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA that plays physiological and pathological roles in many aspects of genome function as well as biological processes involved in cell development, differentiation, proliferation, invasion, and migration. In this article, we will review the effects of lncRNA MALAT1 on the progression of six prevalent human cancers by focusing on MALAT1 ability to regulate post-transcriptional modification and signaling pathways.
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Affiliation(s)
- Faezeh Malakoti
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student's Research committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haniye Karimzadeh
- Department of Clinical Biochemistry, School of Pharmacy & Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Erfan Mohammadi
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.,Drugs Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Asadi
- Drugs Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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25
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SPTBN2 regulated by miR-424-5p promotes endometrial cancer progression via CLDN4/PI3K/AKT axis. Cell Death Dis 2021; 7:382. [PMID: 34887379 PMCID: PMC8660803 DOI: 10.1038/s41420-021-00776-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/16/2021] [Accepted: 11/29/2021] [Indexed: 12/24/2022]
Abstract
Endometrioid Endometrial Cancer (EEC) is the main subtype of endometrial cancer. In our study, we demonstrated that SPTBN2 was significantly overexpressed in EEC tissues. Upregulated SPTBN2 expression was positively associated with poor prognosis. In addition, we testified that SPTBN2 knockdown significantly inhibited the proliferation, migration, and invasion of EEC cells. Moreover, we found SPTBN2 could interact with CLDN4 to promote endometrial cancer metastasis via PI3K/AKT pathway. Then we further demonstrated that CLDN4 is upregulated in EEC and promotes EEC metastasis. CLDN4 overexpression could partially reversed the decrease in cell migration and invasion caused by SPTBN2 downregulation. In addition, we confirmed that SPTBN2 was a target of miR-424-5p, which plays a tumor suppressor in endometrial cancer. Rescue experiments showed that inhibition of SPTBN2 could partially reverse the effect of miR-424-5p in EEC. In conclusion, we demonstrated that by acting as a significant target of miR-424-5p, SPTBN2 could interact with CLDN4 to promote endometrial cancer metastasis via PI3K/AKT pathway in EEC. Our study revealed the prognostic and metastatic effects of SPTBN2 in EEC, suggesting that SPTBN2 could serve as a prognostic biomarker and a target for metastasis therapy.
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26
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Rana NK, Srivastava N, Koch B. Identification of the key miRNA; hsa-miR-1269a targeting TP53, Caspase-9 and FOXO3a in breast cancer cells under hypoxia by integrated bioinformatics analysis. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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27
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Pan W, Wang K, Li J, Li H, Cai Y, Zhang M, Wang A, Wu Y, Gao W, Weng W. Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer. Front Oncol 2021; 11:771528. [PMID: 34790580 PMCID: PMC8591167 DOI: 10.3389/fonc.2021.771528] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/11/2021] [Indexed: 12/27/2022] Open
Abstract
Emerging evidence suggests that hypermethylation of HOXD10 plays an important role in human cancers. However, the biological and clinical impacts of HOXD10 overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of HOXD10 in paired cancer and normal tissues (n = 42) by using pyrosequencing, followed by validation of the methylation status of HOXD10 from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of HOXD10 was characterized in cell lines. We further evaluated the effects of HOXD10 and its targets on chemoresistance in our established resistant cell lines and clinical cohort (n = 66). HOXD10 was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, HOXD10 acts as a tumor suppressor gene, in which HOXD10-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the HOXD10 promoter, and demethylation by 5-Aza-2′-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce HOXD10 expression. HOXD10 regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of HOXD10 in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that HOXD10 is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of HOXD10 activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).
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Affiliation(s)
- Weijie Pan
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kaijing Wang
- Department of Hepatological Surgery, General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiayong Li
- Clinical Laboratory Medicine Center, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Hanhua Li
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuchan Cai
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Min Zhang
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Aili Wang
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.,Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai, China
| | - Yazhou Wu
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wei Gao
- Department of General Surgery, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Wenhao Weng
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
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28
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Methylation Modification, Alternative Splicing, and Noncoding RNA Play a Role in Cancer Metastasis through Epigenetic Regulation. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4061525. [PMID: 34660788 PMCID: PMC8514273 DOI: 10.1155/2021/4061525] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022]
Abstract
Metastasis is the leading cause of cancer-related deaths. Understanding the pathogenesis of metastasis at the molecular levels is of great significance for cancer research. However, the molecular diagnosis or treatment of cancer metastasis is limited. Accumulating and growing evidence shows that epigenetic changes are present in all human cancers, and epigenetic regulation is an indispensable factor to promote tumor metastasis. With the deepening of research and the advancement of technology, the function and mechanism of epigenetic regulation, including DNA methylation, histone/RNA modification, and precursor messenger RNA alternative splicing and noncoding RNAs, has become more increasingly clear. At present, the application of epigenetic therapies in tumor treatment is becoming a feasible therapeutic route. In this review, we looked for the key molecules in epigenetic regulation and discuss their relative regulating mechanisms in cancer metastasis. Furthermore, we highlight promising therapeutic strategies, including monitoring serum DNA for diagnostic purposes and early phase clinical trial therapies that target DNA and histone methylation. This may also be beneficial in finding new targets for further prognosis and diagnosis of cancer metastasis.
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29
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Xiong HL, Zhong XH, Guo XH, Liao HJ, Yuan X. circASS1 overexpression inhibits the proliferation, invasion and migration of colorectal cancer cells by regulating the miR-1269a/VASH1 axis. Exp Ther Med 2021; 22:1155. [PMID: 34504600 PMCID: PMC8393656 DOI: 10.3892/etm.2021.10589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 07/09/2021] [Indexed: 12/25/2022] Open
Abstract
Colorectal cancer (CRC), the third most common cancer worldwide, poses a threat to human life. However, its underlying mechanism is unclear and no satisfactory treatment is available. The present study aimed to investigate the role of circular RNA argininosuccinate synthase 1 (circASS1) in CRC cells and tissues to identify the potential mechanism underlying the pathogenesis of CRC. The expression of circASS1 in CRC cells and tissues was determined by reverse transcription-quantitative PCR. Following circASS1 overexpression in HT29 cells, cell viability, colony formation and apoptosis were measured using MTT, colony formation and TUNEL assays, respectively. Cell invasion and migration were also assessed. After confirming the associations among circASS1, microRNA (miR)-1269a and vasohibin 1 (VASH1), the characteristics of the HT29 cell line were assessed by performing the aforementioned assays. circASS1 expression was decreased in CRC cells and tissues, and circASS1 overexpression suppressed CRC cell proliferation, invasion and migration. circASS1 adsorbed miR-1269a and regulated its expression, and VASH1 was a target protein of miR-1269a. circASS1 overexpression decreased cell proliferation, invasion and migration, but enhanced cell apoptosis in HT29 cells, which was reversed by co-transfection with miR-1269a mimic or short hairpin RNA-VASH1. In conclusion, circASS1 overexpression inhibited CRC cell proliferation, invasion and migration by regulating miR-1269a/VASH1, which indicated a potential molecular mechanism underlying the pathogenesis of CRC.
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Affiliation(s)
- Hai-Lin Xiong
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Xiao-Hua Zhong
- Department of Gastroenterological Surgery, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Xiao-Hong Guo
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Hao-Jie Liao
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Xia Yuan
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
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30
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Wang L, Wang E, Prado Balcazar J, Wu Z, Xiang K, Wang Y, Huang Q, Negrete M, Chen K, Li W, Fu Y, Dohlman A, Mines R, Zhang L, Kobayashi Y, Chen T, Shi G, Shen JP, Kopetz S, Tata PR, Moreno V, Gersbach C, Crawford G, Hsu D, Huang E, Bu P, Shen X. Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2004673. [PMID: 34378358 PMCID: PMC8498885 DOI: 10.1002/advs.202004673] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/09/2021] [Indexed: 06/13/2023]
Abstract
Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1-remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment-induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.
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Affiliation(s)
- Lihua Wang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Ergang Wang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | | | - Zhenzhen Wu
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
| | - Kun Xiang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Yi Wang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Qiang Huang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Marcos Negrete
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Kai‐Yuan Chen
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Wei Li
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Yujie Fu
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Anders Dohlman
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Robert Mines
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Liwen Zhang
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
| | - Yoshihiko Kobayashi
- Department of Cell BiologyRegeneration NextDuke University School of MedicineDurhamNC27710USA
| | - Tianyi Chen
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Guizhi Shi
- Laboratory Animal Research CenterInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - John Paul Shen
- Department of Gastrointestinal Medical OncologyMD AndersonDurhamNC77030USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical OncologyMD AndersonDurhamNC77030USA
| | - Purushothama Rao Tata
- Department of Cell BiologyRegeneration NextDuke University School of MedicineDurhamNC27710USA
| | - Victor Moreno
- Department of Clinical SciencesUniversity of BarcelonaBarcelona08193Spain
- Prevention and Control ProgramCatalan Institute of Oncology‐IDIBELLCIBERESPBarcelonaE08907Spain
| | - Charles Gersbach
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Gregory Crawford
- Department of PediatricsDuke University School of MedicineDurhamNC27710USA
| | - David Hsu
- Department of MedicineDuke University School of MedicineDurhamNC27710USA
| | - Emina Huang
- Department of Cancer Biology and Colorectal SurgeryLerner Research Institute, Cleveland ClinicClevelandOH44195USA
| | - Pengcheng Bu
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
- Center for Excellence in BiomacromoleculesChinese Academy of SciencesBeijing100101China
| | - Xiling Shen
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
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Yu Y, Ren KM. Development of a prognostic prediction model based on microRNA-1269a in esophageal cancer. World J Gastrointest Oncol 2021; 13:943-958. [PMID: 34457197 PMCID: PMC8371514 DOI: 10.4251/wjgo.v13.i8.943] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/27/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Esophageal cancer (ESCA) is a heterogeneous cancer with variable outcomes that are challenging to predict. MicroRNA (miR)-1269a is a newly discovered non-coding RNA that shows promising prognostic prediction in other cancers, but its clinical value in ESCA remains unclear.
AIM To explore the relationship between miR-1269a and its clinical value and to develop a nomogram to succinctly display this relationship.
METHODS We analyzed the expression of miR-1269a in 125 ESCA tissue samples with complete clinical data and 52 normal tissue samples. We determined the prognostic value of miR-1269a for overall survival (OS) and cancer-specific survival (CSS) and evaluated the association between miR-1269a and clinical variables including tumor location, histologic grade, metastatic stage, and American Joint Committee on Cancer (AJCC) stage using multivariate Cox analysis. Additionally, we developed a nomogram for OS and CSS based on miR-1269a expression using age and AJCC stage and assessed its prognostic performance. Using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes analyses, we predicted the target genes of miR-1269a and analyzed their potential function in caner development.
RESULTS The expression of miR-1269a was significantly higher in ESCA patients than healthy controls. Patients with high expression of miR-1269a showed poor prognosis in OS and CSS, suffered increased rates of low differentiation and metastasis, and exhibited tumor stage T3 + T4, positive lymph stage, and AJCC stage III + IV. The area under the receiver operating characteristic curve of miR-1269a was 0.716 for OS and 0.764 for CSS. Multivariate Cox analysis revealed that AJCC stage and miR-1269a were independent factors for OS and CSS. Combing with age, we constructed a nomogram for prognostic prediction. Additionally, our nomogram showed excellent predictive performance for OS and CSS after 3 years and 5 years and was easy to use. Ultimately, the functional analysis suggested that miR-1269a was mostly involved in the PI3K-AKT signaling pathway.
CONCLUSION miR-1269a can be used as a potential indicator for the prognosis of ESCA patients. We developed an easy-to-use nomogram with excellent ESCA prognostic prediction for clinical use.
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Affiliation(s)
- Yong Yu
- Department of Ophtalmology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Kai-Ming Ren
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
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32
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Yu Y, Ren KM. Development of a prognostic prediction model based on microRNA-1269a in esophageal cancer. World J Gastrointest Oncol 2021. [DOI: 10.4251/wjgo.v13.i8.941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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33
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Creatine promotes cancer metastasis through activation of Smad2/3. Cell Metab 2021; 33:1111-1123.e4. [PMID: 33811821 DOI: 10.1016/j.cmet.2021.03.009] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 02/15/2021] [Accepted: 03/11/2021] [Indexed: 12/24/2022]
Abstract
As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.
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34
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Weidle UH, Brinkmann U, Auslaender S. microRNAs and Corresponding Targets Involved in Metastasis of Colorectal Cancer in Preclinical In Vivo Models. Cancer Genomics Proteomics 2021; 17:453-468. [PMID: 32859626 DOI: 10.21873/cgp.20204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/17/2020] [Indexed: 12/27/2022] Open
Abstract
The high death toll of colorectal cancer patients is due to metastatic disease which is difficult to treat. The liver is the preferred site of metastasis, followed by the lungs and peritoneum. In order to identify new targets and new modalities of intervention we surveyed the literature for microRNAs (miRs) which modulate metastasis of colorectal cancer in preclinical in vivo models. We identified 12 up-regulated and 19 down-regulated miRs corresponding to the latter criterium. The vast majority (n=16) of identified miRs are involved in modulation of epithelial-mesenchymal transition (EMT). Other categories of metastasis-related miRs exhibit tumor- and metastasis-suppressing functions, modulation of signaling pathways, transmembrane receptors and a class of miRs, which interfere with targets which do not fit into these categories. Finally, we discuss the principles of miR inhibition and reconstitution of function, prospective clinical evaluation of with miR-related agents in the context of clinical evaluation in metastasis relevant settings.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Simon Auslaender
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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35
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Zhang Q, Lin ZN, Chen J, Zheng WX. A multi-omics study on cutaneous and uveal melanoma. Int J Ophthalmol 2021; 14:32-41. [PMID: 33469481 DOI: 10.18240/ijo.2021.01.05] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 09/15/2020] [Indexed: 12/20/2022] Open
Abstract
AIM To present the multi-omics landscape of cutaneous melanoma (CM) and uveal melanoma (UM) from The Cancer Genome Atlas (TCGA). METHODS The differentially expressed genes (DEGs) between CM and UM were found and integrated into a gene ontology enrichment analysis. Besides, the differentially expressed miRNAs were also identified. We also compared the methylation level of CM with UM and identified the differentially methylated regions to integrate with the DEGs to display the relationship between the gene expression and DNA methylation. The differentially expressed transcription factors (TFs) were identified. RESULTS Though CM had more mutational burden than UM, they shared several similarities such as the same rankings in diverse variant types. Except GNAQ and GNA11, the other top 18 mutated genes of the combined group were mostly detected in CM instead of UM. On the transcriptomic level, 4610 DEGs were found and integrated into a gene ontology enrichment analysis. We also identified 485 differentially expressed miRNAs. The methylation analysis showed that UM had a significantly higher methylation level than CM. The integration of differentially methylated regions and DEGs demonstrated that most DEGs were downregulated in UM and the hypo- and hypermethylation presented no obvious difference within these DEGs. Finally, 116 hypermethylated TFs and 114 hypomethylated TFs were identified as differentially expressed TFs in CM when compared with UM. CONCLUSION This multi-omics study on comparing CM with UM confirms that they differ in all analyzed levels. Of notice, the results also offer new insights with implications for elucidating certain unclear problems such as the distinct role of epithelial mesenchymal transition in two melanomas, the different metastatic routes of CM and UM and the liver tropism of metastatic UM.
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Affiliation(s)
- Qi Zhang
- Institute of Pathology and Neuropathology, University of Tuebingen, Tuebingen 72076, Germany
| | - Ze-Nan Lin
- University Eye Hospital, Center for Ophthalmology, University of Tuebingen, Tuebingen 72076, Germany
| | - Jie Chen
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Wen-Xu Zheng
- Department of Ophthalmology, the Second Hospital Affiliated to Jilin University, Jilin University, Changchun 130041, Jilin Province, China
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36
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Bai X, Wang Q, Rui X, Li X, Wang X. Upregulation of miR-1269 Contributes to the Progression of Esophageal Squamous Cell Cancer Cells and Is Associated With Poor Prognosis. Technol Cancer Res Treat 2021; 20:1533033820985858. [PMID: 33416035 PMCID: PMC8097309 DOI: 10.1177/1533033820985858] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background: MicroRNA-1269 (miR-1269) has been identified upregulated in several cancers,
as well as in esophageal cancer. In the present study, we investigated the
clinical prognostic significance and potential functional role of miR-1269
in esophageal squamous cell carcinoma (ESCC). Methods: A total of 107 ESCC patients who underwent surgical resection were enrolled
in this study. miR-1269 expression was measured using quantitative real-time
PCR (qRT-PCR). Kaplan-Meier method and multivariate Cox regression analysis
were used to explore the prognostic significance of miR-1269. CCK-8 assays
and Transwell assays were used to investigate the effects of miR-1269 on
cell proliferation, migration, and invasion. The direct association between
miR-1269 and SOX6 was evaluated using a dual-luciferase reporter assay. Results: The expression of miR-1269 was significantly upregulated in ESCC tissues and
cell lines compared with adjacent normal tissues and esophageal epithelial
cell line, respectively. What’s more, the upregulation of miR-1269 was
associated with positive lymph node metastasis and advanced TNM stage. ESCC
patients with high miR-1269 expression had shorter overall survival than
those with low miR-1269 expression levels. Compared with the control group,
overexpression of miR-1269 promoted cell proliferation, migration, and
invasion, while knockdown of miR-1269 inhibited cell proliferation,
migration, and invasion. SOX6 was a direct target of miR-1269. Conclusion: These results suggest that miR-1269 plays an important role in the
progression of ESCC by targeting SOX6 and may be a potential prognostic
biomarker and the miR-1269/SOX6 axis may be a therapeutic target for the
patient with ESCC.
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Affiliation(s)
- Xiuhui Bai
- Department of Gastroenterology, Caoxian People's hospital, Heze, Shandong, China
| | - Qiang Wang
- Department of Ultrasound, Yidu Central Hospital of Weifang, Weifang, Shandong, China
| | - Xueqi Rui
- Department of Cardiovasology, Liyang People's Hospital, Liyang, Jiangsu, China
| | - Xiaohua Li
- Department of Ultrasonography, Zibo City Linzi District People's Hospital, Zibo, Shandong, China
| | - Xianming Wang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.,Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
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37
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Sarabandi S, Sattarifard H, Kiumarsi M, Karami S, Taheri M, Hashemi M, Bahari G, Ghavami S. Association between Genetic Polymorphisms of miR-1307, miR- 1269, miR-3117 and Breast Cancer Risk in a Sample of South East Iranian Women. Asian Pac J Cancer Prev 2021; 22:201-208. [PMID: 33507700 PMCID: PMC8184203 DOI: 10.31557/apjcp.2021.22.1.201] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION MicroRNAs (miRNAs) play an essential role in the susceptibility and development of cancer cells. OBJECTIVE Examining the dependency of breast cancer risk with genetic polymorphisms of miR-1307, miR-1269, and miR-3117 in a sample of Iranian women (southeast region). METHODS The case-control study consisted of 520 individuals (260 diagnosed BC patients, 260 healthy individuals). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping of miR-1307 rs7911488, miR-1269 rs73239138, and miR-3117 (rs4655646 and rs7512692) polymorphisms. RESULTS AND CONCLUSION This study provided evidence that miR-1307 rs7911488 polymorphism significantly reduced the risk of BC in heterozygous AG genotype, as well as dominant (AG+GG) genotype and G allele. A significant correlation was found between dominant (AA+AG) genotype, the A allele and protection against BC due to miR-1269 rs73239138 in the sample of study. In contrast, our findings suggested that AG genotype and G allele of miR-3117 rs4655646 polymorphism could increase BC's susceptibility among the southeastern Iranian females. The miR-3117 rs7512692 variant also increased the risk of BC in codominant, dominant and recessive models, as well as the T allele. The possible dependency of miR-1307, miR-1269, and miR-3117 variants with patients' clinicopathological characteristics and BC was also studied. It was concluded that there is a correlation between miR-3117 rs7512692 variant and tumor grade (p=0.031); also, a correlation between miR-1269 rs73239138 variant and progesterone receptor status (p=0.006). The current investigation revealed that miR-1307, miR-1269, and miR-3117 polymorphisms might play a crucial role in the Iranian population's vulnerability to BC.<br />.
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Affiliation(s)
- Sahel Sarabandi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hedieh Sattarifard
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Mohammad Kiumarsi
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Shima Karami
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohsen Taheri
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohammad Hashemi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Gholamreza Bahari
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.,Children and Adolescent Health Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.,Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland.,Autophagy Research Center, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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38
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Fu S, Wang Y, Li H, Chen L, Liu Q. Regulatory Networks of LncRNA MALAT-1 in Cancer. Cancer Manag Res 2020; 12:10181-10198. [PMID: 33116873 PMCID: PMC7575067 DOI: 10.2147/cmar.s276022] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/03/2020] [Indexed: 12/18/2022] Open
Abstract
Long noncoding (lnc)RNAs are a group of RNAs with a length greater than 200 nt that do not encode a protein but play an essential role in regulating the expression of target genes in normal biological contexts as well as pathologic processes including tumorigenesis. The lncRNA metastasis-associated lung adenocarcinoma transcript (MALAT)-1 has been widely studied in cancer. In this review, we describe the known functions of MALAT-1; its mechanisms of action; and associated signaling pathways and their clinical significance in different cancers. In most malignancies, including lung, colorectal, thyroid, and other cancers, MALAT-1 functions as an oncogene and is upregulated in tumors and tumor cell lines. MALAT-1 has a distinct mechanism of action in each cancer type and is thus at the center of large gene regulatory networks. Dysregulation of MALAT-1 affects cellular processes such as alternative splicing, epithelial–mesenchymal transition, apoptosis, and autophagy, which ultimately results in the abnormal cell proliferation, invasion, and migration that characterize cancers. In other malignancies, such as glioma and endometrial carcinoma, MALAT-1 functions as a tumor suppressor and thus forms additional regulatory networks. The current evidence indicates that MALAT-1 and its associated signaling pathways can serve as diagnostic or prognostic biomarker or therapeutic target in the treatment of many cancers.
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Affiliation(s)
- Shijian Fu
- The First Affiliated Hospital of Harbin Medical University, Harbin 150081, People's Republic of China
| | - Yanhong Wang
- Department of Laboratory Medicine, Yuebei People's Hospital of Shaoguan, The Affiliated Hospital of Shantou University, Shaoguan 512025, People's Republic of China
| | - Hang Li
- The First Affiliated Hospital of Harbin Medical University, Harbin 150081, People's Republic of China
| | - Leilei Chen
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Capital Medical University, Beijing 100029, People's Republic of China
| | - Quanzhong Liu
- Department of Medical Genetics, Harbin Medical University, Harbin 150081, People's Republic of China
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Zhang Y, Wang Q, Luo N, Liu J, Ren H, Shao X, Zhang L, Yu Y. MicroRNA-1269a Promotes Proliferation and Arrest of Apoptosis of Glioma Cells by Directly Targeting ATRX. Front Oncol 2020; 10:563901. [PMID: 33194637 PMCID: PMC7659443 DOI: 10.3389/fonc.2020.563901] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 08/20/2020] [Indexed: 12/16/2022] Open
Abstract
Glioma is one of the deadliest malignant brain tumors in adults worldwide. MicroRNA (miR) has been reported to be a pivotal regulator in human tumors. The aim of this study was to determine the expression, function, and mechanism of action of miR-1269a in glioma progression. The expression of miR-1269a was higher in both glioma cases reported in databases and glioma cell lines, and it was highly associated with poorer prognosis. Next, it was shown in vitro that mimic of miR-1269a could promote glioma progression and arrest apoptosis, whereas the inhibition of miR-1269a exhibited the opposite effects. In addition, miR-1269a was found to directly target ATRX chromatin remodeler by a dual-luciferase reporter assay. Moreover, ATRX overexpression could reverse the suppressive effects of miR-1269a on proliferation and apoptosis in vitro. In vivo subcutaneous xenograft tumor assay was also performed to confirm the phenotypes and molecular mechanism involved. Taking the findings together, our study implies that the miR-1269a/ATRX axis is a novel therapeutic target of glioma.
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Affiliation(s)
- Yulian Zhang
- Department of Neurosurgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
| | - Qi Wang
- Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
| | - Na Luo
- Department of Neurosurgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
| | - Jiang Liu
- Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
| | - Hongxiang Ren
- Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
| | - Xu Shao
- Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
| | - Li Zhang
- Department of Neurosurgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China.,Department of Neurosurgery, Graduate School of Peking Union Medical College, Beijing, China
| | - Yanbing Yu
- Department of Neurosurgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China.,Department of Neurosurgery, Graduate School of Peking Union Medical College, Beijing, China
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40
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Wang X, Jiang X, Li J, Wang J, Binang H, Shi S, Duan W, Zhao Y, Zhang Y. Serum exosomal miR-1269a serves as a diagnostic marker and plays an oncogenic role in non-small cell lung cancer. Thorac Cancer 2020; 11:3436-3447. [PMID: 33107700 PMCID: PMC7705625 DOI: 10.1111/1759-7714.13644] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/10/2020] [Accepted: 08/11/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Early diagnosis improves the prognosis for non-small cell lung cancer (NSCLC); therefore, there is a pressing need for effective diagnostic methods for NSCLC. Increasing evidence indicates that serum exosomal micro RNAs (miRNAs) represent promising diagnostic and prognostic markers for multiple cancers. Here, we explored a panel of miRNAs for NSCLC diagnosis and functionally characterized miR-1269a in the pathogenesis of NSCLC. METHODS First, we analyzed high-throughput data from The Cancer Genome Atlas (TCGA) to identify differentially expressed miRNAs between NSCLC patients and healthy controls. We examined the expression profiles of the identified miRNAs using qRT-PCR. RESULTS We found that four micro-RNAs (hsa-miR-9-3p, hsa-miR-205-5p, hsa-miR-210-5p, and hsa-miR-1269a) were more abundant in serum exosomes from NSCLC patients. A logistic regression model validated the diagnostic efficacy of the four-microRNA panel, allowing us to distinguish NSCLC patients from healthy controls with AUCs of 0.915 and 0.878 for the training and validation sets, respectively. Functionally, NSCLC cell proliferation, migration, and invasion were affected by the aberrant expression of hsa-miR-1269a in culture. Reduced expression of miR-1269a resulted in reduced proliferation, migration, and invasion through targeting the forkhead box O1 gene (FOXO1). CONCLUSIONS Taken together, our study identified a panel of four serum exosomal miRNAs as a potential noninvasive diagnostic biomarker for NSCLC. The interactions between FOXO1 and miR-1269a represent novel potential targets for NSCLC therapy.
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Affiliation(s)
- Xue Wang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Xinquan Jiang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Jingzheng Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China.,Dongping County Peoples Hospital, Tai'an, China.,Dongping Hospital Affiliated to Shandong First Medical University, Tai'an, China
| | - Helen Binang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Shuang Shi
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Weili Duan
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Yinghui Zhao
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Yi Zhang
- Respiratory and Critical Care Medicine Department, Qilu Hospital, Shandong University, Jinan, China
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Wen XQ, Qian XL, Sun HK, Zheng LL, Zhu WQ, Li TY, Hu JP. MicroRNAs: Multifaceted Regulators of Colorectal Cancer Metastasis and Clinical Applications. Onco Targets Ther 2020; 13:10851-10866. [PMID: 33149603 PMCID: PMC7602903 DOI: 10.2147/ott.s265580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/12/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third-commonest malignant cancer, and its metastasis is the major reason for cancer-related death. The process of metastasis is highly coordinated and involves a complex cascade of multiple steps. In recent years, miRNAs, as highly conserved, endogenous, noncoding, single-stranded RNA, has been confirmed to be involved in the development of various cancers. Considering that miRNA is also involved in a series of biological behaviors, regulating CRC occurrence and development, we review and summarize the role of miRNAs and related signaling pathways in several CRC-metastasis stages, including invasion and migration, mobility, metabolism, epithelial-mesenchymal transition, tumor-microenvironment communication, angiogenesis, anoikis, premetastatic-niche formation, and cancer stemness. In addition, we review the application of miRNAs as diagnostic CRC markers and in clinical treatment resistance. This review can contribute to understanding of the mechanism of miRNAs in CRC progression and provide a theoretical basis for clinical CRC treatment.
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Affiliation(s)
- Xiang-Qiong Wen
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Xian-Ling Qian
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China
- Department of Medical Imaging, Shanghai Medical College,Fudan University, Shanghai, 200032, People's Republic of China
| | - Huan-Kui Sun
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Lin-Lin Zheng
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Wei-Quan Zhu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Tai-Yuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Jia-Ping Hu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
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de Ceuninck van Capelle C, Spit M, Ten Dijke P. Current perspectives on inhibitory SMAD7 in health and disease. Crit Rev Biochem Mol Biol 2020; 55:691-715. [PMID: 33081543 DOI: 10.1080/10409238.2020.1828260] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Transforming growth factor β (TGF-β) family members play an extensive role in cellular communication that orchestrates both early development and adult tissue homeostasis. Aberrant TGF-β family signaling is associated with a pathological outcome in numerous diseases, and in-depth understanding of molecular and cellular processes could result in therapeutic benefit for patients. Canonical TGF-β signaling is mediated by receptor-regulated SMADs (R-SMADs), a single co-mediator SMAD (Co-SMAD), and inhibitory SMADs (I-SMADs). SMAD7, one of the I-SMADs, is an essential negative regulator of the pleiotropic TGF-β and bone morphogenetic protein (BMP) signaling pathways. In a negative feedback loop, SMAD7 inhibits TGF-β signaling by providing competition for TGF-β type-1 receptor (TβRI), blocking phosphorylation and activation of SMAD2. Moreover, SMAD7 recruits E3 ubiquitin SMURF ligases to the type I receptor to promote ubiquitin-mediated proteasomal degradation. In addition to its role in TGF-β and BMP signaling, SMAD7 is regulated by and implicated in a variety of other signaling pathways and functions as a mediator of crosstalk. This review is focused on SMAD7, its function in TGF-β and BMP signaling, and its role as a downstream integrator and crosstalk mediator. This crucial signaling molecule is tightly regulated by various mechanisms. We provide an overview of the ways by which SMAD7 is regulated, including noncoding RNAs (ncRNAs) and post-translational modifications (PTMs). Finally, we discuss its role in diseases, such as cancer, fibrosis, and inflammatory bowel disease (IBD).
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Affiliation(s)
| | - Maureen Spit
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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43
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Guo C, Shi H, Shang Y, Zhang Y, Cui J, Yu H. LncRNA LINC00261 overexpression suppresses the growth and metastasis of lung cancer via regulating miR-1269a/FOXO1 axis. Cancer Cell Int 2020; 20:275. [PMID: 32607060 PMCID: PMC7318380 DOI: 10.1186/s12935-020-01332-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 06/09/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND LncRNAs are key regulators in cancer. The current study explored the role of lncRNA LINC00261 (LINC00261) in lung cancer (LC). METHODS Expression of LINC00261 in LC tissues and cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Pearson's Chi square test and Kaplan-Meier analysis were performed to evaluate the correlations between LINC00261 expression and clinical characteristics, and overall survival time. A549 and SPC-A1 cells were transfected with LINC00261 overexpression plasmid, cell viability, cell number, and apoptosis were detected by CCK-8 assay, colony formation, and flow cytometry. Moreover, wound-healing and transwell assay were performed to detect cell metastasis and invasion. Expressions of proteins related to cell proliferation and metastasis were determined by Western blot. Xenograft was constructed, and tumor size and weight were measured and the effects of LINC00261 overexpression on tumor growth were detected. Bioinformatics analysis, dual-luciferase reporter assay, qRT-PCR, correlation analysis, and functional rescue experiments were conducted on clinical cases and LC cells to explore the molecular mechanism of LINC00261 in LC. RESULTS In LC, LINC00261 expression was down-regulated, and was associated with more advanced TNM stage, metastasis and a shorter survival time. LINC00261 overexpression inhibited the growth and metastasis of LC cells in vitro and tumor growth in vivo. Furthermore, miR-1269a directly interacted with LINC00261 and FOXO1. The expressions of miR-1269a and FOXO1 were dysregulated by LINC00261 in LC. Additionally, miR-1269a promoted the progression of LC through targeting FOXO1. CONCLUSIONS Down-regulation of LINC00261 expression has a prognostic value in LC, and overexpression LINC00261 inhibits LC progression via targeting miR-1269a/FOXO1 axis.
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Affiliation(s)
- Caixia Guo
- Department of Respiratory Medicine, Henan Provincial Chest Hospital, No.1, Weiwu Road, Zhengzhou, 450000 Henan Province China
| | - Hongmei Shi
- Department of Respiratory Medicine, Henan Provincial Chest Hospital, No.1, Weiwu Road, Zhengzhou, 450000 Henan Province China
| | - Yuli Shang
- Department of Respiratory Medicine, Henan Provincial Chest Hospital, No.1, Weiwu Road, Zhengzhou, 450000 Henan Province China
| | - Yafei Zhang
- Department of Respiratory Medicine, Henan Provincial Chest Hospital, No.1, Weiwu Road, Zhengzhou, 450000 Henan Province China
| | - Jiajia Cui
- Department of Respiratory Medicine, Henan Provincial Chest Hospital, No.1, Weiwu Road, Zhengzhou, 450000 Henan Province China
| | - Hongtao Yu
- Department of Respiratory Medicine, Henan Provincial Chest Hospital, No.1, Weiwu Road, Zhengzhou, 450000 Henan Province China
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44
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Park JH, Park KS. SMAD3 promotes ELK3 expression following transforming growth factor β-mediated stimulation of MDA-MB231 cells. Oncol Lett 2020; 19:2749-2754. [PMID: 32218827 PMCID: PMC7068580 DOI: 10.3892/ol.2020.11375] [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: 10/01/2019] [Accepted: 12/19/2019] [Indexed: 12/05/2022] Open
Abstract
Transforming growth factor-β (TGFβ) is a secreted cytokine whose aberrant spatiotemporal expression is related to cancer progression and metastasis. While TGFβ acts as a tumor suppressor in normal and premalignant stages, TGFβ functions as a tumor promoter during the malignant phases of tumor progression by prompting cancer cells to undergo epithelial-mesenchymal transition (EMT), which enhances tumor cell invasion and ultimately promotes metastasis to other organs. Extensive studies have been performed to uncover the molecular and cellular mechanisms underlying TGFβ inducing EMT in cancer cells. Here, we suggested that ELK3, which encodes a protein that orchestrates invasion and metastasis of triple negative breast cancer cells, is a downstream target of TGFβ-SMAD3 in MDA-MB231 cells. ELK3 expression was increased in a time-dependent manner upon TGFβ treatment. Chemical and molecular inhibition of the TGFβ receptor blocked the ability of TGFβ to induce ELK3 expression. Small interfering RNA-mediated suppression analysis revealed that SMAD3 induces TGFβ signaling to express ELK3. Moreover, the results of the luciferase reporter assay and chromatin immunoprecipitation analysis showed that SMAD3 directly binds to the SMAD-binding element on the promoter of ELK3 to activate gene expression following TGFβ stimulation. We concluded that ELK3 is a novel downstream target of TGFβ-SMAD3 signaling in aggressive breast cancer cells.
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Affiliation(s)
- Ji-Hoon Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea
| | - Kyung-Soon Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea
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45
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Common and Unique microRNAs in Multiple Carcinomas Regulate Similar Network of Pathways to Mediate Cancer Progression. Sci Rep 2020; 10:2331. [PMID: 32047181 PMCID: PMC7012856 DOI: 10.1038/s41598-020-59142-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 01/14/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is a complex disease with a fatal outcome. Early detection of cancer, by monitoring appropriate molecular markers is very important for its therapeutic management. In this regard, the short non-coding RNA molecules, microRNAs (miRNAs) have shown great promise due to their availability in circulating fluids facilitating non-invasive detection of cancer. In this study, an in silico comparative analysis was performed to identify specific signature miRNAs dysregulated across multiple carcinomas and simultaneously identify unique miRNAs for each cancer type as well. The miRNA-seq data of cancer patient was obtained from GDC portal and their differential expressions along with the pathways regulated by both common and unique miRNAs were analyzed. Our studies show twelve miRNAs commonly dysregulated across seven different cancer types. Interestingly, four of those miRNAs (hsa-mir-210, hsa-mir-19a, hsa-mir-7 and hsa-mir-3662) are already reported as circulatory miRNAs (circRNAs); while, the miR-183 cluster along with hsa-mir-93 have been found to be incorporated in exosomes signifying the importance of the identified miRNAs for their use as prospective, non-invasive biomarkers. Further, the target mRNAs and pathways regulated by both common and unique miRNAs were analyzed, which interestingly had significant commonality. This suggests that miRNAs that are commonly de-regulated and specifically altered in multiple cancers might regulate similar pathways to promote cancer. Our data is of significance because we not only identify a set of common and unique miRNAs for multiple cancers but also highlight the pathways regulated by them, which might facilitate the development of future non-invasive biomarkers conducive for early detection of cancers.
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46
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Guo H, Thio FYC, Binderbauer MW, Buttery RJ, Jarboe TR, Maingi R, Sarff JS, Stangeby PC, Sutherland DA, Wade MR, Zarnstorff MC. Innovative approaches towards an economic fusion reactor. Natl Sci Rev 2020; 7:245-247. [PMID: 34692038 PMCID: PMC8288883 DOI: 10.1093/nsr/nwz162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
| | - Francis Y C Thio
- Breakthrough Fusion International Corporation, USA
- School of Science, Xi’an Jiaotong University, China
| | | | | | - Thomas R Jarboe
- Department of Aeronautics & Astronautic, University of Washington, USA
| | | | - John S Sarff
- Department of Physics, University of Wisconsin, USA
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47
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Yang W, Xiao W, Cai Z, Jin S, Li T. miR-1269b Drives Cisplatin Resistance of Human Non-Small Cell Lung Cancer via Modulating the PTEN/PI3K/AKT Signaling Pathway. Onco Targets Ther 2020; 13:109-118. [PMID: 32021259 PMCID: PMC6954839 DOI: 10.2147/ott.s225010] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 11/23/2019] [Indexed: 12/21/2022] Open
Abstract
Background MiRNAs have been reported to induce certain drug resistance in multiple solid tumors via various mechanisms. Our study aimed to investigate whether miRNA-1269b was involved in the chemoresistance and the progression of non-small cell lung cancer (NSCLC). Methods MTT and colony formation assay were conducted to determine cell proliferation and cell apoptosis was analyzed by flow cytometry with annexin V/PI. Luciferase reporter assay was performed to validate miRNA-targeting sequences. The function of miR-1269b in cisplatin-resistant was evaluated in vivo in a mouse tumor model. Results We found that miR-1269b expression was up-regulated in cisplatin-resistant NSCLC specimens and NSCLC cell lines, which resulted in the promotion of chemoresistance and tumorigenicity. miR-1269b overexpression enhanced drug resistance and promoted cell proliferation in vitro and tumor growth in vivo, with reduced apoptosis rate of A549 cells inin vitro cell culture. Mechanistically, we identified PTEN as the direct target of miR-1269b, and the PTEN level was negatively correlated with miR-1269b in NSCLC specimens. Further study demonstrated that miR-1269b targeted PTEN to modulate PI3K/AKT signaling pathway. Conclusion In conclusion, these findings suggest that the miR-1269b/PTEN/PI3K/AKT-mediated network might promote cisplatin resistance in NSCLC, and that miR-1269b can be a potential therapeutic target for chemoresistance in NSCLC patients.
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Affiliation(s)
- Wu Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, People's Republic of China
| | - Wei Xiao
- Department of Radiotherapy, Nanjing Chest Hospital, Nanjing, Jiangsu Province 210029, People's Republic of China
| | - Zhengrong Cai
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu Province 210029, People's Republic of China
| | - Shidai Jin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, People's Republic of China
| | - Tian Li
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu Province 210029, People's Republic of China
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Solé C, Lawrie CH. MicroRNAs and Metastasis. Cancers (Basel) 2019; 12:cancers12010096. [PMID: 31906022 PMCID: PMC7016783 DOI: 10.3390/cancers12010096] [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: 11/27/2019] [Revised: 12/20/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023] Open
Abstract
Metastasis, the development of secondary malignant growths at a distance from the primary site of a cancer, is associated with almost 90% of all cancer deaths, and half of all cancer patients present with some form of metastasis at the time of diagnosis. Consequently, there is a clear clinical need for a better understanding of metastasis. The role of miRNAs in the metastatic process is beginning to be explored. However, much is still to be understood. In this review, we present the accumulating evidence for the importance of miRNAs in metastasis as key regulators of this hallmark of cancer.
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Affiliation(s)
- Carla Solé
- Molecular Oncology Group, Biodonostia Research Institute, 20014 San Sebastián, Spain;
| | - Charles H. Lawrie
- Molecular Oncology Group, Biodonostia Research Institute, 20014 San Sebastián, Spain;
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
- Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
- Correspondence: or ; Tel.: +34-943-006138
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Moradi-Marjaneh R, Khazaei M, Ferns GA, Aghaee-Bakhtiari SH. The Role of TGF-β Signaling Regulatory MicroRNAs in the Pathogenesis of Colorectal Cancer. Curr Pharm Des 2019; 24:4611-4618. [PMID: 30636580 DOI: 10.2174/1381612825666190110150705] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is one of the most common cancers globally and is associated with a high mortality rate. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in normal intestinal tissue function, but has also been implicated in the development of CRC. MicroRNAs (miRNAs) have also recently emerged as important regulators of cancer development and progression. They act by targeting multiple signaling pathways including the TGF-β signaling pathway. There is growing evidence demonstrating that miRNAs target various components of the TGF-β signaling pathway, including TGF-β1, TGF-β2, regulatory SMADs (SMAD1, 2, 3, 5 and 9), co-mediator SMAD4, inhibitory SMADs (SMAD6 and 7) and the TGF-β receptors, and thereby alter the proliferation and migration of CRC cells. In this review, we summarize the data concerning the interaction between TGF-β signaling pathway and miRNAs with the aim to better understanding the CRC molecular mechanisms and hence better management of this disease.
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Affiliation(s)
- Reyhaneh Moradi-Marjaneh
- Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Seyed H Aghaee-Bakhtiari
- Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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50
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Liu WL, Wang HX, Shi CX, Shi FY, Zhao LY, Zhao W, Wang GH. MicroRNA-1269 promotes cell proliferation via the AKT signaling pathway by targeting RASSF9 in human gastric cancer. Cancer Cell Int 2019; 19:308. [PMID: 31768130 PMCID: PMC6873743 DOI: 10.1186/s12935-019-1026-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/11/2019] [Indexed: 12/13/2022] Open
Abstract
Background MicroRNAs (miRNAs) play key roles in tumorigenesis and progression of gastric cancer (GC). miR-1269 has been reported to be upregulated in several cancers and plays a crucial role in carcinogenesis and cancer progression. However, the biological function of miR-1269 in human GC and its mechanism remain unclear and need to be further elucidated. Methods The expression of miR-1269 in GC tissues and cell lines was detected by quantitative real-time PCR (qRT-PCR). Target prediction programs (TargetScanHuman 7.2 and miRBase) and a dual-luciferase reporter assay were used to confirm that Ras-association domain family 9 (RASSF9) is a target gene of miR-1269. The expression of RASSF9 was measured by qRT-PCR and Western blotting in GC tissues. MTT and cell counting assays were used to explore the effect of miR-1269 on GC cell proliferation. The cell cycle and apoptosis were measured by flow cytometry. RASSF9 knockdown and overexpression were used to further verify the function of the target gene. Results We found that miR-1269 expression was upregulated in human GC tissues and cell lines. The overexpression of miR-1269 promoted GC cell proliferation and cell cycle G1-S transition and suppressed apoptosis. The inhibition of miR-1269 inhibited cell growth and G1-S transition and induced apoptosis. miR-1269 expression was inversely correlated with RASSF9 expression in GC tissues. RASSF9 was verified to be a direct target of miR-1269 by using a luciferase reporter assay. The overexpression of miR-1269 decreased RASSF9 expression at both the mRNA and protein levels, and the inhibition of miR-1269 increased RASSF9 expression. Importantly, silencing RASSF9 resulted in the same biological effects in GC cells as those induced by overexpression of miR-1269. Overexpression of RASSF9 reversed the effects of miR-1269 overexpression on GC cells. Both miR-1269 overexpression and RASSF9 silencing activated the AKT signaling pathway, which modulated cell cycle regulators (Cyclin D1 and CDK2). In contrast, inhibition of miR-1269 and RASSF9 overexpression inhibited the AKT signaling pathway. Moreover, miR-1269 and RASSF9 also regulated the Bax/Bcl-2 signaling pathway. Conclusions Our results demonstrate that miR-1269 promotes GC cell proliferation and cell cycle G1-S transition by activating the AKT signaling pathway and inhibiting cell apoptosis via regulation of the Bax/Bcl-2 signaling pathway by targeting RASSF9. Our findings indicate an oncogenic role of miR-1269 in GC pathogenesis and the potential use of miR-1269 in GC therapy.
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Affiliation(s)
- Wen-Li Liu
- 1Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061 Shaanxi China
| | - Hu-Xia Wang
- 2Mammary Department, Shaanxi Provincial Tumor Hospital, Xi'an, 710061 Shaanxi China
| | - Cheng-Xin Shi
- 3Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061 Shaanxi China
| | - Fei-Yu Shi
- 3Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061 Shaanxi China
| | - Ling-Yu Zhao
- 4Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi China
| | - Wei Zhao
- 3Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061 Shaanxi China
| | - Guang-Hui Wang
- 3Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061 Shaanxi China
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