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Fujiwara-Tani R, Nakashima C, Ohmori H, Fujii K, Luo Y, Sasaki T, Ogata R, Kuniyasu H. Significance of Malic Enzyme 1 in Cancer: A Review. Curr Issues Mol Biol 2025; 47:83. [PMID: 39996805 PMCID: PMC11854147 DOI: 10.3390/cimb47020083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/26/2025] Open
Abstract
Malic enzyme 1 (ME1) plays a key role in promoting malignant phenotypes in various types of cancer. ME1 promotes epithelial-mesenchymal transition (EMT) and enhances stemness via glutaminolysis, energy metabolism reprogramming from oxidative phosphorylation to glycolysis. As a result, ME1 promotes the malignant phenotypes of cancer cells and poor patient prognosis. In particular, ME1 expression is promoted in hypoxic environments associated with hypoxia-inducible factor (HIF1) α. ME1 is overexpressed in budding cells at the cancer invasive front, promoting cancer invasion and metastasis. ME1 also generates nicotinamide adenine dinucleotide (NADPH), which, together with glucose-6-phosphate dehydrogenase (G6PD) and isocitrate dehydrogenase (IDH1), expands the NADPH pool, maintaining the redox balance in cancer cells, suppressing cell death by neutralizing mitochondrial reactive oxygen species (ROS), and promoting stemness. This review summarizes the latest research insights into the mechanisms by which ME1 contributes to cancer progression. Because ME1 is involved in various aspects of cancer and promotes many of its malignant phenotypes, it is expected that ME1 will become a novel drug target in the near future.
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Affiliation(s)
- Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara 634-8521, Japan; (C.N.); (H.O.); (K.F.); (Y.L.); (T.S.); (R.O.)
| | | | | | | | | | | | | | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara 634-8521, Japan; (C.N.); (H.O.); (K.F.); (Y.L.); (T.S.); (R.O.)
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Zhang J, Li S, Zhang M, Wang Z, Xing Z. Targeting HOXA11-AS to mitigate prostate cancer via the glycolytic metabolism: In vitro and in vivo. J Cell Mol Med 2024; 28:e18227. [PMID: 38520207 PMCID: PMC10960170 DOI: 10.1111/jcmm.18227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 02/10/2024] [Accepted: 02/26/2024] [Indexed: 03/25/2024] Open
Abstract
As oncogenes or oncogene suppressors, long-stranded non-coding RNAs are essential for the formation and progression of human tumours. However, the mechanisms behind the regulatory role of RNA HOXA11-AS in prostate cancer (PCa) are unclear. PCa is a common malignant tumour worldwide, and an increasing number of studies have focused on its metabolic profile. Studies have shown that the long non-coding RNA (lncRNA) HOXA11-AS is aberrantly expressed in many tumours. However, the role of HOXA11-AS in PCa is unclear. This work aimed to determine how HOXA11-AS regulated PCa in vitro and in vivo. We first explored the clinical role of HOXA11-AS in PCa using bioinformatics methods, including single sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO)-logistics systematically. In this study, PCa cell lines were selected to assess the PCa regulatory role of HOXA11-AS overexpression versus silencing in vitro, and tumour xenografts were performed in nude mice to assess tumour suppression by HOXA11-AS silencing in vivo. HOXA11-AS expression was significantly correlated with clinicopathological factors, epithelial-mesenchymal transition (EMT) and glycolysis. Moreover, key genes downstream of HOXA11-AS exhibited good clinical diagnostic properties for PCa. Furthermore, we studied both in vitro and in vivo effects of HOXA11-AS expression on PCa. Overexpression of HOXA11-AS increased PCa cell proliferation, migration and EMT, while silencing HOXA11-AS had the opposite effect on PCa cells. In addition, multiple metabolites were downregulated by silencing HOXA11-AS via the glycolytic pathway. HOXA11-AS silencing significantly inhibited tumour development in vivo. In summary, silencing HOXA11-AS can inhibit PCa by regulating glucose metabolism and may provide a future guidance for the treatment of PCa.
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Affiliation(s)
- Jiankang Zhang
- Department of UrologyAffiliated Haikou Hospital of Xiangya Medical School, Central South UniversityHaikouChina
| | - Sailian Li
- Department of GastroenterologyAffiliated Haikou Hospital of Xiangya Medical School, Central South UniversityHaikouChina
| | - Mengyu Zhang
- Department of UrologyAffiliated Haikou Hospital of Xiangya Medical School, Central South UniversityHaikouChina
| | - Zhenting Wang
- Department of UrologyAffiliated Haikou Hospital of Xiangya Medical School, Central South UniversityHaikouChina
| | - Zengshu Xing
- Department of UrologyAffiliated Haikou Hospital of Xiangya Medical School, Central South UniversityHaikouChina
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Zhu S, Zhou R, Tang X, Fu W, Jia W. Hypoxia/inflammation-induced upregulation of HIF-1α and C/EBPβ promotes nephroblastoma cell EMT by improving HOXA11-AS transcription. Heliyon 2024; 10:e27654. [PMID: 38524550 PMCID: PMC10958367 DOI: 10.1016/j.heliyon.2024.e27654] [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: 08/02/2022] [Revised: 02/27/2024] [Accepted: 03/05/2024] [Indexed: 03/26/2024] Open
Abstract
Background Homeobox (HOX) A11 antisense RNA (HOXA11-AS) has been identified as a cancer promoting lncRNA and is overexpressed in nephroblastoma. However, how HOXA11-AS is regulated in a hypoxic inflammatory environment has not been studied. Methods In this study, gene expression and epithelial-mesenchymal transition (EMT) ability were detected in the nephroblastoma cell line WiT49 under conditions of hypoxia and inflammation. Next, HOXA11-AS transcription factors were predicted by datasets and subsequently confirmed by CHIP-QPCR, EMSA, and dual-luciferase reporter assays. Moreover, the regulatory relationships of HOXA11-AS and its transcription factors were further confirmed by rescue experiments. Results Our results showed that a hypoxic microenvironment promoted HOXA11-AS expression and nephroblastoma progression, induced EMT, and activated the Wnt signaling pathway. Combined hypoxia and inflammation had a more substantial effect on nephroblastoma than either hypoxia or inflammation alone. HIF-1α and C/EBPβ were confirmed to be the transcription factors for HOXA11-AS. Silencing of HIF-1α or C/EBPβ downregulated HOXA11-AS expression and suppressed EMT and the Wnt signaling pathway in nephroblastoma cells exposed to a hypoxic or inflammatory microenvironment. HOXA11-AS overexpression partly reversed the effect of HIF-1α or C/EBPβ knockdown. Conclusion We demonstrated that hypoxia/inflammation-induced upregulation of HIF-1α and C/EBPβ promoted nephroblastoma EMT by improving HOXA11-AS transcription. HOXA11-AS might be a therapy target for nephroblastoma.
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Affiliation(s)
- Shibo Zhu
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Rui Zhou
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiangliang Tang
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wen Fu
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wei Jia
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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Teng Y, Chen Y, Tang X, Wang S, Yin K. PAD2: A potential target for tumor therapy. Biochim Biophys Acta Rev Cancer 2023; 1878:188931. [PMID: 37315720 DOI: 10.1016/j.bbcan.2023.188931] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/16/2023]
Abstract
Peptide arginine deiminase 2(PAD2) catalyzes the conversion of arginine residues on target proteins to citrulline residues in the presence of calcium ions. This particular posttranslational modification is called citrullination. PAD2 can regulate the transcriptional activity of genes through histone citrullination and nonhistone citrullination. In this review, we summarize the evidence from recent decades and systematically illustrate the role of PAD2-mediated citrullination in tumor pathology and the regulation of tumor-associated immune cells such as neutrophils, monocytes, macrophages and T cells. Several PAD2-specific inhibitors are also presented to discuss the feasibility of anti-PAD2 therapy to treat tumors and the urgent problems to be solved. Finally, we review some recent developments in the development of PAD2 inhibitors.
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Affiliation(s)
- Yi Teng
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yuhang Chen
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xinyi Tang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Shengjun Wang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China; Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
| | - Kai Yin
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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Fang ZX, Hou YY, Wu Z, Wu BX, Deng Y, Wu HT, Liu J. Immune responses of six-transmembrane epithelial antigen of the prostate 4 functions as a novel biomarker in gastric cancer. World J Clin Oncol 2023; 14:297-310. [PMID: 37700807 PMCID: PMC10494559 DOI: 10.5306/wjco.v14.i8.297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/19/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Immune cells play an important role in regulating the behavior of tumor cells. According to emerging evidence, six-transmembrane epithelial antigen of the prostate 4 (STEAP4) performs a crucial part in tumor microenvironmental immune response and tumorigenesis, and serves as the potential target for cellular and antibody immunotherapy. However, the immunotherapeutic role of STEAP4 in gastric cancer (GC) remains unclear. AIM To investigate the expression of STEAP4 in GC and its relationship with immune infiltrating cells, and explore the potential value of STEAP4 as an immune prognostic indicator in GC. METHODS The expression level of STEAP4 was characterized by immunohistochemistry in tumors and adjacent non-cancerous samples in 96 GC patients. Tumor Immune Estimation Resource was used to study the correlation between STEAP4 and tumor immune infiltration level and immune infiltration gene signature. R package was used to analyze the relationship between STEAP4 expression and immune and stromal scores in GC (GSE62254) by the ESTIMATE algorithm, and Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis were applied to analyze the effect of STEAP4 on clinical prognosis. RESULTS Immunohistochemistry analysis showed that STEAP4 expression was higher in GC tissues than in adjacent tissues, and STEAP4 expression was positively correlated with the clinical stage of GC. In GC, the expression of STEAP4 was positively correlated with the infiltration levels of B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The expression level of STEAP4 was strongly correlated with most of the immune markers. In addition, STEAP4 expression was inversely correlated with tumor purity, but correlated with stromal score (r = 0.43, P < 0.001), immune score (r = 0.29, P < 0.001) and estimate score (r = 0.39, P < 0.001). Moreover, stromal, immune, and estimate scores were higher in the STEAP4 high expression group, whereas tumor purity was higher in the STEAP4 Low expression group. The relationship between STEAP4 expression and prognosis of patients with GC was further investigated, and the results showed that high STEAP4 expression was associated with poor overall survival and disease-free survival. In addition, Kaplan-Meier Plotter showed that high expression of STEAP4 was significantly correlated with poor survival of patients with GC. CONCLUSION The current findings suggest an oncogenic role for STEAP4 in GC, with significantly high levels being associated with poor prognosis. Investigation of the GC tumor microenvironment suggests the potential function of STEAP4 is connected with the infiltration of diverse immune cells, which may contribute to the regulation of the tumor microenvironment. In conclusion, STEAP4 may serve as a potential therapeutic target for GC to improve the immune infiltration, as well as serve as a prognostic biomarker for judging the prognosis and immune infiltration status of GC.
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Affiliation(s)
- 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
| | - 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
| | - Bing-Xuan Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, 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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Zhang Y, Dong K, Jia X, Du S, Wang D, Wang L, Qu H, Zhu S, Wang Y, Wang Z, Zhang S, Sun W, Fu S. A novel extrachromosomal circular DNA related genes signature for overall survival prediction in patients with ovarian cancer. BMC Med Genomics 2023; 16:140. [PMID: 37337170 DOI: 10.1186/s12920-023-01576-x] [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: 07/17/2022] [Accepted: 06/09/2023] [Indexed: 06/21/2023] Open
Abstract
OBJECTIVE Ovarian cancer (OV) has a high mortality rate all over the world, and extrachromosomal circular DNA (eccDNA) plays a key role in carcinogenesis. We wish to study more about the molecular structure of eccDNA in the UACC-1598-4 cell line and how its genes are associated with ovarian cancer prognosis. METHODS We sequenced and annotated the eccDNA by Circle_seq of the OV cell line UACC-1598-4. To acquire the amplified genes of OV on eccDNA, the annotated eccDNA genes were intersected with the overexpression genes of OV in TCGA. Univariate Cox regression was used to find the genes on eccDNA that were linked to OV prognosis. The least absolute shrinkage and selection operator (LASSO) and cox regression models were used to create the OV prognostic model, as well as the receiver operating characteristic curve (ROC) curve and nomogram of the prediction model. By applying the median value of the risk score, the samples were separated into high-risk and low-risk groups, and the differences in immune infiltration between the two groups were examined using ssGSEA. RESULTS EccDNA in UACC-1598-4 has a length of 0-2000 bp, and some of them include the whole genes or gene fragments. These eccDNA originated from various parts of chromosomes, especially enriched in repeatmasker, introns, and coding regions. They were annotated with 2188 genes by Circle_seq. Notably, the TCGA database revealed that a total of 198 of these eccDNA genes were overexpressed in OV (p < 0.05). They were mostly enriched in pathways associated with cell adhesion, ECM receptors, and actin cytoskeleton. Univariate Cox analysis showed 13 genes associated with OV prognosis. LASSO and Cox regression analysis were used to create a risk model based on remained 9 genes. In both the training (TCGA database) and validation (International Cancer Genome Consortium, ICGC) cohorts, a 9-gene signature could successfully discriminate high-risk individuals (all p < 0.01). Immune infiltration differed significantly between the high-risk and low-risk groups. The model's area under the ROC curve was 0.67, and a nomograph was created to assist clinician. CONCLUSION EccDNA is found in UACC-1598-4, and part of its genes linked to OV prognosis. Patients with OV may be efficiently evaluated using a prognostic model based on eccDNA genes, including SLC7A1, NTN1, ADORA1, PADI2, SULT2B1, LINC00665, CILP2, EFNA5, TOMM.
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Affiliation(s)
- Ying Zhang
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Kexian Dong
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Xueyuan Jia
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Shuomeng Du
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Dong Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Liqiang Wang
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Han Qu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Shihao Zhu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Yang Wang
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Zhao Wang
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Shuopeng Zhang
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Wenjing Sun
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Songbin Fu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China.
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China.
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Mas AM, Huarte M. Long Noncoding RNA Signatures as Cancer Biomarkers. J Clin Oncol 2023; 41:3059-3062. [PMID: 37043713 DOI: 10.1200/jco.23.00381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023] Open
Affiliation(s)
- Aina M Mas
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Maite Huarte
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
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Shenoy US, Adiga D, Gadicherla S, Kabekkodu SP, Hunter KD, Radhakrishnan R. HOX cluster-embedded lncRNAs and epithelial-mesenchymal transition in cancer: Molecular mechanisms and therapeutic opportunities. Biochim Biophys Acta Rev Cancer 2023; 1878:188840. [PMID: 36403923 DOI: 10.1016/j.bbcan.2022.188840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 11/05/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022]
Abstract
Although there has been substantial improvement in the treatment modalities, cancer remains the major cause of fatality worldwide. Metastasis, recurrence, and resistance to oncological therapies are the leading causes of cancer mortality. Epithelial-mesenchymal transition (EMT) is a complex biological process that allows cancer cells to undergo morphological transformation into a mesenchymal phenotype to acquire invasive potential. It encompasses reversible and dynamic ontogenesis by neoplastic cells during metastatic dissemination. Hence, understanding the molecular landscape of EMT is imperative to identify a reliable clinical biomarker to combat metastatic spread. Accumulating evidence reveals the role of HOX (homeobox) cluster-embedded long non-coding RNAs (lncRNAs) in EMT and cancer metastasis. They play a crucial role in the induction of EMT, modulating diverse biological targets. The present review emphasizes the involvement of HOX cluster-embedded lncRNAs in EMT as a molecular sponge, chromatin remodeler, signaling regulator, and immune system modulator. Furthermore, the molecular mechanisms behind therapy resistance and the potential use of novel drugs targeting HOX cluster-embedded lncRNAs in the clinical management of distant metastasis will be discussed.
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Affiliation(s)
- U Sangeetha Shenoy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal- 576104, Karnataka, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal- 576104, Karnataka, India
| | - Srikanth Gadicherla
- Deparment of Oral and Maxillofacial Surgery, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal- 576104, Karnataka, India
| | - Keith D Hunter
- Liverpool Head and Neck Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India; Oral and Maxillofacial Pathology, School of Clinical Dentistry, The University of Sheffield, Sheffield, UK.
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Zhu C, Liu C, Chai Z. Role of the PADI family in inflammatory autoimmune diseases and cancers: A systematic review. Front Immunol 2023; 14:1115794. [PMID: 37020554 PMCID: PMC10067674 DOI: 10.3389/fimmu.2023.1115794] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/08/2023] [Indexed: 04/07/2023] Open
Abstract
The peptidyl arginine deiminase (PADI) family is a calcium ion-dependent group of isozymes with sequence similarity that catalyze the citrullination of proteins. Histones can serve as the target substrate of PADI family isozymes, and therefore, the PADI family is involved in NETosis and the secretion of inflammatory cytokines. Thus, the PADI family is associated with the development of inflammatory autoimmune diseases and cancer, reproductive development, and other related diseases. In this review, we systematically discuss the role of the PADI family in the pathogenesis of various diseases based on studies from the past decade to provide a reference for future research.
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Affiliation(s)
- Changhui Zhu
- Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Chunyan Liu
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- *Correspondence: Chunyan Liu, ; Zhengbin Chai,
| | - Zhengbin Chai
- Department of Clinical Laboratory Medicine, Shandong Public Health Clinical Center, Shandong University, Jinan, China
- *Correspondence: Chunyan Liu, ; Zhengbin Chai,
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Luo X, Chang S, Xiao S, Peng Y, Gao Y, Hu F, Liang J, Xu Y, Du K, Chen Y, Qin J, Meltzer SJ, Deng S, Feng X, Fan X, Hou G, Jin Z, Zhang X. PAD4-dependent citrullination of nuclear translocation of GSK3β promotes colorectal cancer progression via the degradation of nuclear CDKN1A. Neoplasia 2022; 33:100835. [PMID: 36113195 PMCID: PMC9483803 DOI: 10.1016/j.neo.2022.100835] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/15/2022] [Accepted: 08/23/2022] [Indexed: 11/06/2022]
Abstract
Peptidylarginine deiminase 4 (PAD4), a Ca2+-dependent enzyme, catalyzes the conversion of arginine to citrulline and has been strongly associated with many malignant tumors. However, the molecular mechanisms of PAD4 in the development and progression of colorectal cancer (CRC) remain unclearly defined. In our study, PAD4 expression was increased in CRC tissues and cells, and was closely related to tumor size, lymph node metastasis. Moreover, the transcription factor KLF9 directly bound to PADI4 gene promoter, leading to overexpression of PAD4 in CRC cells, which augmented cell growth and migration. We revealed that PAD4 interacted with and citrullinated glycogen synthase kinase-3β (GSK3β) in CRC cells, and GSK3β Arg-344 was the dominating PAD4-citrullination site. Furthermore, IgL2 and catalytic domains of PAD4 directly bound to the kinase domain of GSK3β in CRC cells. Mechanistically, PAD4 promoted the transport of GSK3β from the cytoplasm to the nucleus, thereby increasing the ubiquitin-dependent proteasome degradation of nuclear cyclin-dependent kinase inhibitor 1 (CDKN1A). Our study is the first to reveal the details of a critical PAD4/GSK3β/CDKN1A signaling axis for CRC progression, and provides evidence that PAD4 is a potential diagnosis biomarker and therapeutic target in CRC.
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Affiliation(s)
- Xiaonuan Luo
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Shanshan Chang
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Siyu Xiao
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Yin Peng
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Yuli Gao
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Fan Hu
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Jianxue Liang
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Yidan Xu
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Kaining Du
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Yang Chen
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Jiequan Qin
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Stephen J Meltzer
- Department of Medicine/GI Division, Johns Hopkins University School of Medicine and Sidney Ki-mmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Shiqi Deng
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Xianling Feng
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Xinmin Fan
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Gangqiang Hou
- Department of Medical Image Center, Kangning Hospital of Shenzhen, Shenzhen, Guangdong Province, People's Republic of China
| | - Zhe Jin
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Xiaojing Zhang
- Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
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11
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Fang ZX, Li CL, Chen WJ, Wu HT, Liu J. Potential of six-transmembrane epithelial antigen of the prostate 4 as a prognostic marker for colorectal cancer. World J Gastrointest Oncol 2022; 14:1675-1688. [PMID: 36187390 PMCID: PMC9516649 DOI: 10.4251/wjgo.v14.i9.1675] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/23/2022] [Accepted: 08/06/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Immune cells play a role in the regulation of tumor cell behavior, and accumulating evidence supports their significance in predicting outcomes and therapeutic efficacy in colorectal cancers (CRC). Human six-transmembrane epithelial antigen of the prostate (STEAP) proteins have been recognized and utilized as promising targets for cell- and antibody-based immunotherapy. One STEAP family member, STEAP4, is expected to be an attractive biomarker for the immunotherapy of prostate and breast cancer. However, the immunotherapeutic role of STEAP4 for colorectal carcinomas has not been demonstrated. AIM To explore the expression pattern of STEAPs in CRC and their relationship with immune infiltration, and investigate the potential utilization of STEAPs as novel prognostic indicators in colorectal carcinomas. METHODS The expression level of STEAPs in CRC was evaluated using various open-resource databases and online tools to explore the expression characteristics and prognostic significance of STEAPs, as well as their correlation with immune-related biomarkers, such as immune infiltration. Immunohistochemical (IHC) experiments were subsequently performed to verify the database conclusions. RESULTS The levels of STEAPs in CRC were inconsistent. The expression of STEAPs 1-3 in CRC was not significantly different from that in normal tissues. However, STEAP4 mRNA levels were significantly lower in CRC than in normal tissue and were positively correlated with immune-related biomarkers, such as immune cell infiltration, immune stimulation, major histocompatibility complex levels, and chemokines. Interestingly, the expression of STEAP4 in microsatellite instability-high CRC subtype was higher than that in microsatellite stability subtype. IHC staining was performed on colon cancer tissue samples and showed that high expression of STEAP4 in adjacent tissues positively correlated with immune-related biomarkers, including MLH1, MLH6, and PMS2, but negatively correlated with programmed death ligand 1, to varying degrees. CONCLUSION Our results provide an analysis of the expression of STEAP family members in CRC. Among different STEAP family members, STEAP4 plays a different role in CRC compared to STEAPs 1-3. In CRC, STEAP4 expression is not only lower than that in normal tissues, but it is also positively correlated with immune infiltration and immune-related biomarkers. These findings suggest that STEAP4 may be a potential biomarker for predicting CRC immune infiltration status.
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Affiliation(s)
- 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
| | - Chun-Lan Li
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer 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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12
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Akhbari MH, Zafari Z, Sheykhhasan M. Competing Endogenous RNAs (ceRNAs) in Colorectal Cancer: A Review. Expert Rev Mol Med 2022; 24:e27. [PMID: 35748050 DOI: 10.1017/erm.2022.21] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Colorectal cancer (CRC) is a common type of cancer and the second leading cause of cancer-related deaths worldwide. Competing endogenous RNAs (ceRNAs) that contain microRNA response elements (MREs) are involved in CRC progression. They can compete with microRNAs (miRNAs) via their MREs, which can combine non-coding and coding RNAs via complex ceRNA networks. This molecular interaction has the potential to affect a wide variety of biological processes, and many cancers can occur as a result of an imbalanced ceRNA network. Recent research indicates that numerous dysregulated RNAs in CRC may function as ceRNAs, regulating multiple biological functions of the tumour, including proliferation, apoptosis, metastasis, invasion and migration. In this review, we discuss the role of protein-coding and non-coding RNAs, such as long non-coding RNAs, circular RNAs and pseudogenes, in the occurrence of ceRNA networks in CRC, and their function in cancer-related pathways, such as Wnt/β-catenin, mitogen-activated protein kinase and transforming growth factor-β signalling pathways. Additionally, we discuss validated ceRNAs associated with CRC biological functions and their potential role as novel prognostic and diagnostic biomarkers. Examining the role of ceRNAs in CRC sheds new light on cancer treatment and pathogenesis.
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Affiliation(s)
| | - Zahra Zafari
- Department of Biology, Shahed University, Tehran, Iran
| | - Mohsen Sheykhhasan
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
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13
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Jin Z, Shen H, Cha W, Xia H, Liu L. Predictive value of using plasma long non-coding RNAs ANRIL and HOXA11-AS for in-stent restenosis. Exp Ther Med 2022; 23:115. [PMID: 34970338 PMCID: PMC8713178 DOI: 10.3892/etm.2021.11038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
In-stent restenosis (ISR) can pose serious challenges for cardiologists following coronary stent implantation. Early identification of patients at high risk of ISR is considered to be effective for its prevention. However, factors that can reliably predict the risk of ISR remain elusive at present. The present study aimed to investigate the possible association between plasma long non-coding RNA (lncRNA) levels and ISR. A total of 410 patients with single-vessel lesion who received drug-eluting stents (DES) were included in the present study. After 12-36 months of follow-up, coronary angiography was performed and ISR was defined as >50% diameter stenosis at follow-up. RT-qPCR was used to measure lncRNA expression. Expression of the lncRNA RNA antisense non-coding RNA at the INK4 locus (ANRIL) was found to be upregulated whereas the lncRNA homeobox A11 antisense (HOXA11-AS) was downregulated in the plasma of patients with ISR compared with that from patients without ISR (P<0.001). Logistic regression analysis revealed that ANRIL [odds ratio (OR)=2.95; 95% confidence interval (CI)=1.68-8.08] was an independent risk factor for ISR, whilst HOXA11-AS (OR=0.58; 95% CI=0.48-0.71) was found to be an independent protective factor for ISR. Receiver operating characteristic (ROC) analysis demonstrated that high ANRIL expression [area under the ROC (auROC)=0.755; 95% CI=0.702-0.803] and low HOXA11-AS levels (auROC=0.712; 95% CI=0.657-0.763) predicted a high risk for ISR, and the combined score of ANRIL and HOXA11-AS (auROC=0.844; 95% CI=0.798-0.884) was more efficient at predicting ISR than either ANRIL or HOXA11-AS alone (P<0.001). In conclusion, increased ANRIL and decreased HOXA11-AS expressions were associated with ISR. However, combined ANRIL and HOXA11-AS plasma levels proved to be more effective at predicting ISR compared with either ANRIL or HOXA11-AS alone, suggesting that the multiplex detection of lncRNAs could be used to predict ISR in the future.
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Affiliation(s)
- Zhijiang Jin
- Department of Cardiology, The Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang 312000, P.R. China.,Department of Cardiology, Shaoxing Municipal Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Hongfeng Shen
- Department of Cardiology, The Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang 312000, P.R. China.,Department of Cardiology, Shaoxing Municipal Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Wei Cha
- Department of Cardiology, The Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang 312000, P.R. China.,Department of Cardiology, Shaoxing Municipal Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Haijiang Xia
- Department of Cardiology, The Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang 312000, P.R. China.,Department of Cardiology, Shaoxing Municipal Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Longbin Liu
- Department of Cardiology, The Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang 312000, P.R. China.,Department of Cardiology, Shaoxing Municipal Hospital, Shaoxing, Zhejiang 312000, P.R. China
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14
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Zheng W, Wu F, Fu K, Sun G, Sun G, Li X, Jiang W, Cao H, Wang H, Tang W. Emerging Mechanisms and Treatment Progress on Liver Metastasis of Colorectal Cancer. Onco Targets Ther 2021; 14:3013-3036. [PMID: 33986602 PMCID: PMC8110277 DOI: 10.2147/ott.s301371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is currently the third largest malignant tumor in the world, with high new cases and high mortality. Metastasis is one of the most common causes of death of colorectal cancer, of which liver metastasis is the most fatal. Since the beginning of the Human Genome Project in 2001, people have gradually recognized the 3 billion base pairs that make up the human genome, of which only about 1.5% of the nucleic acid sequences are used for protein coding, including proto-oncogenes and tumor suppressor genes. A large number of differences in the expression of proto-oncogenes and tumor suppressor genes have also been found in the study of colorectal cancer, which proves that they are also actively involved in the progression of colorectal cancer and promote the occurrence of liver metastasis. Except for 1.5% of the coding sequence, the rest of the nucleic acid sequence does not encode any protein, which is called non-coding RNA. With the deepening of research, genome sequences without protein coding potential that were originally considered “junk sequences” may have important biological functions. Many years of studies have found that a large number of abnormal expression of ncRNA in colorectal cancer liver metastasis, indicating that ncRNA plays an important role in it. To explore the role and mechanism of these coding sequences and non-coding RNA in liver metastasis of colorectal cancer is very important for the early diagnosis and treatment of liver metastasis of colorectal cancer. This article reviews the coding genes and ncRNA that have been found in the study of liver metastasis of colorectal cancer in recent years, as well as the mechanisms that have been identified or are still under study, as well as the clinical treatment of liver metastasis of colorectal cancer.
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Affiliation(s)
- Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Kai Fu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guoqiang Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiao Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Wei Jiang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hanjin Wang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
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15
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Ghafouri-Fard S, Hussen BM, Gharebaghi A, Eghtedarian R, Taheri M. LncRNA signature in colorectal cancer. Pathol Res Pract 2021; 222:153432. [PMID: 33857856 DOI: 10.1016/j.prp.2021.153432] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/25/2021] [Accepted: 04/01/2021] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is among the most frequent cancers and is associated with high mortality particularly when being diagnosed in advanced stages. Although several environmental and intrinsic risk factors have been identified, the underlying cause of CRC is not clear in the majority of cases. Several studies especially in the recent decade have pointed to the role of epigenetic factors in this kind of cancer. Long non-coding RNAs (lncRNAs) as important contributors in the epigenetic mechanisms are involved in the initiation, progression and metastasis of CRC. Tens of oncogenic lncRNAs and a lower number of tumor suppressor lncRNAs have been recently identified to be dysregulated in CRC cells and tissues. Notably, expressions of a number of these transcripts have been dysregulated in serum samples of CRC patients, providing a non-invasive route for detection of this kind of cancer. The involvement of lncRNAs in the regulation of autophagy has provided them the ability to modulate response of CRC cells to chemotherapeutic modalities. In the current manuscript, we review the studies which evaluated the role of lncRNAs in the pathogenesis and progression of CRC to appraise their application as diagnostic/ prognostic markers.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Alireza Gharebaghi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Reyhane Eghtedarian
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Lin YC, Chen TH, Huang YM, Wei PL, Lin JC. Involvement of microRNA in Solid Cancer: Role and Regulatory Mechanisms. Biomedicines 2021; 9:biomedicines9040343. [PMID: 33805515 PMCID: PMC8065716 DOI: 10.3390/biomedicines9040343] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) function as the post-transcriptional factor that finetunes the gene expression by targeting to the specific candidate. Mis-regulated expression of miRNAs consequently disturbs gene expression profile, which serves as the pivotal mechanism involved in initiation or progression of human malignancy. Cancer-relevant miRNA is potentially considered the therapeutic target or biomarker toward the precise treatment of cancer. Nevertheless, the regulatory mechanism underlying the altered expression of miRNA in cancer is largely uncovered. Detailed knowledge regarding the influence of miRNAs on solid cancer is critical for exploring its potential of clinical application. Herein, we elucidate the regulatory mechanism regarding how miRNA expression is manipulated and its impact on the pathogenesis of distinct solid cancer.
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Affiliation(s)
- Ying-Chin Lin
- Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Tso-Hsiao Chen
- Division of Nephrology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Yu-Min Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Gastrointestinal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
| | - Jung-Chun Lin
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
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17
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Misawa A, Kondo Y, Takei H, Takizawa T. Long Noncoding RNA HOXA11-AS and Transcription Factor HOXB13 Modulate the Expression of Bone Metastasis-Related Genes in Prostate Cancer. Genes (Basel) 2021; 12:genes12020182. [PMID: 33514011 PMCID: PMC7912412 DOI: 10.3390/genes12020182] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/17/2021] [Accepted: 01/21/2021] [Indexed: 12/31/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression, which play fundamental roles in cancer development. In this study, we found that homeobox A11 antisense RNA (HOXA11-AS), a highly expressed lncRNA in cell lines derived from prostate cancer bone metastases, promoted the cell invasion and proliferation of PC3 prostate cancer cells. Transcription factor homeobox B13 (HOXB13) was identified as an upstream regulator of HOXA11-AS.HOXA11-AS regulated bone metastasis-associated C-C motif chemokine ligand 2 (CCL2)/C-C chemokine receptor type 2 (CCR2) signaling in both PC3 prostate cancer cells and SaOS2 osteoblastic cells. The HOXB13/HOXA11-AS axis also regulated integrin subunits (ITGAV and ITGB1) specific to prostate cancer bone metastasis. HOXB13, in combination with HOXA11-AS, directly regulated the integrin-binding sialoprotein (IBSP) promoter. Furthermore, conditioned medium containing HOXA11-AS secreted from PC3 cells could induce the expression of CCL2 and IBSP in SaOS2 osteoblastic cells. These results suggest that prostate cancer HOXA11-AS and HOXB13 promote metastasis by regulation of CCL2/CCR2 cytokine and integrin signaling in autocrine and paracrine manners.
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Affiliation(s)
- Aya Misawa
- Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan;
| | - Yukihiro Kondo
- Department of Urology, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan;
| | - Hiroyuki Takei
- Department of Breast Surgical Oncology, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan;
| | - Toshihiro Takizawa
- Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan;
- Correspondence: ; Tel.: +81-3-3822-2131; Fax: +81-3-5685-3052
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18
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Yang J, Xu QC, Wang ZY, Lu X, Pan LK, Wu J, Wang C. Integrated Analysis of an lncRNA-Associated ceRNA Network Reveals Potential Biomarkers for Hepatocellular Carcinoma. J Comput Biol 2020; 28:330-344. [PMID: 33185458 DOI: 10.1089/cmb.2019.0250] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide. In this study, we aimed to explore the potential biomarkers and key regulatory pathways related to HCC using integrated bioinformatic analysis and validation. The microarray data of GSE12717 and GSE54238 were downloaded from the Gene Expression Omnibus database. A competing endogenous RNA (ceRNA) network was constructed based on potential long-noncoding RNA (lncRNA)-microRNA (miRNA)-mRNA interactions. A total of 191 mRNAs, 8 miRNAs, and 5 lncRNAs were selected to construct the ceRNA network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to predict their biological functions. The PI3K-Akt signaling pathway was significantly enriched. Kaplan-Meier survival analysis based on the Gene Expression Profiling Interactive Analysis (GEPIA) database was conducted for the weighted mRNAs and lncRNAs. The results showed that SRC, GMPS, CDK2, FEN1, EZH2, ZWINT, MTHFD1L, GINS2, and MAPKAPK5-AS1 were significantly upregulated in tumor tissues. The relative expression levels of these genes were significantly upregulated in HCC patients based on the StarBase database. For further validation, the expression levels of these genes were detected by real-time quantitative reverse transcription-polymerase chain reaction in 20 HCC tumor tissues and paired paracancerous tissues. Receiver operating characteristic analysis revealed that CDK2, MTHFD1L, SRC, ZWINT, and MAPKAPK5-AS1 had significant diagnostic value in HCC, but further studies are needed to explore their mechanisms in HCC.
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Affiliation(s)
- Jie Yang
- Department of Emergency Surgery, The Second People's Hospital of Wuhu, Wuhu, China
| | - Qing-Chun Xu
- Department of Emergency Surgery, The Second People's Hospital of Wuhu, Wuhu, China
| | - Zhen-Yu Wang
- Department of Emergency Surgery, The Second People's Hospital of Wuhu, Wuhu, China
| | - Xun Lu
- Department of Emergency Surgery, The Second People's Hospital of Wuhu, Wuhu, China
| | - Liu-Kui Pan
- Department of Emergency Surgery, The Second People's Hospital of Wuhu, Wuhu, China
| | - Jun Wu
- Department of Emergency Surgery, The Second People's Hospital of Wuhu, Wuhu, China
| | - Chen Wang
- Department of Emergency Surgery, The Second People's Hospital of Wuhu, Wuhu, China
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19
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Liu L, Zhang Z, Zhang G, Wang T, Ma Y, Guo W. Down-regulation of PADI2 prevents proliferation and epithelial-mesenchymal transition in ovarian cancer through inhibiting JAK2/STAT3 pathway in vitro and in vivo, alone or in combination with Olaparib. J Transl Med 2020; 18:357. [PMID: 32951601 PMCID: PMC7504643 DOI: 10.1186/s12967-020-02528-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/15/2020] [Indexed: 12/22/2022] Open
Abstract
Background Epithelial ovarian cancer (EOC) is the most lethal disease among female genital malignant tumors. Peptidylarginine deiminase type II(PADI II) has been shown to enhance a variety of cancers carcinogenesis, including ovarian cancer. The purpose of this study was to investigate the biological role of PADI2 in ovarian cancer (OC) and the relative mechanism. Methods Gene Expression Profiling Interactive Analysis (GEPIA) (https://gepia.pku.cn/) and ONCOMINE (https://www.oncomine.org/) were used to analyze PADI2 Gene Expression data. The survival curve for the PADI2 gene was generated by using the online Kaplan–Meier mapping site (https://www.kmplot.com/). We conducted MTT assay, cloning formation assay and EdU cell proliferation assay to detect the cell activity of PADI2 knockdown A2780 and SKOV3 ovarian cancer cells treated with Olaparib. Cell migration and invasion were observed by would healing and transwell assay. The pathway changes after the treatment of PADI2 were detected by transcriptome sequencing and western blot. The role of PADI2 combined with Olaparib treatment in vivo was studied in nude mouse model bearing ovarian cancer tumor. Results We investigated the role of PADI2 on EOC in vitro and in vivo. PADI2 was upregulated in ovarian cancer samples and high PADI2 expression was correlated with poor outcome. Downregulating PADI2 suppressed colony formation, proliferation, migration and invasion of A2780 and SKOV3 cells. Furthermore, downregulating PADI2 and Olaparib combination treatment attenuated the viability, migration and invasion of A2780 and SKOV3 cells. We identified differentially expressed genes in A2780-shPADI2 and SKOV3-shPADI2 cell by transcriptome sequencing analysis and verified that downregulating PADI2 and Olaparib combination treatment suppresses EMT and JAK2/STAT3 signaling pathway in A2780 and SKOV3 cells in vitro and in vivo. Conclusions Downregulation of PADI2 and Olaparib combination treatment attenuated the proliferation, migration and invasion of A2780 and SKOV3 cells by inhibiting the EMT through JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Lidong Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, People's Republic of China.,Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, People's Republic of China.,Obstetrics Department, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People's Republic of China
| | - Zhiwei Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, People's Republic of China
| | - Guoxiang Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, People's Republic of China
| | - Ting Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, People's Republic of China
| | - Yingchun Ma
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, People's Republic of China
| | - Wei Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, People's Republic of China.
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20
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Liu Y, Yan W, Zhou D, Jin G, Cheng X. Long non‑coding RNA HOXA11‑AS accelerates cell proliferation and epithelial‑mesenchymal transition in hepatocellular carcinoma by modulating the miR‑506‑3p/Slug axis. Int J Mol Med 2020; 46:1805-1815. [PMID: 32901858 PMCID: PMC7521580 DOI: 10.3892/ijmm.2020.4715] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressively malignant type of cancer with a complex pathogenesis. Multiple studies have identified that lncRNA HOXA11-AS is involved in the development of HCC. Nevertheless, the pathological mechanisms of HOXA11-AS in the development of HCC require further investigation. In the present study, the role and underlying mechanisms of HOXA11-AS in HCC were examined. RT-qPCR revealed that HOXA11-AS expression was increased, while that of miR-506-3p was decreased in HCC tissues and cells compared with that in adjacent non-tumor tissues and normal hepatic cells. Dual-luciferase reporter assay and RNA pull-down assay indicated that HOXA11-AS directly interacted with miR-506-3p. miR-506-3p downregulation reversed the inhibitory effects of HOXA11-AS deletion on cell proliferation, invasion and epithelial-mesenchymal transition (EMT), as shown by CCK-8 and Transwell assays, as well as western blot analysis. Bioinformatics analysis and dual-luciferase reporter assay indicated that Slug was a target gene of miR-506-3p. The overexpression of Slug reversed the effects of HOXA11-AS deletion on the viability, invasion and the EMT of HCC cells. Taken together, the present study demonstrates that HOXA11-AS functions as an oncogene to promote the progression of HCC via the miR-506-3p/Slug axis, providing a therapeutic target for patients with HCC.
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Affiliation(s)
- Yinghui Liu
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Wenzhao Yan
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Dongfang Zhou
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Guohua Jin
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xin Cheng
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Chen D, Zhang M, Ruan J, Li X, Wang S, Cheng X, Zhao H, Zeng Y, Liu J, He K, Zhao P. The long non-coding RNA HOXA11-AS promotes epithelial mesenchymal transition by sponging miR-149-3p in Colorectal Cancer. J Cancer 2020; 11:6050-6058. [PMID: 32922545 PMCID: PMC7477413 DOI: 10.7150/jca.49809] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 08/02/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Metastasis is the primary cause of death in colorectal cancer (CRC); the underlying mechanisms remain partly unknown. In this study, we aim to investigate the value of HOXA11-AS in survival evaluation and the potential role of HOXA11-AS/miR-149-3p axis in the CRC metastasis. Methods: The expressions of HOXA11-AS, both in obtained CRC samples and adjacent noncancerous tissues, were analyzed in survival evaluation. Competing endogenous RNAs (CeRNAs) Analysis were employed to reveal the potential relationship between HOXA11-AS and miR-149-3p. It was further confirmed by Quantitative real-time polymerase chain reaction (qRT-PCR) and Dual-luciferase reporter assay. Migration and invasion assay were used to verify the potential role of HOXA11-AS and miR-149-3p in the regulation of CRC metastasis. The potential pathway was explored by Western blot analysis. Results: The expression of HOXA11-AS in the CRC tissue is significantly higher than the expression in adjacent noncancerous tissue (p<0.0001). High expressions of HOXA11-AS were noticeably correlated with clinicopathologic characteristics including advanced clinical stage (p=0.021), larger tumor size (p<0.001) and frequent tumor recurrence (p=0.001). The overall survival in HOXA11-AS-High group was significantly shorter than the HOXA11-AS-Low group (p<0.001). Advanced clinical stage, tumor size and high expression of HOXA11-AS were showed as independent prognostic prediction factors for the 5-year tumor relapse of CRC patients (p<0.001). HOXA11-AS acts as a potential molecular sponge for miR-149-3p, in the promotion of CRC metastasis. In the miR-149-3p mimic-treated group, the expression of E-cadherin was increased, whereas the expression of N-cadherin, Snail, Slug, TGF-β1, Wnt2b, Twist and C/EBPβ was decreased. Conclusion: This study demonstrates that high expression of HOXA11-AS is correlated with CRC progression and poor prognosis and may promote metastasis via EMT by modulating miR-149-3p.
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Affiliation(s)
- Dong Chen
- Department of Colorectal Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Min Zhang
- College of Medicine, Zhejiang University, Hangzhou 310058, Zhejiang Province, China
| | - Jian Ruan
- Department of Medical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Xiaolin Li
- Department of Emergency, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Saisai Wang
- Department of Colorectal Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Xiaofei Cheng
- Department of Colorectal Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Huiying Zhao
- Department of Colorectal Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ying Zeng
- Department of Colorectal Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Jingjing Liu
- Department of Colorectal Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Kangxin He
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Peng Zhao
- Department of Medical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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Pidíkova P, Reis R, Herichova I. miRNA Clusters with Down-Regulated Expression in Human Colorectal Cancer and Their Regulation. Int J Mol Sci 2020; 21:E4633. [PMID: 32610706 PMCID: PMC7369991 DOI: 10.3390/ijms21134633] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/24/2020] [Accepted: 06/27/2020] [Indexed: 02/07/2023] Open
Abstract
Regulation of microRNA (miRNA) expression has been extensively studied with respect to colorectal cancer (CRC), since CRC is one of the leading causes of cancer mortality worldwide. Transcriptional control of miRNAs creating clusters can be, to some extent, estimated from cluster position on a chromosome. Levels of miRNAs are also controlled by miRNAs "sponging" by long non-coding RNAs (ncRNAs). Both types of miRNA regulation strongly influence their function. We focused on clusters of miRNAs found to be down-regulated in CRC, containing miR-1, let-7, miR-15, miR-16, miR-99, miR-100, miR-125, miR-133, miR-143, miR-145, miR-192, miR-194, miR-195, miR-206, miR-215, miR-302, miR-367 and miR-497 and analysed their genome position, regulation and functions. Only evidence provided with the use of CRC in vivo and/or in vitro models was taken into consideration. Comprehensive research revealed that down-regulated miRNA clusters in CRC are mostly located in a gene intron and, in a majority of cases, miRNA clusters possess cluster-specific transcriptional regulation. For all selected clusters, regulation mediated by long ncRNA was experimentally demonstrated in CRC, at least in one cluster member. Oncostatic functions were predominantly linked with the reviewed miRNAs, and their high expression was usually associated with better survival. These findings implicate the potential of down-regulated clusters in CRC to become promising multi-targets for therapeutic manipulation.
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Affiliation(s)
- Paulína Pidíkova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
| | - Richard Reis
- First Surgery Department, University Hospital, Comenius University in Bratislava, 811 07 Bratislava, Slovakia;
| | - Iveta Herichova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
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Wei C, Zhao L, Liang H, Zhen Y, Han L. Recent advances in unraveling the molecular mechanisms and functions of HOXA11‑AS in human cancers and other diseases (Review). Oncol Rep 2020; 43:1737-1754. [PMID: 32236611 PMCID: PMC7160552 DOI: 10.3892/or.2020.7552] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 01/24/2020] [Indexed: 12/13/2022] Open
Abstract
A large number of previously published research articles have demonstrated that the expression levels of long noncoding RNAs (lncRNAs) are generally dysregulated, either through overexpression or underexpression, in cancer and other types of disease. As a recently discovered lncRNA, HOXA11 antisense RNA (HOXA11‑AS) is able to serve as an oncogenic or tumor‑suppressor gene and serves a vital role in the processes of proliferation, invasion, and migration of cancer cells. HOXA11‑AS appears to be a major factor contributing to epigenetic modification, and exerts transcriptional, post‑transcriptional, translational and post‑translational regulatory effects on genes through a variety of mechanisms; for example, by competing endogenous RNA (ceRNA) and a molecular scaffold mechanism. A number of reports have demonstrated that HOXA11‑AS functions as a protein scaffold for polycomb repressive complex 2 (PRC2), lysine‑specific histone demethylase 1 (LSD1) and DNA methyltransferase 1 (DNMT1) to perform epigenetic modifications on chromosomes in the nucleus. Furthermore, HOXA11‑AS is also located in the cytoplasm and can act as a ceRNA, which sponges miRNAs. In addition, HOXA11‑AS may be useful as a biomarker for the diagnosis and prognosis of cancer. In the present review article, the clinical value, phenotype and mechanism of HOXA11‑AS in a variety of tumors types are briefly summarized, as well as its clinical value in certain additional diseases. The perspective of the authors is that HOXA11‑AS may represent an effective tumor marker and therapeutic target for cancer diagnosis and therapy.
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Affiliation(s)
- Cheng Wei
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
| | - Liangjuan Zhao
- Tianjin Customs District China, Heping, Tianjin 300041, P.R. China
| | - Hao Liang
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
| | - Yingwei Zhen
- Department of Neurosurgery, The First Affliated Hospital of Zhengzhou University, Zhengzhou, Henan 453002, P.R. China
| | - Lei Han
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
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Long non-coding RNA CCAT1 promotes colorectal cancer progression by regulating miR-181a-5p expression. Aging (Albany NY) 2020; 12:8301-8320. [PMID: 32380476 PMCID: PMC7244037 DOI: 10.18632/aging.103139] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/31/2020] [Indexed: 01/30/2023]
Abstract
The vital roles of long noncoding RNAs (lncRNAs) have been implicated in growing number of studies in tumor development. LncRNA CCAT1 has been recognized as associated with tumor development, yet its relation with colorectal cancer (CRC) remains elusive. Our study aimed at elucidating the function and mechanisms of long non-coding RNA CCAT1 in CRC. From a lncRNA profile dataset of 38 pairs of matched tumor-control colon tissues from colorectal patients housed in The Cancer Genome Atlas (TCGA), we detected 10 upregulated and 10 down-regulated lncRNAs in CRC. Fifty cases of CRC patients were enrolled to analyze the correlation between the expression of CCAT1 and clinical pathology. The inverse correlation of expression and target relationship between CCAT1 and miR-181a-5p were verified using qRT-PCR and dual-luciferase reporter gene assay. Cell viability, colony formation ability, aggression and apoptosis were determined by MTT assay, colony formation assay, Transwell and wound healing assays and flow cytometry analysis. Furthermore, Xenograft model was used to show that knockdown of CCAT1 inhibits tumor growth in vivo. The expression of lncRNA CCAT1 was significantly upregulated in CRC tissues. The CCAT1 expression was positively associated with cancer stage (American Joint Committee on Cancer stage, P<0.05). CCAT1 promoted cell proliferation, growth and mobility by targeting miR-181a-5p and the silence of CCAT1 increased the cell apoptosis. Same effect was observed in an in vivo xenograft model, which the tumor size and pro-tumor proteins were significantly diminished by knocking down of CCAT1.
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Cao Q, Wang N, Ren L, Tian J, Yang S, Cheng H. miR-125a-5p post-transcriptionally suppresses GALNT7 to inhibit proliferation and invasion in cervical cancer cells via the EGFR/PI3K/AKT pathway. Cancer Cell Int 2020; 20:117. [PMID: 32308562 PMCID: PMC7147043 DOI: 10.1186/s12935-020-01209-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/06/2020] [Indexed: 02/08/2023] Open
Abstract
Background The carcinogenesis and progression of cervical cancer is a complex process in which numerous microRNAs are involved. The purpose of this study is to investigate the role of miR-125a-5p in progression of cervical cancer. Methods RT-qPCR was used to detect the expression of miR-125a-5p and GALNT7 in cervical cancer tissues and cell lines. Then, the miR-125a-5p mimic, miR-125a-5p inhibitor, GALNT7 siRNA, or/and pcDNA-GALNT7 were respectively transfected into HeLa and Caski cervical cancer cells, and Cell Counting kit-8 assay, Transwell assay and flow cytometry analysis were respectively used to observe cell proliferation, invasion and apoptosis. Subsequently, luciferase reporter gene assay was employed in confirming the target relationship between miR-125a-5p and GALNT7. MiR-125a-5p mimic or/and pcDNA-GALNT7 were transfected into the cervical cancer cells at the absence of epidermal growth factor (EGF) or not, and the pcDNA-GALNT7 was transfected into the cervical cancer cells at the absence of inhibitors of multiple kinases or not. Furthermore, the effect of miR-125a-5p on tumor growth was also studied using a xenograft model of nude mice. Results MiR-125a-5p was down-regulated in both cervical cancer tissues and cell lines and it inhibited cell proliferation and invasion of cervical cancer cells. MiR-125a-5p directly targeted and post-transcriptionally downregulated GALNT7 that was strongly upregulated in cervical cancer tissues and cell lines. Similar to the effect of miR-125a-5p mimic, silencing GALNT7 inhibited proliferation and invasion of cervical cancer cells. In addition, miR-125a-5p overexpression could counteract both GALNT7- and EGF-induced cell proliferation and invasion. GALNT7 promoted cell proliferation and invasion by activating the EGFR/PI3K/AKT kinase pathway, which could be abated by the inhibitors of the kinases. Moreover, the role of miR-125a-5p inhibited tumor formation in cervical cancer by suppressing the expression of GALNT7 in vivo. Conclusion In conclusion, miR-125a-5p suppressed cervical cancer progression by post-transcriptionally downregulating GALNT7 and inactivating the EGFR/PI3K/AKT pathway.
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Affiliation(s)
- Qinxue Cao
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Ning Wang
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Lu Ren
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Jun Tian
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Shaoqin Yang
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Hailing Cheng
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
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Jin J, Jia ZH, Luo XH, Zhai HF. Long non-coding RNA HOXA11-AS accelerates the progression of keloid formation via miR-124-3p/TGFβR1 axis. Cell Cycle 2020; 19:218-232. [PMID: 31878829 PMCID: PMC6961662 DOI: 10.1080/15384101.2019.1706921] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Emerging evidence reveals the importance of long non-coding RNAs (lncRNAs) in the development and progression of keloid formation, whereas the underlying mechanisms are not well understood. In the present study, we investigated the biological effects and molecular mechanisms of lncRNA HOXA11-AS in keloid formation. First, the expression levels of HOXA11-AS, miR-124-3p, and transforming growth factor β receptor type I (TGFβR1) were measured in both keloid tissues and human keloid fibroblasts (HKFs) using qRT-PCR and western blot analysis, respectively. Next, we adopted both gain- and loss-of-function strategies to explore the significance of HOXA11-AS. TUNEL, flow cytometry, DNA ladder, and tube formation assays were performed to measure cell apoptosis and angiogenesis, respectively. Besides, the potential binding relationship between HOXA11-AS and miR-124-3p, as well as miR-124-3p and TGFβR1 was identified using bioinformatic screening and verified by luciferase reporter assay. Furthermore, we explored the importance of miR-124-3p in HOXA11-AS-induced phenotypes and regulations on TGFβ signaling or PI3K/Akt signaling. We found that HOXA11-AS and TGFβR1 were significantly up-regulated, while miR-124-3p was down-regulated both in keloid tissues or fibroblasts than in normal skin tissues or fibroblasts. Functionally, high expression of HOXA11-AS essentially inhibited cell apoptosis and promoted fibroblast-induced angiogenesis. Mechanistically, miR-124-3p was identified as a downstream effector to be involved in HOXA11-AS-mediated phenotypes through directly targeting TGFβR1, thus modulating PI3K/Akt signaling pathway. Taken together, our findings revealed that HOXA11-AS inhibits cell apoptosis and promotes angiogenesis through miR-124-3p/TGFβR1 axis, contributing to the progression of keloid formation, which might provide a novel target for keloid therapy.
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Affiliation(s)
- Jun Jin
- Department of Plastic Surgery, People's Hospital of Zhengzhou University, Henan People's Hospital, Zhengzhou, P.R. China
| | - Zhen-Hua Jia
- Department of Plastic Surgery, People's Hospital of Zhengzhou University, Henan People's Hospital, Zhengzhou, P.R. China
| | - Xiao-Hua Luo
- Department of Plastic Surgery, People's Hospital of Zhengzhou University, Henan People's Hospital, Zhengzhou, P.R. China
| | - Hong-Feng Zhai
- Department of Plastic Surgery, People's Hospital of Zhengzhou University, Henan People's Hospital, Zhengzhou, P.R. China
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Yang M, Tang X, Wang Z, Wu X, Tang D, Wang D. miR-125 inhibits colorectal cancer proliferation and invasion by targeting TAZ. Biosci Rep 2019; 39:BSR20190193. [PMID: 31782506 PMCID: PMC6911154 DOI: 10.1042/bsr20190193] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 11/06/2019] [Accepted: 11/28/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor worldwide and is a serious threat to human health. MicroRNAs (miRNAs) play a key role in oncogenesis and cancer progression. MiRNA-125 (miR-125) is an important miRNA that is dysregulated in several kinds of cancers. Thus, we investigated the expression and effects of miR-125 and Transcriptional co-activator with PDZ-binding motif (TAZ) for a better understanding of the underlying mechanism of tumor progression in CRC, which may provide an emerging biomarker for diagnosis and treatment of CRC. We measured the expression levels of miR-125 in CRC tissues, adjacent tissues, and cell lines (e.g. HCT116, SW480, FHC) by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of miR-125 on proliferation and invasion in CRC cells was detected by Cell Counting Kit-8 (CCK-8), clone formation assay, and transwell assay. Western blotting and qRT-PCR were used to investigate the expression of TAZ after knocking down miR-125 in HCT116 cells or overexpressing miR-125 in SW480 cells. MiR-125 was significantly down-regulated in CRC compared with pericarcinomatous tissue from 18 patients. An miR-125 inhibitor promoted CRC cell proliferation and invasion, while miR-125 mimic had the opposite effect. Moreover, we found that TAZ was an miR-125 target and the siRNA knockdown of TAZ could reverse the effect of the miR-125 inhibitor on proliferation and invasion in HCT116 cells. The present study shows that miR-125 suppresses CRC proliferation and invasion by targeting TAZ.
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Affiliation(s)
- Meiyuan Yang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Renmin Road No.139, Changsha 410001, China
| | - Xiaoli Tang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Renmin Road No.139, Changsha 410001, China
| | - Zheng Wang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
| | - Xiaoqing Wu
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
| | - Dong Tang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
- Department of General Surgery, Medical College, Yangzhou University, Northern Jiangsu Province Hospital, General Surgery Institute of Yangzhou University, Nantong Road No.98, Yangzhou 225001, China
| | - Daorong Wang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
- Department of General Surgery, Medical College, Yangzhou University, Northern Jiangsu Province Hospital, General Surgery Institute of Yangzhou University, Nantong Road No.98, Yangzhou 225001, China
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Yin X, Zhang J, Li C, Zhang Z, Jin T, Song L, Zhang R, Wang W, Tao Y, Wang X. LncRNA HOXA11-AS accumulation-induced microRNA-761 downregulation regulates cell growth by targeting TRIM29 in papillary thyroid cancer. Am J Transl Res 2019; 11:6826-6837. [PMID: 31814890 PMCID: PMC6895523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 06/22/2019] [Indexed: 06/10/2023]
Abstract
Increasing evidence demonstrate that dysregulated microRNAs (miRNAs) are involved in carcinogenesis and tumor progression in papillary thyroid cancer (PTC). However, the specific miR-761 in cancer remains largely unknown. In this study, we reported for the first that miR-761 expression was down-regulated in PTC tissues and cell lines, and its decrease was associated with tumor size and TNM stage. Gain- and loss-of function experiments revealed that miR-761 inhibited cell proliferation, colony formation and cell cycle progression in vitro and in vivo. Moreover, TRIM29 was identified as a direct downstream target of miR-761 in PTC cells and mediated the functional effects of miR-761 in PTC. Restoration of TRIM29 expression at least partially abolished the biological effects of miR-761 on PTC cells. Furthermore, overexpression of lncRNA HOXA11-AS was inversely correlated with miR-761 expression in PTC tissues. LncRNA HOXA11-AS could modulate the miR-761 expression and regulate cellular behaviors. Taken together, this research supports the first evidence that lncRNA HOXA11-AS-reguated miR-761 plays a functional role in inhibiting PTC progression by targeting TRIM29 and represent a promising therapeutic strategy for patients with PTC.
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Affiliation(s)
- Xiangdang Yin
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
| | - Jian Zhang
- Department of Ultrasonography, Jilin Cancer HospitalChangchun 130001, China
| | - Chaojun Li
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
| | - Zhe Zhang
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
| | - Tong Jin
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
| | - Liyou Song
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
| | - Rui Zhang
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
| | - Wei Wang
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
| | - Youmao Tao
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University126 Xiantai Street, Changchun 130033, China
| | - Xiaochun Wang
- Department of Oral-Maxillofacial-Thyroid Oncosurgery, Jilin Cancer HospitalChangchun 130001, China
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Jiang J, Wang X, Gao G, Liu X, Chang H, Xiong R, Lu J, Sun Z. Silencing of lncRNA HOXA11-AS inhibits cell migration, invasion, proliferation, and promotes apoptosis in human glioma cells via upregulating microRNA-125a: in vitro and in vivo studies. Am J Transl Res 2019; 11:6382-6392. [PMID: 31737190 PMCID: PMC6834490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 08/28/2019] [Indexed: 06/10/2023]
Abstract
Glioma is an aggressive nervous system tumor with poor prognosis. Although the therapeutic strategies to overcome glioma have been improved largely recent years, the potential mechanism of its carcinogenesis remains largely unclear. The present study aimed to investigate the role of long non-coding RNA HOMEOBOX A11 antisense RNA (lncRNA HOXA11-AS) in glioma, and further to explore the underlying mechanism. We forst detected the level of lncRNA HOXA11-AS and microRNA-125a (miR-125a) in glioma tissues and human glioma U251 cells using quantitative real time polymerase chain reaction (qRT-PCR). Then, effect of lncRNA HOXA11-AS silencing on U251 cell migration, invasion, proliferation, and apoptosis was determined. Meanwhile, the expression of caspase-3/8/9 and several tumor-related genes was measured by Western blotting and qRT-PCR. Dual luciferase activity assay was used to confirm the targeting relationship between lncRNA HOXA11-AS and miR-125a. Results indicated that lncRNA HOXA11-AS was significantly increased in U251 cells and positively correlated with glioma World Health Organization (WHO) grade in glioma tissues. lncRNA HOXA11-AS silencing could inhibit cell migration, invasion, proliferation, and promote apoptosis, while up-regulate the expression of caspase-3/8/9 and Bax, inhibit the expression of Bcl-2 and gab2 in U251 cells. miR-125a inhibitor could partially reverse these effects of lncRNA HOXA11-AS silencing on U251 cells. In vivo assays also indicated that lncRNA HOXA11-AS inhibitor could inhibit glioma growth in vivo by regulating the expression of miR-125a. In conclusion, we revealed that lncRNA HOXA11-AS acted as an oncogene in glioma via interacting with miR-125a and considered that lncRNA HOXA11-AS was a potential therapeutic target for glioma.
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Affiliation(s)
- Jianxin Jiang
- Department of Neurosurgery, Taizhou People’s HospitalTaizhou 225300, Jiangsu, China
| | - Xiaolin Wang
- Department of Neurosurgery, Taizhou People’s HospitalTaizhou 225300, Jiangsu, China
| | - Guangzhong Gao
- Department of Neurosurgery, Taizhou People’s HospitalTaizhou 225300, Jiangsu, China
| | - Xiaoxin Liu
- Department of Neurosurgery, Taizhou People’s HospitalTaizhou 225300, Jiangsu, China
| | - Hao Chang
- Department of Neurosurgery, Taizhou People’s HospitalTaizhou 225300, Jiangsu, China
| | - Ran Xiong
- Department of Neurology, Shanghai East HospitalShanghai 200120, China
| | - Jun Lu
- Department of Neurosurgery, Taizhou People’s HospitalTaizhou 225300, Jiangsu, China
| | - Zhiyang Sun
- Department of Neurosurgery, Shanghai East HospitalShanghai 200120, China
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Li F, Miao L, Xue T, Qin H, Mondal S, Thompson PR, Coonrod SA, Liu X, Zhang X. Inhibiting PAD2 enhances the anti-tumor effect of docetaxel in tamoxifen-resistant breast cancer cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:414. [PMID: 31601253 PMCID: PMC6785896 DOI: 10.1186/s13046-019-1404-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/02/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance. METHODS We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells. RESULTS We report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation. CONCLUSION Our results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.
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Affiliation(s)
- Fujun Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.,Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, 211100, China
| | - Lixia Miao
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Teng Xue
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Hao Qin
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Santanu Mondal
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Paul R Thompson
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Scott A Coonrod
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, New York, 14853, USA
| | - Xiaoqiu Liu
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Microbiology, Nanjing Medical University, Nanjing, 211166, China.
| | - Xuesen Zhang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.
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Jin J, Zhai HF, Jia ZH, Luo XH. Long non-coding RNA HOXA11-AS induces type I collagen synthesis to stimulate keloid formation via sponging miR-124-3p and activation of Smad5 signaling. Am J Physiol Cell Physiol 2019; 317:C1001-C1010. [PMID: 31411918 DOI: 10.1152/ajpcell.00319.2018] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Keloid, characterized by exuberant collagen deposition and invasive growth beyond original wound margins, results from abnormal wound healing. A recent microarray analysis identified homeobox (HOX) A11 antisense (HOXA11-AS) as a keloid-specific long non-coding RNA, although its potential role in keloid formation remains elusive. In this study, hematoxylin-eosin, Masson, and immunohistochemical staining of type I collagen (ColI) revealed abnormal arrangement and hyperplasia of fibers in keloid tissues along with increased ColI level. qRT-PCR and Western blot showed that HOXA11-AS and ColI were significantly upregulated, while miR-124-3p was decreased in both keloid tissues and human keloid fibroblasts (HKFs). Knockdown of HOXA11-AS inhibited cell proliferation (by CCK-8 and immunofluorescence staining of Ki67) and cell migration (by wound healing and transwell assays). Mechanistic experiments verified that HOXA11-AS acted as a sponge of micro-RNA (miR)-124-3p and Smad5 was a target of miR-124-3p. miR-124-3p sufficiently reversed the regulatory effects of HOXA11-AS, and Smad5 was involved in miR-124-3p-mediated biological functions. Furthermore, HOXA11-AS induced ColI synthesis via sponging miR-124-3p-mediated Smad5 signaling, thus promoting keloid formation. Overall, our study implied that HOXA11-AS induces ColI synthesis to promoted keloid formation via sponging miR-124-3p-mediated Smad5 signaling, which might offer a novel target for developing the therapy of keloid formation.
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Affiliation(s)
- Jun Jin
- Department of Plastic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, People's Republic of China
| | - Hong-Feng Zhai
- Department of Plastic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, People's Republic of China
| | - Zhen-Hua Jia
- Department of Plastic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, People's Republic of China
| | - Xiao-Hua Luo
- Department of Plastic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, People's Republic of China
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Liu Y, Zhang YM, Ma FB, Pan SR, Liu BZ. Long noncoding RNA HOXA11-AS promotes gastric cancer cell proliferation and invasion via SRSF1 and functions as a biomarker in gastric cancer. World J Gastroenterol 2019; 25:2763-2775. [PMID: 31235999 PMCID: PMC6580350 DOI: 10.3748/wjg.v25.i22.2763] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/15/2019] [Accepted: 05/03/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is the fourth most frequent malignancy all over the world. The diagnosis of GC is challenging and the prognosis of GC is very unfavorable. Accumulating evidence reveals that serum long noncoding RNAs (lncRNAs) can function as biomarkers in various types of cancers, including GC.
AIM To explore the level and molecular mechanism of the lncRNA HOXA11-AS in GC and the diagnostic and prognostic significance of serum HOXA11-AS in GC.
METHODS HOXA11-AS levels in GC tissue, cell lines, and serum samples were measured. The correlation between HOXA11-AS expression and clinicopathological characteristics was analyzed. The role of HOXA11-AS in the diagnosis and prognosis of GC was evaluated. Cell function assays were performed for exploration of the roles of HOXA11-AS in GC cells. Moreover, Western blot was performed to explore the target regulated by HOXA11-AS in GC cells.
RESULTS Up-regulation of HOXA11-AS was found in GC tissues, cell lines, and serum samples. In GC patients, decreased serum HOXA11-AS levels were negatively related with tumor size, TNM stage, and lymph node metastasis. The area under the receiver operating characteristic curve of serum HOXA11-AS in the diagnosis of GC was 0.924 (95%CI: 0.881-0.967; sensitivity, 0.787; specificity 0.978). Results of the Kaplan-Meier survival curves suggested the GC patients with a lower HOXA11-AS level having a better overall survival rate. HOXA11-AS promoted GC cell proliferation and invasion. SRSF1 may be the target regulated by HOXA11-AS in GC cells.
CONCLUSION HOXA11-AS promotes GC cell proliferation and invasion via SRSF1 and may function as a promising marker in GC.
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Affiliation(s)
- Yun Liu
- Department of Operating Room, Binzhou People's Hospital, Binzhou 256610, Shandong Province, China
| | - Yu-Mei Zhang
- Department of Return Visit, Binzhou People's Hospital, Binzhou 256610, Shandong Province, China
| | - Feng-Bo Ma
- Department of Gastroenterology, Binzhou People's Hospital, Binzhou 256610, Shandong Province, China
| | - Su-Rong Pan
- Department of Gastroenterology, Binzhou People's Hospital, Binzhou 256610, Shandong Province, China
| | - Bao-Zhen Liu
- Department of Gastroenterology, Binzhou People's Hospital, Binzhou 256610, Shandong Province, China
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Cao K, Fang Y, Wang H, Jiang Z, Guo L, Hu Y. The lncRNA HOXA11-AS regulates Rab3D expression by sponging miR-125a-5p promoting metastasis of osteosarcoma. Cancer Manag Res 2019; 11:4505-4518. [PMID: 31191012 PMCID: PMC6529177 DOI: 10.2147/cmar.s196025] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 04/22/2019] [Indexed: 12/22/2022] Open
Abstract
Objective: Many studies have shown that long non-coding RNAs (lncRNAs) are closely related to various cancers. This study aims to explore the roles of lncRNA HOXA11-AS in the development and progression of osteosarcoma (OS). Methods: The expression levels of HOXA11-AS and miR-125a-5p in tumor tissues and the adjacent tissues were detected by RT-PCR method. The proliferation, migration and invasion of MG-63 and KHOS cells were determined. Results: It was found that HOXA11-AS expression levels in OS tissues and OS cell lines were higher than those in OS adjacent tissues and normal human osteoblast cell lines. The higher expression level of HOXA11-AS was positively correlated with more severe clinical stage, distant metastasis and poor prognosis of OS. Inhibition of HOXA11-AS expression could reduce metastasis and invasion of OS cell lines. In addition, HOXA11-AS was found to be an endogenous inhibitor of miR-125a-5p, it down regulated the expression level of miR-125a-5p, and this process could promote the expression of Rab3D, the target gene of miR-125a-5p. Conclusion: Our study elucidated the role of a new HOXA11-AS/miR-125a-5p/Rab3D regulatory pathway in promoting OS metastasis.
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Affiliation(s)
- Kun Cao
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Yueyang Fang
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Hao Wang
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Zheng Jiang
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Li Guo
- Department of Orthopaedics, The Second Hospital Of Shanxi Medical University, Taiyuan, People's Republic of China
| | - Yong Hu
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
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Ren YL, Zhang W. Propofol promotes apoptosis of colorectal cancer cells via alleviating the suppression of lncRNA HOXA11-AS on miRNA let-7i. Biochem Cell Biol 2019; 98:90-98. [PMID: 31013434 DOI: 10.1139/bcb-2018-0235] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
To date, surgical resection is the mainstay for the treatment of colorectal cancer (CRC). Propofol (2,6-diisopropylphenol), one of the most commonly used intravenous anaesthetic agents, has been reported to be involved in modulating the malignancy of a variety of human cancers. However, the underlying mechanisms remain poorly understood. In this study, using a cell counting kit (CCK-8), flow cytometry, and caspase-3 cleavage assays, we found that propofol promoted cell apoptosis and inhibited cell proliferation in both Colo205 and SW620 cells, through the down-regulation of HOXA11-AS and up-regulation of let-7i. Moreover, gain-of-function studies of HOXA11-AS or loss-of-function studies of let-7i also revealed a negative correlation between HOXA11-AS and let-7i in propofol-mediated biological functions of CRC cells. Furthermore, our mechanistic experiments revealed that HOXA11-AS acts as a molecular sponge for let-7i, thereby regulating the expression of ABCC10. We investigate the theory that propofol suppresses colorectal cancer tumorigenesis by modulating the HOXA11-AS-let-7i-ABCC10 regulatory network, indicating the potential for propofol to control CRC development.
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Affiliation(s)
- Yan-Ling Ren
- Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.,Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Wei Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.,Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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Bian Y, Gao G, Zhang Q, Qian H, Yu L, Yao N, Qian J, Liu B, Qian X. KCNQ1OT1/miR-217/ZEB1 feedback loop facilitates cell migration and epithelial-mesenchymal transition in colorectal cancer. Cancer Biol Ther 2019; 20:886-896. [PMID: 30794031 DOI: 10.1080/15384047.2019.1579959] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Long noncoding RNAs are widely acknowledged as a group of regulatory factors in various diseases, especially in cancers. KCNQ1 overlapping transcript 1 (KCNQ1OT1) has been reported as oncogene in human cancers. However, the role of KCNQ1OT1 in colorectal cancer (CRC) has not been fully explained. Based on the database analysis, KCNQ1OT1 was highly expressed in CRC samples and predicted the poor prognosis for CRC patients. Functional experiments revealed that KCNQ1OT1 knockdown negatively affected the proliferation, migration and epithelial-mesenchymal transition (EMT) in CRC cells. Moreover, we identified the cytoplasmic localization of KCNQ1OT1 in CRC cells, indicating the post-transcriptional regulation of KCNQ1OT1 on gene expression. Mechanism experiments including RNA Immunoprecipitation (RIP) assay and dual luciferase reporter assays verified that KCNQ1OT1 acted as a competing endogenous RNA (ceRNA) in CRC by sponging microRNA-217 (miR-217) to up-regulate the expression of zinc finger E-box binding homeobox 1 (ZEB1). Further mechanism investigation revealed that ZEB1 enhanced the transcription activity of KCNQ1OT1 by acting as a transcription activator. Finally, rescue assays were designed to demonstrate the effect of KCNQ1OT1-miR-217-ZEB1 feedback loop on proliferation, migration, and EMT of CRC cells. In brief, our research findings revealed that ZEB1-induced upregulation of KCNQ1OT1 improved the proliferation, migration and EMT formation of CRC cells via regulation of miR-217/ZEB1 axis.
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Affiliation(s)
- Yinzhu Bian
- a Comprehensive Cancer Center , Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University , Nanjing , China.,b Department of Oncology, First People's Hospital of Yancheng , Fourth Affiliated Hospital of Nantong University , Yancheng , China
| | - Guangyi Gao
- c Department of Traditional Chinese Medicine , The Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's Hospital , Huai'an , Jiangsu , China
| | - Qun Zhang
- d Comprehensive Cancer Center, Nanjing Drum Tower Hospital , Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University , Nanjing , China
| | - Hanqing Qian
- d Comprehensive Cancer Center, Nanjing Drum Tower Hospital , Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University , Nanjing , China
| | - Lixia Yu
- d Comprehensive Cancer Center, Nanjing Drum Tower Hospital , Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University , Nanjing , China
| | - Ninghua Yao
- e Radiotherapy of oncology , The Affiliated hospital of Nantong University , Nantong , Jiangsu , China
| | - Jing Qian
- e Radiotherapy of oncology , The Affiliated hospital of Nantong University , Nantong , Jiangsu , China
| | - Baorui Liu
- d Comprehensive Cancer Center, Nanjing Drum Tower Hospital , Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University , Nanjing , China
| | - Xiaoping Qian
- a Comprehensive Cancer Center , Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University , Nanjing , China.,d Comprehensive Cancer Center, Nanjing Drum Tower Hospital , Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University , Nanjing , China
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Zhao X, Li X, Zhou L, Ni J, Yan W, Ma R, Wu J, Feng J, Chen P. LncRNA HOXA11-AS drives cisplatin resistance of human LUAD cells via modulating miR-454-3p/Stat3. Cancer Sci 2018; 109:3068-3079. [PMID: 30099826 PMCID: PMC6172072 DOI: 10.1111/cas.13764] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/20/2018] [Accepted: 07/29/2018] [Indexed: 12/30/2022] Open
Abstract
Over the past several years, long non‐coding RNAs (lncRNAs) have attracted more and more attention due to their special functions. They are vital biomarkers in multiple diseases. LncRNA HOMEOBOX A11 (HOXA11) has been found to be aberrantly expressed in some kinds of malignant tumors. In this study, we mainly discuss the oncogenic role of it in promoting malignant progression and chemoresistance in lung adenocarcinoma (LUAD) cells. The expression of HOXA11‐AS was much stronger in cisplatin‐resistant LUAD cells. Based on The Cancer Genome Atlas database, patients with high expression of HOXA11‐AS had shorter survival time. Additionally, knockdown of HOXA11‐AS caused positive changes in cell activities of LUAD. For example, cell proliferation and migration were weakened, the epithelial mesenchymal transition process was reversed, and apoptosis was induced. These changes were more obvious in cells treated with cisplatin. Next, the HOXA11‐AS/miR‐454‐3p/Stat3 (signal transducer and activator of transcription 3) pathway was found to influence the cisplatin resistance of LUAD cells. HOXA11‐AS specifically acted as a competing endogenous RNA (ceRNA) in LUAD cells. The combinations among these three genes were demonstrated. Finally, rescue assays were applied to demonstrate the ceRNA pattern consisting of HOXA11‐AS, miR‐454‐3p and Stat3. In conclusion, lncRNA HOXA11‐AS acted as a ceRNA to promote cisplatin resistance of human LUAD cells via the miR‐454‐3p/Stat3 axis.
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Affiliation(s)
- Xia Zhao
- Department of Oncology, First People's Hospital of Yancheng, Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Xiaoyou Li
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Leilei Zhou
- Department of Oncology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Jie Ni
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Wenyue Yan
- Department of Oncology, First People's Hospital of Yancheng, Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Rong Ma
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jianzhong Wu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jifeng Feng
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Ping Chen
- Department of Oncology, First People's Hospital of Yancheng, Fourth Affiliated Hospital of Nantong University, Yancheng, China
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Lu S, Jiang X, Su Z, Cui Z, Fu W, Tai S. The role of the long non-coding RNA HOXA11-AS in promoting proliferation and metastasis of malignant tumors. Cell Biol Int 2018; 42:1596-1601. [PMID: 30095197 DOI: 10.1002/cbin.11045] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 08/05/2018] [Indexed: 12/14/2022]
Abstract
Long non-coding RNA (lncRNA) is one of the focuses and hotspots of biological research in recent years. At the same time, tumors have become the main disease that endangers human health. In recent years, a large number of researchers have explored the relationship between lncRNA and tumors. HOXA11-AS is one of these lncRNAs. The long non-coding RNA HOXA11 antisense RNA (HOXA11-AS) is a novel lncRNA recently discovered. It is found in a variety of tumors such as ovarian cancer, glioma, and gastric cancer (GC) and so on, and is defined as an oncogene. It promotes tumor proliferation and metastasis by interacting with proteins such as miRNA and EZH2. In this paper, we review the mechanism of interaction between HOXA11-AS and various tumors in recent years, and believe that it can be a potential tumor marker and therapeutic target in the future prevention and treatment of tumors.
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Affiliation(s)
- Shounan Lu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Xingming Jiang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Zhilei Su
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Zhankun Cui
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Wen Fu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Sheng Tai
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Huang F, Wen C, Zhuansun Y, Huang L, Chen W, Yang X, Liu H. A novel long noncoding RNA OECC promotes colorectal cancer development and is negatively regulated by miR-143-3p. Biochem Biophys Res Commun 2018; 503:2949-2955. [PMID: 30126634 DOI: 10.1016/j.bbrc.2018.08.075] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 08/08/2018] [Indexed: 12/22/2022]
Abstract
Emerging evidence indicates that aberrant long non-coding RNA (lncRNA) expression contributes to CRC pathogenesis. To explore the biological functions of lncRNAs in CRC and to identify the underlying mechanisms, we first conducted a lncRNA microarray assay to investigate lncRNA expression patterns in CRC. We identified a novel lncRNA OECC, originating from chromosome 8q24 that is highly expressed in CRC tissues and cell lines and has a positive correlation with liver metastasis. Attenuation of lncRNA OECC expression prohibited CRC cell proliferation, induced apoptosis, and inhibited migration. Furthermore, an inverse correlation between lncRNA OECC and miR-143-3p was observed. Bioinformatic analyses predicted, and a luciferase reporter assay demonstrated, that lncRNA OECC is a direct target of miR-143-3p, leading to down-regulation in the expression of its target genes, the NF-κB and p38 MAPK pathways. Taken together, our results suggest that lncRNA OECC is overexpressed in CRC and may play an oncogenic role through NF-κB and p38 MAPK pathway activation via miR-143-3p.
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Affiliation(s)
- Fengting Huang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Chuangyu Wen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Yongxun Zhuansun
- Department of Respirology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Lanlan Huang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Wenying Chen
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Xiangling Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Huanliang Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
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Qu F, Cao P. Long noncoding RNA SOX2OT contributes to gastric cancer progression by sponging miR-194-5p from AKT2. Exp Cell Res 2018; 369:187-196. [DOI: 10.1016/j.yexcr.2018.05.017] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 05/11/2018] [Accepted: 05/17/2018] [Indexed: 12/12/2022]
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40
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Xue JY, Huang C, Wang W, Li HB, Sun M, Xie M. HOXA11-AS: a novel regulator in human cancer proliferation and metastasis. Onco Targets Ther 2018; 11:4387-4393. [PMID: 30100744 PMCID: PMC6067783 DOI: 10.2147/ott.s166961] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Multiple studies have demonstrated that lncRNAs extensively participate in human cancer proliferation and metastasis. Epigenetic modification, transcriptional and posttranscriptional regulatory mechanisms are involved in lncRNA-led tumorigenesis and transfer. Recently, a novel identified homeobox (HOX) A11 antisense lncRNA, HOXA11-AS, 1,628 bp in length, has been excessively highlighted to be an essential initiator and facilitator in the process of malignant tumor proliferation and metastasis. As found in many reports, HOXA11-AS can not only act as a molecular scaffold of PRC2, LSD1 and DNMT1 to epigenetically modify chromosomes in the nucleus but also occur as ceRNA competitively sponging miRNAs in the cytoplasm. Furthermore, HOXA11-AS may function as a potential biomarker for cancer diagnosis and prognosis. In this review, we summarize the evolvement and mechanisms of HOXA11-AS in proliferation and metastasis of various human cancers.
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Affiliation(s)
- Jiang-Yang Xue
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Chao Huang
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China,
| | - Wei Wang
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Hai-Bo Li
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Ming Sun
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA,
| | - Min Xie
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China,
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41
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Yang S, Sun Z, Zhou Q, Wang W, Wang G, Song J, Li Z, Zhang Z, Chang Y, Xia K, Liu J, Yuan W. MicroRNAs, long noncoding RNAs, and circular RNAs: potential tumor biomarkers and targets for colorectal cancer. Cancer Manag Res 2018; 10:2249-2257. [PMID: 30100756 PMCID: PMC6065600 DOI: 10.2147/cmar.s166308] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Noncoding RNAs (ncRNAs) can be divided into microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), pRNAs, and tRNAs. Traditionally, miRNAs exert their biological function mainly through the inhibition of translation via the induction of target RNA transcript degradation. lncRNAs and circRNAs were once considered to have no potential to code proteins. Here, we will review the current knowledge on ncRNAs in relation to their origins, characteristics, and functions. We will also review how ncRNAs work as competitive endogenous RNA, gene transcription and expression regulators, and RNA-binding protein sponges in colorectal cancer (CRC). Notably, except for the abovementioned mechanisms, recent advances revealed that lncRNAs can also act as the precursor of miRNAs, and a small portion of lncRNAs and circRNAs was verified to have the potential to code proteins, providing new evidence for the significance of ncRNAs in CRC tumorigenesis and development.
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Affiliation(s)
- Shuaixi Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Quanbo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Weiwei Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China.,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan 450002, People's Republic of China
| | - Guixian Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Junmin Song
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Zhen Li
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Zhiyong Zhang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Yuan Chang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Kunkun Xia
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Jinbo Liu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China, ;
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Zhang L, Li J, Hao C, Guo W, Wang D, Zhang J, Zhao Y, Duan S, Yao W. Up-regulation of exosomal miR-125a in pneumoconiosis inhibits lung cancer development by suppressing expressions of EZH2 and hnRNPK. RSC Adv 2018; 8:26538-26548. [PMID: 35541090 PMCID: PMC9083100 DOI: 10.1039/c8ra03081b] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 10/10/2018] [Accepted: 07/01/2018] [Indexed: 01/01/2023] Open
Abstract
Exposure to nanoparticles may lead to pneumoconiosis and lung cancer; however, whether patients suffering from pneumoconiosis also face a high risk of lung cancer has been under debate for decades. Recently, exosomes have been found to play critical roles in many diseases via intercellular cargo transportation, which has provided a new insight into the mechanistic investigation of nanoparticle-induced respiratory disorders. Herein, we isolated exosomes from the venous blood of patients with pneumoconiosis and healthy controls and then, we profiled the expression signatures of exosomal miRNAs using high-throughput sequencing technology. A total of 14 aberrantly expressed miRNAs were identified and used to process target gene prediction and functional annotation. Specially, miR-125a along with its target genes EZH2 and hnRNPK was found to play a significant role in the development of lung cancer. We then adopted a series of cellular experiments to validate the role of miR-125a in lung cancer. From the results obtained, we found that the suppression of EZH2 and hnRNPK by high levels of miR-125a inhibited the development of nanoparticle-induced lung adenocarcinoma, which contributed to the clarification of the relation between pneumoconiosis and lung cancer.
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Affiliation(s)
- Lin Zhang
- Department of Reproductive Medical Center, Third Affiliated Hospital of Zhengzhou University 7 Kangfuqian Road Zhengzhou 450001 China
- Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China +86-371-67781922
| | - Jiangfeng Li
- School of Basic Medicine, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China
| | - Changfu Hao
- Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China +86-371-67781922
| | - Wei Guo
- Department of Occupational Disease, Henan Provincial Institute of Occupational Health Middle Street of Kangfu Zhengzhou 450052 China
| | - Di Wang
- Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China +86-371-67781922
| | - Jianhui Zhang
- Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China +86-371-67781922
| | - Youliang Zhao
- Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China +86-371-67781922
| | - Shuyin Duan
- Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China +86-371-67781922
| | - Wu Yao
- Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University 100 Science Avenue Zhengzhou 450001 China +86-371-67781922
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43
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Deciphering the Far-Reaching Functions of Non-coding RNA in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2018. [DOI: 10.1007/s11888-018-0408-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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44
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Yang FQ, Zhang JQ, Jin JJ, Yang CY, Zhang WJ, Zhang HM, Zheng JH, Weng ZM. HOXA11-AS promotes the growth and invasion of renal cancer by sponging miR-146b-5p to upregulate MMP16 expression. J Cell Physiol 2018; 233:9611-9619. [PMID: 29953617 DOI: 10.1002/jcp.26864] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 05/23/2018] [Indexed: 12/18/2022]
Abstract
Recently, increasing studies showed that long noncoding RNAs (lncRNAs) play critical roles in tumor progression. However, the function and underlying mechanism of HOMEOBOX A11 antisense RNA (HOXA11-AS) on renal cancer remain unclear. In the current study, our data showed that the expression of HOXA11-AS was significantly upregulated in clear cell renal cell carcinoma (ccRCC) tissues and cell lines. High HOXA11-AS expression was associated with the advanced clinical stage, tumor stage, and lymph node metastasis. Function assays showed that HOXA11-AS inhibition significantly suppressed renal cancer cells growth, invasion, and ETM phenotype. In addition, underlying mechanism revealed that HOXA11-AS could act as a competing endogenous RNA (ceRNA) that repressed miR-146b-5p expression, which regulated its downstream target MMP16 in renal cancer. Taken together, our findings suggested that HOXA11-AS could promote renal cancer cells growth and invasion by modulating miR-146b-5p-MMP16 axis. Thus, our findings suggested that HOXA11-AS could serve as potential therapeutic target for the treatment of renal cancer.
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Affiliation(s)
- Feng-Qiang Yang
- Department of Urology, Ninghai First Hospital, Zhejiang, China.,Department of Urology, Ninghai Hospital, Branch of Shanghai Tenth People's Hospital, Zhejiang, China.,Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Jian-Qiu Zhang
- Department of Urology, Ninghai First Hospital, Zhejiang, China.,Department of Urology, Ninghai Hospital, Branch of Shanghai Tenth People's Hospital, Zhejiang, China
| | - Jiang-Jiang Jin
- Department of Urology, Ninghai First Hospital, Zhejiang, China.,Department of Urology, Ninghai Hospital, Branch of Shanghai Tenth People's Hospital, Zhejiang, China
| | - Chong-Yi Yang
- Department of Urology, Ninghai First Hospital, Zhejiang, China.,Department of Urology, Ninghai Hospital, Branch of Shanghai Tenth People's Hospital, Zhejiang, China
| | - Wei-Jie Zhang
- Department of Urology, Ninghai First Hospital, Zhejiang, China.,Department of Urology, Ninghai Hospital, Branch of Shanghai Tenth People's Hospital, Zhejiang, China
| | - Hai-Ming Zhang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Jun-Hua Zheng
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ze-Ming Weng
- Department of Urology, Ninghai First Hospital, Zhejiang, China.,Department of Urology, Ninghai Hospital, Branch of Shanghai Tenth People's Hospital, Zhejiang, China
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Zhan M, He K, Xiao J, Liu F, Wang H, Xia Z, Duan X, Huang R, Li Y, He X, Yin H, Xiang G, Lu L. LncRNA HOXA11-AS promotes hepatocellular carcinoma progression by repressing miR-214-3p. J Cell Mol Med 2018; 22:3758-3767. [PMID: 29761918 PMCID: PMC6050501 DOI: 10.1111/jcmm.13633] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 03/08/2018] [Indexed: 12/11/2022] Open
Abstract
Accumulating studies supported that lncRNAs played important roles in tumorigenesis. LncRNA HOXA11‐AS was a novel lncRNA that has been proved to involved in several tumours. However, the role of HOXA11‐AS in the development of hepatocellular carcinoma (HCC) remains to be explained. In our study, we showed that HOXA11‐AS expression was up‐regulated in the HCC tissues, and the higher expression of HOXA11‐AS was associated with the advanced stage in the HCC samples. In addition, we indicated that the expression of HOXA11‐AS was up‐regulated in HCC cell lines (Hep3B, SMMC‐7721, MHCC97‐H and BEL‐7402) compared with normal liver cell lines (HL‐7702). Overexpression of HOXA11‐AS promoted HCC proliferation and invasion and induced the epithelial‐mesenchymal transition (EMT) and knockdown of HOXA11‐AS suppressed the HCC cell proliferation and invasion. However, we showed that miR‐214‐3p expression was down‐regulated in the HCC tissues and cell lines. Ectopic expression of miR‐214‐3p suppressed HCC cell proliferation and invasion. Furthermore, we indicated that overexpression of HOXA11‐AS decreased the miR‐214‐3p expression and the expression of miR‐214‐3p was negatively related with the HOXA11‐AS expression in HCC samples. Ectopic expression of HOXA11‐AS increased HCC proliferation and invasion and induced EMT through inhibiting miR‐214‐3p expression. These data suggested that HOXA11‐AS/miR‐214‐3p axis was responsible for development of HCC.
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Affiliation(s)
- Meixiao Zhan
- Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, Guangdong, China
| | - Ke He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong Province, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jing Xiao
- Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, Guangdong, China
| | - Fei Liu
- Department of General Surgery, Guangdong Second Provincial General Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong Province, China.,Department of Dental Medicine, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhenglin Xia
- Department of General Surgery, Guangdong Second Provincial General Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong Province, China
| | - Xiaopeng Duan
- Department of General Surgery, Guangdong Second Provincial General Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong Province, China
| | - Rui Huang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong Province, China
| | - Yong Li
- Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, Guangdong, China
| | - Xu He
- Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, Guangdong, China
| | - Hua Yin
- Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, Guangdong, China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong Province, China
| | - Ligong Lu
- Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, Guangdong, China
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Fan Q, Liu B. Comprehensive analysis of a long noncoding RNA-associated competing endogenous RNA network in colorectal cancer. Onco Targets Ther 2018; 11:2453-2466. [PMID: 29760555 PMCID: PMC5937496 DOI: 10.2147/ott.s158309] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Purpose This study was aimed to develop a lncRNA-associated competing endogenous RNA (ceRNA) network to provide further understanding of the ceRNA regulatory mechanism and pathogenesis in colorectal cancer (CRC). Patients and methods Expression profiles of mRNAs, lncRNAs, and miRNAs, and clinical information for CRC patients were obtained from The Cancer Genome Atlas. The differentially expressed mRNAs, lncRNAs, and miRNAs (referred to as “DEmRNAs”, “DElncRNAs”, and “DEmiRNAs”, respectively) were screened out between 539 CRC samples and 11 normal samples. The interactions between DElncRNAs and DEmiRNAs were predicted by miRcode. The DEmRNAs targeted by the DEmiRNAs were retrieved according to TargetScan, miRTar-Base, and miRDB. The lncRNA–miRNA–mRNA ceRNA network was constructed based on the DEmiRNA–DElncRNA and DEmiRNA–DEmRNA interactions. Functional enrichment analysis revealed the biological processes and pathways of DEmRNAs involved in the development of CRC. Key lncRNAs were further analyzed for their associations with overall survival and clinical features of CRC patients. Results A total of 1,767 DEmRNAs, 608 DElncRNAs, and 283 DEmiRNAs were identified as CRC-specific RNAs. Three hundred eighty-two DEmiRNA–DElncRNA interactions and 68 DEmiRNA–DEmRNA interactions were recognized according to the relevant databases. The lncRNA–miRNA–mRNA ceRNA network was constructed using 25 DEmiRNAs, 52 DEmRNAs, and 64 DElncRNAs. Two DElncRNAs, five DEmiRNAs, and six DEmRNAs were demonstrated to be related to the prognosis of CRC patients. Four DElncRNAs were found to be associated with clinical features. Twenty-eight Gene Ontology terms and 10 Kyoto Encyclopedia of Genes and Genomes pathways were found to be significantly enriched by the DEmRNAs in the ceRNA network. Conclusion Our results showed cancer-specific mRNA, lncRNA, and miRNA expression patterns and enabled us to construct an lncRNA-associated ceRNA network that provided new insights into the molecular mechanisms of CRC. Key RNA transcripts related to the overall survival and clinical features were also found with promising potential as biomarkers for diagnosis, survival prediction, and classification of CRC.
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Affiliation(s)
- Qiaowei Fan
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang, People's Republic of China
| | - Bingrong Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
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Li Y, Lv M, Song Z, Lou Z, Wang R, Zhuang M. Long non-coding RNA NNT-AS1 affects progression of breast cancer through miR-142-3p/ZEB1 axis. Biomed Pharmacother 2018; 103:939-946. [PMID: 29710510 DOI: 10.1016/j.biopha.2018.04.087] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 04/09/2018] [Accepted: 04/10/2018] [Indexed: 12/20/2022] Open
Abstract
Some evidences have been provided to verify the effects of lncRNA NNT-AS1 on cancer progression. However, the crucial impacts of NNT-AS1 on the malignancy of breast cancer have not been elaborated. This study aims to detect the expression pattern and functional effects of NNT-AS1 in breast cancer. qRT-PCR analysis was applied to detect the expression of NNT-AS1 in both BC tissues and matched normal tissues. Loss of function assay was carried out to detect the effects of silenced NNT-AS1 on proliferation, metastasis and EMT process of BC cells. To understand the functional mechanism of NNT-AS1, mechanism assays were designed and performed in BC cells. Subcellular fractionation assay demonstrated that NNT-AS1 was located in the cytoplasm of BC cells. Therefore, NNT-AS1 might exert ceRNA functions in BC cells. To validate this hypothesis, we found the combination between NNT-AS1 and miR-142-3p through conducting bioinformatics analysis, RIP and luciferase reporter assays. Similarly, the combination between miR-142-3p and ZEB1 was verified. Finally, the recue assays were carried out to demonstrate the effects of NNT-AS1/miR-142-3p/ZEB1 axis on the biological behaviors of BC cells. All the above findings revealed a fact that NNT-AS1 affects breast cancer progression through modulating miR-142-3p/ZEB1 axis.
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Affiliation(s)
- Yan Li
- Department of Oncology, Lianyungang First People's Hospital, Lianyungang, Jiangsu, 222002, China.
| | - Min Lv
- Department of Scientific Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China
| | - Ziyan Song
- Department of Oncology, Lianyungang First People's Hospital, Lianyungang, Jiangsu, 222002, China
| | - Zhi Lou
- Department of Oncology, Lianyungang First People's Hospital, Lianyungang, Jiangsu, 222002, China
| | - Ran Wang
- Department of Oncology, Lianyungang First People's Hospital, Lianyungang, Jiangsu, 222002, China
| | - Min Zhuang
- Department of Oncology, Lianyungang First People's Hospital, Lianyungang, Jiangsu, 222002, China.
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