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Shi Y, Men X, Wang F, Li X, Zhang B. Role of long non-coding RNAs (lncRNAs) in gastric cancer metastasis: A comprehensive review. Pathol Res Pract 2024; 262:155484. [PMID: 39180802 DOI: 10.1016/j.prp.2024.155484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/27/2024]
Abstract
One of the greatest frequent types of malignancy is gastric cancer (GC). Metastasis, an essential feature of stomach cancer, results in a high rate of mortality and a poor prognosis. However, metastasis biological procedures are not well recognized. Long non-coding RNAs (lncRNAs) have a role in numerous gene regulation pathways via epigenetic modification as well as transcriptional and post-transcriptional control. LncRNAs have a role in a variety of disorders, such as cardiovascular disease, Alzheimer's, and cancer. LncRNAs are substantially related to GC incidence, progression, metastasis and drug resistance. Several research released information on the molecular processes of lncRNAs in GC pathogenesis. By interacting with a gene's promoter or enhancer region to influence gene expression, lncRNAs can operate as an oncogene or a tumor suppressor. This review includes the lncRNAs associated with metastasis of GC, which may give insights into the processes as well as potential clues for GC predicting and tracking.
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Affiliation(s)
- Yue Shi
- Department of Microbiology and Immunology, Changchun University of Chinese Medicine, Jilin 130117, PR China.
| | - Xiaoping Men
- Department of Clinical Laboratory, The First Affiliated Hospital to Changchun University of Chinese Medicine, Jilin 130021, PR China.
| | - Fang Wang
- Department of Microbiology and Immunology, Changchun University of Chinese Medicine, Jilin 130117, PR China.
| | - Xueting Li
- Experimental Center, Changchun University of Chinese Medicine, Jilin 130021, PR China.
| | - Biao Zhang
- School of Health Management, Changchun University of Chinese Medicine, Jilin 130117, PR China.
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Elimam H, Abdel Mageed SS, Hatawsh A, Moussa R, Radwan AF, Elfar N, Alhamshry NAA, Abd-Elmawla MA, Mohammed OA, Zaki MB, Doghish AS. Unraveling the influence of LncRNA in gastric cancer pathogenesis: a comprehensive review focus on signaling pathways interplay. Med Oncol 2024; 41:218. [PMID: 39103705 DOI: 10.1007/s12032-024-02455-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 07/16/2024] [Indexed: 08/07/2024]
Abstract
Gastric cancers (GCs) are among the most common and fatal malignancies in the world. Despite our increasing understanding of the molecular mechanisms underlying GC, further biomarkers are still needed for more in-depth examination, focused prognosis, and treatment. GC is one among the long non-coding RNAs, or lncRNAs, that have emerged as key regulators of the pathophysiology of cancer. This comprehensive review focuses on the diverse functions of long noncoding RNAs (lncRNAs) in the development of GC and their interactions with important intracellular signaling pathways. LncRNAs affect GC-related carcinogenic signaling cascades including pathways for EGFR, PI3K/AKT/mTOR, p53, Wnt/β-catenin, JAK/STAT, Hedgehog, NF-κB, and hypoxia-inducible factor. Dysregulated long non-coding RNA (lncRNA) expression has been associated with multiple characteristics of cancer, such as extended growth, apoptosis resistance, enhanced invasion and metastasis, angiogenesis, and therapy resistance. For instance, lncRNAs such as HOTAIR, MALAT1, and H19 promote the development of GC via altering these pathways. Beyond their main roles, GC lncRNAs exhibit potential as diagnostic and prognostic biomarkers. The overview discusses CRISPR/Cas9 genome-modifying methods, antisense oligonucleotides, small molecules, and RNA interference as potential therapeutic approaches to regulate the expression of long noncoding RNAs (lncRNAs). An in-depth discussion of the intricate functions that lncRNAs play in the development of the majority of stomach malignancies is provided in this review. It provides the groundwork for future translational research in lncRNA-based whole processes toward GC by highlighting their carcinogenic effects, regulatory roles in significant signaling cascades, and practical scientific uses as biomarkers and therapeutic targets.
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Affiliation(s)
- Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt.
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Abdulrahman Hatawsh
- Biotechnology School, Nile University, 26th of July Corridor, Sheikh Zayed City, 12588, Giza, Egypt
| | - Rewan Moussa
- Faculty of Medicine, Helwan University, Cairo, 11795, Egypt
| | - Abdullah F Radwan
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, 11829, Cairo, Egypt
| | - Nourhan Elfar
- School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, 11578, Cairo, Egypt
- Egyptian Drug Authority (EDA), Ministry of Health and Population, Cairo, 11567, Egypt
| | - Nora A A Alhamshry
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Mai A Abd-Elmawla
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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Kong W, Yin G, Zheng S, Liu X, Zhu A, Yu P, Zhang J, Shan Y, Ying R, Jin H. Long noncoding RNA (lncRNA) HOTAIR: Pathogenic roles and therapeutic opportunities in gastric cancer. Genes Dis 2022; 9:1269-1280. [PMID: 35873034 PMCID: PMC9293693 DOI: 10.1016/j.gendis.2021.07.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 06/21/2021] [Accepted: 07/06/2021] [Indexed: 01/17/2023] Open
Abstract
Gastric cancer is one of the first malignant cancers in the world and a large number of people die every year due to this disease. Many genetic and epigenetic risk factors have been identified that play a major role in gastric cancer. HOTAIR is an effective epigenetic agent known as long noncoding RNA (lncRNA). HOTAIR has been described to have biological functions in biochemical and cellular processes through interactions with many factors, leading to genomic stability, proliferation, survival, invasion, migration, metastasis, and drug resistance. In the present article, we reviewed the prognostic value of the molecular mechanisms underlying the HOTAIR regulation and its function in the development of Gastric Cancer, whereas elucidation of HOTAIR–protein and HOTAIR–DNA interactions can be helpful in the identification of cancer processes, leading to the development of potential therapeutic strategies.
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Affiliation(s)
- Wencheng Kong
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Guang Yin
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Sixin Zheng
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Xinchun Liu
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Akao Zhu
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Panpan Yu
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Jian Zhang
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Yuqiang Shan
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Rongchao Ying
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Huicheng Jin
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
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Kang S, Park M, Cho JY, Ahn SJ, Yoon C, Kim SG, Cho SJ. Tumorigenic mechanisms of estrogen and Helicobacter pylori cytotoxin-associated gene A in estrogen receptor α-positive diffuse-type gastric adenocarcinoma. Gastric Cancer 2022; 25:678-696. [PMID: 35391613 DOI: 10.1007/s10120-022-01290-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 03/09/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND Diffuse-type gastric cancer (DGC), for which Helicobacter pylori infection is a causal factor, is associated with poor prognosis among young women, possibly due to female hormones such as estrogen. We aimed to identify the carcinogenesis induced by estrogen and H. pylori in DGC. METHODS We screened and selected estrogen receptor alpha (ERα)-positive (MKN45) and ERα-negative (SNU5) DGC cell lines. H. pylori strain 60190 and its isogenic mutant strain lacking cytotoxin-associated gene A (60190ΔCagA) were used to infect MKN45 cells. And the cytotoxin-related gene A (CagA) cDNA which was cloned into pSP65-SR-HA (cagA-pSP65SRa) vector was used to transfect MKN45 cells. Tumor samples were used for DGC organoid culture. RESULTS In MKN45 cells, we found that estradiol promotes epithelial-mesenchymal transition (EMT) and stemness phenotypes via HOTAIR expression. These effects were further enhanced by the addition of CagA secreted by H. pylori but were reversed by co-treatment with fulvestrant (ICI 182,780), a selective ER degrader. We also validated the effect of estrogen on DGC organoids. ERα expression was associated with tumor invasion and HOTAIR expression in DGC patients with overt H. pylori infection. CONCLUSIONS These findings may explain the rapid DGC progression in young women with physiologically high levels of estrogen and suggest that fulvestrant with ovarian function suppression could serve as a tumor-suppressive agent in premenopausal patients with DGC.
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Affiliation(s)
- Seungkyung Kang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Miree Park
- Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jung Yeon Cho
- Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Su Jin Ahn
- Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Changhwan Yoon
- Department of Surgery, Columbia University Irving Medical Center, 630 W. 168th St, New York, NY, 10032, USA
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Soo-Jeong Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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Hu J, Wang M, Yang Y, Xing Y, Li S. LncRNA DLEU2 silencing impedes the migration, invasion and EMT in gastric cancer cell by suppressing PI3K/AKT signaling pathway. Immunopharmacol Immunotoxicol 2022; 44:719-731. [PMID: 35736813 DOI: 10.1080/08923973.2022.2078727] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Context: The high expression of long non-coding RNA deleted in lymphocytic leukaemia 2 (lncRNA DLEU2) has been confirmed in gastric cancer (GC).Objective: However, the detailed mechanism concerning its involvement in GC remained unclear, which we aimed to explore in this study.Materials and methods: LncRNA DLEU2 expression in GC was estimated by bioinformatic analysis, and the relationship between the expression of DLEU2 and the clinicopathological characteristics of patients with GC was performed. qRT-PCR was employed to detect the expression of lncRNA DLEU2 and confirm the transfection efficiency following the knockdown or overexpression of DLEU2. Functional assays, including CCK-8, flow cytometry, scratching test and Transwell assays, were used to determine the role of DLEU2 in tumor phenotypes. The effects of DLEU2 on the PI3K/Akt pathway were detected by western blot. For elucidating the functions of DLEU2/PI3K/Akt axis in GC, we inhibited the PI3K/Akt pathway in rescue experiments, and evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related proteins by western blot.Results: The expression of DLEU2 was aberrantly up-regulated in GC tissues and cells, which was correlated with the degree of tumor differentiation, cancer antigen 19-9 (CA19-9) and Lauren histologic classification of patients with GC. Silencing of DLEU2 induced apoptosis, attenuated viability, migration and invasion as well as inhibited the PI3K/Akt signaling pathway in GC cells. Mechanistically, the DLEU2/PI3K/Akt axis promoted the progression of GC and the EMT by down-regulating the expression of E-Cadherin and up-regulating those of N-Cadherin and Vimentin.Discussion and conclusions: LncRNA DLEU2 promoted the migration, invasion and EMT in GC by activating the PI3K/Akt pathway.
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Affiliation(s)
- Jun Hu
- Oncology Department, Gaochun People's Hospital, Nanjing City, China
| | - Mingyun Wang
- Oncology Department, Gaochun People's Hospital, Nanjing City, China
| | - Yang Yang
- Oncology Department, Nanjing Drum Tower Hospital (Gaochun Branch), Nanjing City, China
| | - Yajun Xing
- Oncology Department, Gaochun People's Hospital, Nanjing City, China
| | - Shuanggen Li
- Oncology Department, Gaochun People's Hospital, Nanjing City, China
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Tseng HH, Chen YZ, Chou NH, Chen YC, Wu CC, Liu LF, Yang YF, Yeh CY, Kung ML, Tu YT, Tsai KW. Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:180-194. [PMID: 34514098 PMCID: PMC8416970 DOI: 10.1016/j.omto.2021.08.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 08/13/2021] [Indexed: 12/30/2022]
Abstract
Long noncoding RNAs (lncRNAs) are a group of nonprotein coding transcripts that play a critical role in cancer progression. However, the role of lncRNA in metformin-induced inhibition of cell growth and its biological function in gastric cancer remain largely unknown. In this study, we identified an oncogenic lncRNA, Loc100506691, the expression of which was decreased in gastric cancer cells with metformin treatment. Moreover, Loc100506691 was significantly overexpressed in gastric cancer compared with adjacent normal tissues (p < 0.001), and high Loc100506691 expression was significantly correlated with poor survival of patients with gastric cancer. Additionally, Loc100506691 knockdown could significantly suppress gastric cancer cell growth in vitro, and ectopic Loc100506691 expression accelerated tumor growth in an in vivo mouse model. Analysis of the cell cycle revealed that Loc100506691 knockdown induced cell cycle arrest at the G2/M phase by impairing cell entry from the G2/M to G1 phase. Loc100506691 negatively regulated CHAC1 expression by modulating miR-26a-5p/miR-330-5p expression, and CHAC1 knockdown markedly attenuated Loc100506691 knockdown-induced gastric cancer cell growth and motility suppression. We concluded that anti-proliferative effects of metformin in gastric cancer may be partially caused by suppression of the Loc100506691-miR-26a-5p/miR-330-5p-CHAC1 axis.
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Affiliation(s)
- Hui-Hwa Tseng
- Division of Anatomic Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - You-Zuo Chen
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.,Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Nan-Hua Chou
- Department of Surgery Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Yen-Chih Chen
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Chao-Chuan Wu
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Li-Feng Liu
- Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yi-Fang Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Chung-Yu Yeh
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Ya-Ting Tu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
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Wang S, Han H, Meng J, Yang W, Lv Y, Wen X. Long non-coding RNA SNHG1 suppresses cell migration and invasion and upregulates SOCS2 in human gastric carcinoma. Biochem Biophys Rep 2021; 27:101052. [PMID: 34179518 PMCID: PMC8214191 DOI: 10.1016/j.bbrep.2021.101052] [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: 01/18/2021] [Revised: 05/30/2021] [Accepted: 06/07/2021] [Indexed: 11/23/2022] Open
Abstract
Gastric carcinoma (GC) is one of the most common malignancies and the third leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) may be an important class of functional regulators involved in human gastric cancers development. In this study, we investigated the clinical significance and function of lncRNA SNHG1 in GC. SNHG1 was significantly downregulated in GC tumor tissues compared with adjacent noncancerous tissues. Overexpression of SNHG1 in BGC-823 cells remarkably inhibited not only cell proliferation, migration, invasion in vitro, but also tumorigenesis and lung metastasis in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Conversely, inhibition of SNHG1 by transfection of siRNA in AGS cells resulted in opposite phenotype changes. Mechanically, SNHG1 was found interacted with ILF3, NONO and SFPQ. RNA-seq combined with bioinformatic analysis identified a serial of downstream genes of SNHG1, including SOCS2, LOXL2, LTBP3, LTBP4. Overexpression of SNHG1 induced SOCS2 expression whereas knockdown of SNHG1 decreased SOCS2 expression. In addition, knockdown of SNHG1 promoted the activation of JAK2/STAT signaling pathway. Taken together, our data suggested that SNHG1 suppressed aggressive phenotype of GC cells and regulated SOCS2/JAK2/STAT pathway.
SNHG1 was significantly downregulated in GC tumor tissues. SNHG1 suppressed proliferation and migration of GC cells. SNHG1 localized in nucleus of GC cells and interacted with ILF3, NONO and SFPQ. SNHG1 regulate SOCS2 expression in GC cell lines and JAK2/STAT signaling pathway in AGS cells.
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Affiliation(s)
- Shanshan Wang
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
| | - Haibo Han
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
| | - Junling Meng
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
| | - Wei Yang
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
| | - Yunwei Lv
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
| | - Xianzi Wen
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
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Seo SI, Yoon JH, Byun HJ, Lee SK. HOTAIR Induces Methylation of PCDH10, a Tumor Suppressor Gene, by Regulating DNMT1 and Sponging with miR-148b in Gastric Adenocarcinoma. Yonsei Med J 2021; 62:118-128. [PMID: 33527791 PMCID: PMC7859685 DOI: 10.3349/ymj.2021.62.2.118] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/18/2020] [Accepted: 12/07/2020] [Indexed: 12/19/2022] Open
Abstract
PURPOSE HOX transcript antisense intergenic RNA (HOTAIR), as a long non-coding RNA, has been reported to regulate carcinogenesis by epigenetic mechanism in various cancers. Protocadherin 10 (PCDH10) is one of the well-known tumor suppressor genes, and is frequently methylated in gastric cancers (GC). We aimed to investigate the detailed pathway of how HOTAIR contributes to the target gene in gastric carcinogenesis. MATERIALS AND METHODS We investigated the mechanism of HOTAIR on carcinogenesis and metastasis of GC. Methylation-specific PCR was performed to identify the interaction between HOTAIR and PCDH10. In addition, we investigated the interaction between miR-148b and HOTAIR by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULTS The expression of HOTAIR was significantly upregulated in GC tissues (p<0.05) and GC cell lines (p<0.01), while PCDH10 was downregulated in GC tissues (p<0.05). The knockdown of HOTAIR (si-HOTAIR1 and 2) significantly upregulated the mRNA/protein expression of PCDH10 and reduced the methylation of PCDH10 compared to the control in MKN 28 and MKN 74. Si-HOTAIR1 and 2 significantly reduced DNA methyltransferase 1 (DNMT1) expression, and overexpression of HOTAIR increased DNMT1 expression. In RIP, we found that miR-148b interacted with HOTAIR. Si-HOTAIRs increased miR-148b expression, and miR-148b mimic inversely reduced HOTAIR expression. Si-HOTAIRs and miR-148b mimic reduced DNMT1 expression and increased PCDH10 expression compared to the control. CONCLUSION This study demonstrated that HOTAIR interacts with miR-148b and DNMT1, eventually leading to PCDH10 methylation, which contributes to the progression of GC. Our findings provide a better understanding for detailed pathway of HOTAIR in epigenetic mechanism of GC.
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Affiliation(s)
- Seung In Seo
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
- Department of Medicine, The Graduate School, Yonsei University, Seoul, Korea
| | - Jung Ho Yoon
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Hyo Joo Byun
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
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Petkevicius V, Streleckiene G, Balciute K, Link A, Leja M, Malfertheiner P, Skieceviciene J, Kupcinskas J. Association of Long Non-Coding RNA Polymorphisms with Gastric Cancer and Atrophic Gastritis. Genes (Basel) 2020; 11:1505. [PMID: 33333725 PMCID: PMC7765138 DOI: 10.3390/genes11121505] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNAs (lncRNA) play an important role in the carcinogenesis of various tumours, including gastric cancer. This study aimed to assess the associations of lncRNA ANRIL, H19, MALAT1, MEG3, HOTAIR single-nucleotide polymorphisms (SNPs) with gastric cancer and atrophic gastritis. SNPs were analyzed in 613 gastric cancer patients, 118 patients with atrophic gastritis and 476 controls from three tertiary centers in Germany, Lithuania and Latvia. Genomic DNA was extracted from peripheral blood leukocytes. SNPs were genotyped by the real-time polymerase chain reaction. Results showed that carriers of MALAT1 rs3200401 CT genotype had the significantly higher odds of atrophic gastritis than those with CC genotype (OR-1.81; 95% CI 1.17-2.80, p = 0.0066). Higher odds of AG were found in a recessive model (CC vs. TT + CT) for ANRIL rs1333045 (OR-1.88; 95% CI 1.19-2.95, p = 0.0066). Carriers of ANRIL (rs17694493) GG genotype had higher odds of gastric cancer (OR-4.93; 95% CI 1.28-19.00) and atrophic gastritis (OR-5.11; 95% CI 1.10-23.80) compared with the CC genotype, and carriers of HOTAIR rs17840857 TG genotype had higher odds of atrophic gastritis (OR-1.61 95% CI 1.04-2.50) compared with the TT genotype; however, the ORs did not reach the adjusted significance threshold (p < 0.007). In summary, our data provide novel evidence for a possible link between lncRNA SNPs and premalignant condition of gastric cancer, suggesting the involvement of lncRNAs in gastric cancer development.
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Affiliation(s)
- Vytenis Petkevicius
- Department of Gastroenterology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Greta Streleckiene
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Kotryna Balciute
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (A.L.); (P.M.)
| | - Marcis Leja
- Institute for Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia,1586 Riga, Latvia;
- Faculty of Medicine, University of Latvia, 1586 Riga, Latvia
- Department of Research, Riga East University Hospital, 1079 Riga, Latvia
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (A.L.); (P.M.)
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
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10
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Non-coding RNAs underlying chemoresistance in gastric cancer. Cell Oncol (Dordr) 2020; 43:961-988. [PMID: 32495294 DOI: 10.1007/s13402-020-00528-2] [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] [Received: 11/14/2019] [Revised: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major health issue in the Western world. Current clinical imperatives for this disease include the identification of more effective biomarkers to detect GC at early stages and enhance the prevention and treatment of metastatic and chemoresistant GC. The advent of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long-non coding RNAs (lncRNAs), has led to a better understanding of the mechanisms by which GC cells acquire features of therapy resistance. ncRNAs play critical roles in normal physiology, but their dysregulation has been detected in a variety of cancers, including GC. A subset of ncRNAs is GC-specific, implying their potential application as biomarkers and/or therapeutic targets. Hence, evaluating the specific functions of ncRNAs will help to expand novel treatment options for GC. CONCLUSIONS In this review, we summarize some of the well-known ncRNAs that play a role in the development and progression of GC. We also review the application of such ncRNAs in clinical diagnostics and trials as potential biomarkers. Obviously, a deeper understanding of the biology and function of ncRNAs underlying chemoresistance can broaden horizons toward the development of personalized therapy against GC.
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Fu T, Ji X, Bu Z, Zhang J, Wu X, Zong X, Fan B, Jia Z, Ji J. Identification of key long non-coding RNAs in gastric adenocarcinoma. Cancer Biomark 2020; 27:541-553. [PMID: 32176636 DOI: 10.3233/cbm-192389] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Gastric cancer is the third leading cause of cancer-related deaths worldwide. OBJECTIVE The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gastric adenocarcinoma. METHODS The lncRNA and mRNA expression profile between gastric adenocarcinoma and adjacent non-tumor tissues were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between gastric adenocarcinoma and adjacent non-tumor tissues were identified after bioinformatics analysis. DElncRNA-DEmRNA co-expression network and DElncRNA-nearby DEmRNA interaction network were constructed, respectively. Functional annotation for DEmRNAs interacted with DElncRNAs was performed. Receiver operating characteristic (ROC) analysis of selected DElncRNAs was conducted. RESULTS Based on TCGA, the mRNA and lncRNA expression profiles of 375 gastric adenocarcinoma and 32 adjacent non-tumor tissues were downloaded. A total of 1502 DEmRNAs and 928 DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues were identified. HOXC-AS3 might involve with gastric adenocarcinoma by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13) with cis-effect. AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations might play roles in gastric adenocarcinoma through regulating pathways of Fat digestion and absorption and Vitamin digestion and absorption. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) have excellent diagnostic value for gastric adenocarcinoma. CONCLUSIONS This study identifies key lncRNAs in gastric adenocarcinoma which provides clues for exploring the pathogenesis and developing potential biomarkers for gastric adenocarcinoma.
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Sheng Y, Han C, Yang Y, Wang J, Gu Y, Li W, Guo L. Correlation between LncRNA-LINC00659 and clinical prognosis in gastric cancer and study on its biological mechanism. J Cell Mol Med 2020; 24:14467-14480. [PMID: 33145980 PMCID: PMC7754062 DOI: 10.1111/jcmm.16069] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 07/22/2020] [Accepted: 10/20/2020] [Indexed: 01/26/2023] Open
Abstract
Non-coding RNAs play important roles in tumorigenesis and tumour progression. In previous screening, lncRNA-LINC00659 (LINC00659) is highly expressed in gastric cancer; however, its role in gastric cancer has not been illustrated yet. In this study, the expression of LINC00659 was detected in cancer tissues and paracancerous tissues of patients with gastric cancer. As a result, LINC00659 expression was increased in gastric cancer tissues, which was closely associated with tumour stage and lymph node metastasis, but was not correlated with age, gender and tissue differentiation. Survival curve analysis showed that patients with low expression of LINC00659 harboured higher overall survival. In vitro, the level of LINC00659 was increased in gastric cancer cells. Afterwards, the expression of LINC00659 was down-regulated in SGC-7901 and BGC-823 cells by plasmid-mediated si-LINC00659 transfection. Consequently, the cell invasion ability was weakened, the cell cycle was inhibited, and cell viability was also suppressed. Luciferase reporter gene assay and RNA pull-down assay showed that LINC00659 could bind to the transcription factor SUZ12, indicating that SUZ12 was a regulatory gene of LINC00659. The overexpression of SUZ12 could resist the roles of si-LINC00659. In this study, we found that LINC00659 was highly expressed in gastric cancer, which might be related to the regulation of cell proliferation and promotion of cell invasion. Transcription factor, SUZ12, was a regulator of LINC00659. Additionally, LINC00659 could regulate cell cycle and invasion of gastric cancer by promoting the expression of SUZ12.
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Affiliation(s)
- Yongjia Sheng
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Chenyang Han
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Yi Yang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jin Wang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Yanling Gu
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Wenyan Li
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Li Guo
- Department of Center Laboratory, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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13
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Fan W, Shang J, Li F, Sun Y, Yuan S, Liu JX. IDSSIM: an lncRNA functional similarity calculation model based on an improved disease semantic similarity method. BMC Bioinformatics 2020; 21:339. [PMID: 32736513 PMCID: PMC7430881 DOI: 10.1186/s12859-020-03699-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/23/2020] [Indexed: 12/17/2022] Open
Abstract
Background It has been widely accepted that long non-coding RNAs (lncRNAs) play important roles in the development and progression of human diseases. Many association prediction models have been proposed for predicting lncRNA functions and identifying potential lncRNA-disease associations. Nevertheless, among them, little effort has been attempted to measure lncRNA functional similarity, which is an essential part of association prediction models. Results In this study, we presented an lncRNA functional similarity calculation model, IDSSIM for short, based on an improved disease semantic similarity method, highlight of which is the introduction of information content contribution factor into the semantic value calculation to take into account both the hierarchical structures of disease directed acyclic graphs and the disease specificities. IDSSIM and three state-of-the-art models, i.e., LNCSIM1, LNCSIM2, and ILNCSIM, were evaluated by applying their disease semantic similarity matrices and the lncRNA functional similarity matrices, as well as corresponding matrices of human lncRNA-disease associations coming from either lncRNADisease database or MNDR database, into an association prediction method WKNKN for lncRNA-disease association prediction. In addition, case studies of breast cancer and adenocarcinoma were also performed to validate the effectiveness of IDSSIM. Conclusions Results demonstrated that in terms of ROC curves and AUC values, IDSSIM is superior to compared models, and can improve accuracy of disease semantic similarity effectively, leading to increase the association prediction ability of the IDSSIM-WKNKN model; in terms of case studies, most of potential disease-associated lncRNAs predicted by IDSSIM can be confirmed by databases and literatures, implying that IDSSIM can serve as a promising tool for predicting lncRNA functions, identifying potential lncRNA-disease associations, and pre-screening candidate lncRNAs to perform biological experiments. The IDSSIM code, all experimental data and prediction results are available online at https://github.com/CDMB-lab/IDSSIM.
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Affiliation(s)
- Wenwen Fan
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China
| | - Junliang Shang
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China.
| | - Feng Li
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China
| | - Yan Sun
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China
| | - Shasha Yuan
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China
| | - Jin-Xing Liu
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China
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14
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Xu Z, Lv H, Wang Y, Hu C, Chen S, Du Y, Shi C, Cheng X. HAND2-AS1 Inhibits Gastric Adenocarcinoma Cells Proliferation and Aerobic Glycolysis via miRNAs Sponge. Cancer Manag Res 2020; 12:3053-3068. [PMID: 32431548 PMCID: PMC7200253 DOI: 10.2147/cmar.s222878] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/09/2020] [Indexed: 01/14/2023] Open
Abstract
Objective To study the effect of lncRNA HAND2-AS1 on gastric adenocarcinoma (GA) cell property and explore its specific mechanism. Methods Data on stomach adenocarcinoma (STAD) were analyzed to screen differentially expressed lncRNA HAND2-AS1. RNA22-HAS database and dual luciferase reporter assay were applied to confirm the target relationship between HAND2-AS1/HIF3A and miR-184. The HAND2-AS1 and miR-184 expressions in tissue or cells were determined by qRT-PCR and Western blot. Besides, after GA cells (AGS) cultured in normoxic and hypoxic condition, phosphoenolpyruvate (PEP) and lactic acid were quantified by Phosphoenolpyruvate Fluorometric Assay Kit and Lactic Acid Detection kit, respectively. Additionally, colony formation assay, transwell invasion and migration assays were used to evaluate the abilities of cell invasion, migration, and proliferation in distinct conditions. Results The HAND2-AS1 and HIF3A expressions were down-regulated and miR-184 expression was up-regulated in GA tissues and cells. Dual luciferase reporter assay confirmed HAND2-AS1 and HIF3A were targeted by miR-184. AGS cell proliferation abilities were restrained by HAND2-AS1 and HIF3A overexpression and enhanced by miR-184, as well as migration and invasion abilities. In addition, HAND2-AS1 rescued enhanced AGS cell proliferation, cell migration, cell invasion abilities and glycolytic process caused by hypoxia via miR-184/HIF3A. Conclusion LncRNA HAND2-AS1 could inhibit GA cell proliferation, migration and invasion abilities and glycolytic process induced by hypoxia through miR-184/HIF3A signaling.
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Affiliation(s)
- Zhiyuan Xu
- Department of Gastric Surgery, Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People's Republic of China
| | - Hang Lv
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System Tumor, Hangzhou 300020, Zhejiang, People's Republic of China
| | - Yiping Wang
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System Tumor, Hangzhou 300020, Zhejiang, People's Republic of China
| | - Can Hu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, People's Republic of China
| | - Shangqi Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, People's Republic of China
| | - Yian Du
- Department of Gastric Surgery, Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People's Republic of China
| | - Chengwei Shi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, People's Republic of China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People's Republic of China
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15
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Hong JH, Jin EH, Chang IA, Kang H, Lee SI, Sung JK. Association Between lncRNA HULC rs7763881 Polymorphism and Gastric Cancer Risk. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2020; 13:121-126. [PMID: 32308466 PMCID: PMC7154033 DOI: 10.2147/pgpm.s247082] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Purpose Gastric cancer (GC) is one of the most common cancers in the world. Recently, several studies have suggested that single-nucleotide polymorphisms (SNPs) of long noncoding RNA (lncRNA) are associated with GC risk. However, the association of the lncRNA highly upregulated in liver cancer (HULC) SNP with GC risk is not yet known. The aims of this study were to evaluate the association between HULC rs7763881 SNP and the risk of GC and GC subgroups via a case–control study. Patients and Methods rs7763881 was genotyped using TaqMan genotyping assay with 459 GC patients and 379 controls. Results A significant association between HULC rs7763881 SNP and GC risk was not found. However, after adjustment for age and gender, the rs7763881 recessive model (CC) showed a significant association with an increased GC risk in the undifferentiated (odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.17–2.94, P = 0.009), diffuse-type GC (OR = 1.72, 95% CI = 1.05–2.82, P = 0.033), LNM-positive (OR = 2.02, 95% CI = 1.24–3.27, P = 0.004), T3/T4 (OR = 1.75, 95% CI = 1.05–2.91, P = 0.032), and tumor stage III (OR = 2.01, 95% CI = 1.17–3.45, P = 0.011) subgroups when compared to the rs7763881 combined genotypes (AA+AC). Furthermore, after adjusting for age and gender, the rs7763881 additive model (CC) indicated a significantly higher GC risk than rs7763881 AA genotype in the undifferentiated (OR = 1.96, 95% CI = 1.15–3.32, P = 0.013), diffuse-type GC (OR = 2.08, 95% CI = 1.23–3.52, P = 0.004), and LNM-positive (OR = 2.00, 95% CI = 1.14–3.49, P = 0.016) subgroups. Conclusion Our findings suggest that the HULC rs7763881 SNP is associated with increased susceptibility to GC. However, further studies are required to validate our results in large populations as well as different ethnic groups.
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Affiliation(s)
- Jang Hee Hong
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea.,Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Eun-Heui Jin
- Research Institute for Medical Sciences, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - In Ae Chang
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Hyojin Kang
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Sang-Il Lee
- Department of Surgery, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Jae Kyu Sung
- Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Republic of Korea
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16
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Ghafouri-Fard S, Taheri M. Long non-coding RNA signature in gastric cancer. Exp Mol Pathol 2019; 113:104365. [PMID: 31899194 DOI: 10.1016/j.yexmp.2019.104365] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/18/2019] [Accepted: 12/28/2019] [Indexed: 02/07/2023]
Abstract
Gastric cancer as a common human malignancy has been associated with aberrant expressions of several coding and non-coding genes. Long non-coding RNAs (lncRNAs) as regulators of gene expressions at different genomic, transcriptomic and post-transcriptomic levels are among putative biomarkers and therapeutic targets in gastric cancer. In the present study, we have searched available literature and listed lncRNAs that are involved in the pathogenesis of gastric cancer. In addition, we discuss associations between expressions of these lncRNAs and tumoral features or risk factors for gastric cancer. Based on the established role of lncRNAs in regulation of genomic stability, cell cycle, apoptosis, angiogenesis and other aspects of cell physiology, the potential of these transcripts as therapeutic targets in gastric cancer should be evaluated in future studies.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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17
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HOX transcript antisense RNA (HOTAIR) in cancer. Cancer Lett 2019; 454:90-97. [DOI: 10.1016/j.canlet.2019.04.016] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 04/06/2019] [Accepted: 04/08/2019] [Indexed: 01/17/2023]
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18
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HOTAIR as a Prognostic Predictor for Diverse Human Cancers: A Meta- and Bioinformatics Analysis. Cancers (Basel) 2019; 11:cancers11060778. [PMID: 31195674 PMCID: PMC6628152 DOI: 10.3390/cancers11060778] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/30/2019] [Accepted: 06/01/2019] [Indexed: 02/07/2023] Open
Abstract
Several studies suggest that upregulated expression of the long non-coding RNA HOX transcript antisense RNA (HOTAIR) is a negative predictive biomarker for numerous cancers. Herein, we performed a meta-analysis to further investigate the prognostic value of HOTAIR expression in diverse human cancers. To this end, a systematic literature review was conducted in order to select scientific studies relevant to the association between HOTAIR expression and clinical outcomes, including overall survival (OS), recurrence-free survival (RFS)/disease-free survival (DFS), and progression-free survival (PFS)/metastasis-free survival (MFS) of cancer patients. Collectively, 53 eligible studies including a total of 4873 patients were enrolled in the current meta-analysis. Pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were calculated to assess the relationship between HOTAIR and cancer patients’ survival. Elevated HOTAIR expression was found to be significantly associated with OS, RFS/DFS and PFS/MFS in diverse types of cancers. These findings were also corroborated by the results of bioinformatics analysis on overall survival. Therefore, based on our findings, HOTAIR could serve as a potential biomarker for the prediction of cancer patient survival in many different types of human cancers.
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Youn YH, Byun HJ, Yoon JH, Park CH, Lee SK. Long Noncoding RNA N-BLR Upregulates the Migration and Invasion of Gastric Adenocarcinoma. Gut Liver 2019; 13:421-429. [PMID: 30970439 PMCID: PMC6622564 DOI: 10.5009/gnl18408] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/29/2018] [Accepted: 11/08/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND/AIMS Gastric cancer is one of the most common malignant tumors worldwide with poor prognosis due to a lack of effective treatment modalities. Recent research showed that a long noncoding RNA named N-BLR modulates the epithelial-to-mesenchymal transition (EMT) process in colorectal cancer. However, the biological role of N-BLR in gastric cancer still remains to be explored. The aim of this study was to investigate the possibility of N-BLR as an EMT modulator in gastric cancer. METHODS The expression of N-BLR was measured by quantitative polymerase chain reaction in fresh gastric cancer tissue, paired adjacent normal tissues and cell lines. Fresh gastric tissues, paired samples obtained by surgery and clinical data were collected prospectively. Knockdown of N-BLR was induced by small interfering RNA (siRNAs). Cell number and viability were assessed after treatment with siRNAs. The ability of N-BLR to promote metastasis was measured using migration and invasion assays. Additionally, an inverse correlation between N-BLR and miR-200c was measured by TaqMan microRNA assays. Western blotting was performed to detect EMT and apoptosis markers upon knockdown of N-BLR. RESULTS N-BLR expression was significantly elevated in gastric cancer cell lines and tissues compared to that in a normal gastric cell line and adjacent normal tissues (p<0.01). Two different siRNAs significantly reduced cell proliferation of gastric cancer cells compared to the siCT. siRNAs for N-BLR significantly suppressed migration and invasion in AGS and MKN28 cells. N-BLR expression was inversely correlated with miR-200c, which is known to regulate EMT. CONCLUSIONS In this study, we confirmed N-BLR as a regulator of the EMT process in gastric cancer.
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Affiliation(s)
- Young Hoon Youn
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Hyo Joo Byun
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul,
Korea
| | - Jung-Ho Yoon
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Chan Hyuk Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul,
Korea
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Abstract
Biomarker-driven personalized cancer therapy is a field of growing interest, and several molecular tests have been developed to detect biomarkers that predict, e.g., response of cancers to particular therapies. Identification of these molecules and understanding their molecular mechanisms is important for cancer prognosis and the development of therapeutics for late stage diseases. In the past, significant efforts have been placed on the discovery of protein or DNA-based biomarkers while only recently the class of long non-coding RNA (lncRNA) has emerged as a new category of biomarker. The mammalian genome is pervasively transcribed yielding a vast amount of non-protein-coding RNAs including lncRNAs. Hence, these transcripts represent a rich source of information that has the potential to significantly contribute to precision medicine in the future. Importantly, many lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we will highlight prime examples of lncRNAs that serve as marker for cancer progression or therapy response and which might represent promising therapeutic targets. Furthermore, we will introduce lncRNA targeting tools and strategies, and we will discuss potential pitfalls in translating these into clinical trials.
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Chen M, Fan L, Zhang SM, Li Y, Chen P, Peng X, Liu DB, Ma C, Zhang WJ, Zou ZW, Li PD. LINC01939 inhibits the metastasis of gastric cancer by acting as a molecular sponge of miR-17-5p to regulate EGR2 expression. Cell Death Dis 2019; 10:70. [PMID: 30683847 PMCID: PMC6347617 DOI: 10.1038/s41419-019-1344-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 12/17/2018] [Accepted: 01/04/2019] [Indexed: 12/12/2022]
Abstract
Accumulating evidence have suggested that long noncoding RNAs (lncRNAs) are known to regulate diverse tumorigenic processes. Recently, a novel lncRNA LINC01939 was underexpressed and emerged as a tumor suppressive lncRNA in gastric cancer (GC). In this study, we aimed to investigate the biological function and molecular mechanism of LINC01939 in GC. We found that LINC01939 expression was significantly downregulated in GC tissues and cell lines. Low expression of LINC01939 was correlated with tumor metastasis and shorter survival in GC patients. Functionally, LINC01939 overexpression remarkably inhibited the invasion and migration of GC cells in vitro and in vivo. Mechanistically, LINC01939 regulated the expression of early growth response 2 (EGR2) protein by competitively binding to miR-17-5p. Upregulation of miR-17-5p reversed GC metastasis and EMT process caused by LINC01939 by rescue analysis. Taken together, these results suggested that LINC01939 repressed GC invasion and migration by functioning as a ceRNA for miR-17-5p to regulate EGR2 expression. Our findings provided a novel prognostic marker and therapeutic target for GC patients.
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Affiliation(s)
- Mi Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Li Fan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Si-Min Zhang
- Department of Emergency, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yong Li
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Peng Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xin Peng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dong-Bo Liu
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Charlie Ma
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Wen-Jie Zhang
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
| | - Zhen-Wei Zou
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Pin-Dong Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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22
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Yao L, Feng YN, You YJ, Luo M, Xin RJ. Association between polymorphisms of HOTAIR and risk of gastric cancer in a population in Ningxia, China. Shijie Huaren Xiaohua Zazhi 2019; 27:29-35. [DOI: 10.11569/wcjd.v27.i1.29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the association between HOTAIR single nucleotide polymorphisms and susceptibility to gastric cancer (GC) in Ningxia, China.
METHODS Three HOTAIR loci rs12826786 (C>T), rs920778 (C>T), and rs4759314 (A>G) were selected for genotyping their polymorphisms; 152 patients with GC and 307 healthy controls were selected after matching age, weight, gender, and other factors. The association between single nucleotide polymorphisms and genetic susceptibility to GC was analyzed by PCR and high-throughput TaqMan technology.
RESULTS The frequency of HOTAIR rs920778 genotype TT was 26.3% and 24.7% in the case group and the control group, respectively; the frequency of genotype C/T was 21.1% and 31.3%; and the frequency of genotype CC was 52.6% and 44.0%. The TT genotype at this locus was significantly associated with genetic susceptibility to GC (P < 0.05). Rs12826786 and rs4759314 were not associated with the risk of GC (P > 0.05). Further stratified analysis found that rs920778 locus was highly associated with genetic susceptibility to GC in men, smoking population, and GC patients with tumor size ≥ 5 cm, but there was no significant association with age, female gender, non-smokers, distant metastasis, or family history of GC.
CONCLUSION HOTAIR rs920778 single nucleotide polymorphism is associated with genetic susceptibility to GC.
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Affiliation(s)
- Li Yao
- Department of Gastroenterology, People's Hospital of Ningxia Autonomous Region, Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Ya-Ning Feng
- Department of Gastroenterology, People's Hospital of Ningxia Autonomous Region, Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Yan-Jie You
- Department of Gastroenterology, People's Hospital of Ningxia Autonomous Region, Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Ming Luo
- Department of Gastroenterology, People's Hospital of Ningxia Autonomous Region, Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Rui-Juan Xin
- Department of Gastroenterology, People's Hospital of Ningxia Autonomous Region, Yinchuan 750001, Ningxia Hui Autonomous Region, China
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Park CH, Kim H, Jo JH, Hahn KY, Yoon JH, Kim SY, Lee YC, Noh SH, Chung HC, Lee SK. Role of probe-based confocal laser endomicroscopy-targeted biopsy in the molecular and histopathological study of gastric cancer. J Gastroenterol Hepatol 2019; 34:84-91. [PMID: 30221400 DOI: 10.1111/jgh.14471] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 09/05/2018] [Accepted: 09/08/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM A high yield of biopsy is mandatory to perform molecular genetic research with endoscopically obtained gastric cancer tissues. We evaluated whether probe-based confocal laser endomicroscopy (pCLE) can increase the yield of endoscopic biopsy for gastric cancer compared with white light endoscopy (WLE). METHODS All lesions in the pCLE and WLE groups were initially evaluated through WLE. In the pCLE group, lesions were further examined through pCLE. In the pilot study, five and three biopsy specimens were obtained for histopathological examination and tumor marker analysis, respectively. In the confirmatory study, six biopsy specimens for histopathological evaluation were obtained. RESULTS A total of 30 gastric cancers and 61 undifferentiated-type gastric cancers were analyzed in the pilot and confirmatory studies, respectively. The proportion of cancer cells in biopsy samples of poorly differentiated adenocarcinoma or signet ring cell carcinoma was higher in the pCLE group than in the WLE group in both the pilot and confirmatory studies (pilot: median proportion, 65% vs 30%, P = 0.010; confirmatory: mean ± standard deviation, 49.5 ± 29.3 vs 29.3 ± 13.7, P = 0.002). The expression ratio of tumor markers including carcinoembryonic antigen, GW112, HOX transcript antisense RNA, and H19 tended to be higher in the pCLE group than in the WLE group. CONCLUSION Probe-based confocal laser endomicroscopy-targeted biopsy provided superior results in terms of the proportion of cancer cells in biopsy samples compared with WLE-targeted biopsy in gastric cancer with undifferentiated histology.
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Affiliation(s)
- Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Hyunki Kim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jeong Hyeon Jo
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyu Yeon Hahn
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jung-Ho Yoon
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Soon Young Kim
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hoon Noh
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Cheol Chung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Sun D, Wang Y, Jiang S, Wang G, Xin Y. MIIP is downregulated in gastric cancer and its forced expression inhibits proliferation and invasion of gastric cancer cells in vitro and in vivo. Onco Targets Ther 2018; 11:8951-8964. [PMID: 30588008 PMCID: PMC6294070 DOI: 10.2147/ott.s173393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Background MIIP is associated with cancer progression in various cancers. However, its expression pattern, and associated molecular mechanisms in gastric cancer (GC) progression are still mysterious. We aimed to explore the role of MIIP in proliferation and invasion of GC. Materials and methods MIIP expression was evaluated in human GC tissues and cell lines. Public clinical database of GC patients was used to probe the correlation between MIIP expression and prognosis of patients. The effects of forced MIIP expression on GC cells were determined by MTT, cell cycle distribution, colony formation, wound-healing and Transwell assays in vitro, as well as in vivo growth of subcutaneous tumor xenografts and metastasis of xenografted tumors to the lungs in mice. The expressions of GC progression-associated genes, including HOTAIR, MALAT1, HDAC6, AC-tubulin, and cyclin D1, were assessed by Western blotting or qRT-PCR. Results Both GC tissues and GC cell lines had lower MIIP expression. Higher level of MIIP in GC tissues predicts better survival in patients. Ectopic expression of MIIP in GC cell lines BGC823 and HGC27 induced G0/G1 cell cycle arrest and inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as the growth of GC xenografts and metastasis of tumors in vivo. Furthermore, overexpression of MIIP suppressed mRNA expressions of HOTAIR and MALAT1, decreased protein expression of HDAC6 and cyclin D1, and elevated AC-tubulin protein expression. Conclusion MIIP is a suppressor for GC progression and is a potential therapeutic target for treating GC.
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Affiliation(s)
- Dan Sun
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China,
| | - Yiwei Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China,
| | - Shanshan Jiang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China,
| | - Gang Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China,
| | - Yan Xin
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China,
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Wang JJ, Yang YC, Song YX, Gao P, Sun JX, Chen XW, Ma B, Wang ZN. Long non-coding RNA AB007962 is downregulated in gastric cancer and associated with poor prognosis. Oncol Lett 2018; 16:4621-4627. [PMID: 30214597 DOI: 10.3892/ol.2018.9169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 06/18/2018] [Indexed: 12/24/2022] Open
Abstract
A number of previous studies have reported that numerous long non-coding RNAs (lncRNAs) are dysregulated in gastric cancer (GC) and are involved in a series of biological and pathological processes. Total RNA was extracted from the cancerous tissues and matched normal adjacent tissues (NATs) of 96 patients with GC. The expression level of AB007962, a novel lncRNA, was determined by reverse transcription-quantitative polymerase chain reaction. The association between AB007962 expression levels and clinicopathological features were analyzed. Kaplan-Meier curves were also constructed in order to evaluate prognosis. Finally, publicly accessible data from The Cancer Genome Atlas was used to further verify the expression levels and clinical significance of AB007962. In conclusion, it was determined that the expression level of AB007962 was significantly reduced, compared with matched NATs in GC tissues (P=0.003). Survival analysis indicated that patients with intestinal-type GC with a reduced expression of AB007962 had a reduced prognosis, compared with those with an increased expression. AB007962 may be involved in the progression of GC and act as a novel prognostic biomarker for patients with GC, particularly in intestinal-type GC.
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Affiliation(s)
- Jia-Jun Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yu-Chong Yang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yong-Xi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Jing-Xu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiao-Wan Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Bin Ma
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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26
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Lin MT, Song HJ, Ding XY. Long non-coding RNAs involved in metastasis of gastric cancer. World J Gastroenterol 2018; 24:3724-3737. [PMID: 30197478 PMCID: PMC6127659 DOI: 10.3748/wjg.v24.i33.3724] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 05/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most frequently diagnosed malignant diseases. The molecular mechanisms of metastasis remain unclear. Recently, studies have shown that long non-coding RNAs (lncRNAs) play critical roles in metastasis. Therefore, deeper understanding of this mechanism could provide potential diagnostic tools and therapeutic targets for metastatic GC. This review focuses on dysregulated lncRNAs in GC metastases. Due to the identification of multiple diverse mechanisms involved in GC metastasis, we classified them into seven categories, including lncRNAs related to epithelial-mesenchymal transition, regulation of degradation of extracellular matrix, angiopoiesis, vasculogenic mimicry, and immunologic escape. As the TNM stage is pivotal for evaluating the severity and prognosis of GC patients, we summarize the lncRNAs relevant to lymphatic metastasis, distant metastasis and TNM classification. This review summarizes the lncRNAs related to metastasis, which may provide insight into the mechanisms, and provide potential markers for prognostic prediction and monitoring the relapse of GC.
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MESH Headings
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Movement/genetics
- Epithelial-Mesenchymal Transition/genetics
- Extracellular Matrix/genetics
- Extracellular Matrix/metabolism
- Extracellular Matrix/pathology
- Gene Expression Regulation, Neoplastic
- Humans
- Lymphatic Metastasis
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/pathology
- Prognosis
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/immunology
- RNA, Long Noncoding/metabolism
- Stomach Neoplasms/genetics
- Stomach Neoplasms/immunology
- Stomach Neoplasms/mortality
- Stomach Neoplasms/pathology
- Tumor Escape/genetics
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Affiliation(s)
- Meng-Ting Lin
- Medical School of Ningbo University, Ningbo 315000, Zhejiang Province, China
| | - Hao-Jun Song
- Gastroenterology Department, Ningbo First Hospital, Ningbo 315000, Zhejiang Province, China
| | - Xiao-Yun Ding
- Gastroenterology Department, Ningbo First Hospital, Ningbo 315000, Zhejiang Province, China
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27
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Botti G, De Chiara A, Di Bonito M, Cerrone M, Malzone MG, Collina F, Cantile M. Noncoding RNAs within the
HOX
gene network in tumor pathogenesis and progression. J Cell Physiol 2018; 234:395-413. [DOI: 10.1002/jcp.27036] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/25/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Gerardo Botti
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Anna De Chiara
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Maurizio Di Bonito
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Margherita Cerrone
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Maria Gabriella Malzone
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Francesca Collina
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Monica Cantile
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
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Lian D, Amin B, Du D, Yan W. Enhanced expression of the long non-coding RNA SNHG16 contributes to gastric cancer progression and metastasis. Cancer Biomark 2018; 21:151-160. [PMID: 29081409 DOI: 10.3233/cbm-170462] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This paper aimed to probe into the expression of long non-coding RNA (lncRNA) SNHG16 in human gastric cancer (GC) and its potential tumor biological functions. The expression of lncRNA SNHG16 was detected in GC and adjacent tissues and GC cell lines using qRT-PCR. GC MGC-803 cells were transfected with siRNA of lncRNA SNHG16, as well as blank and negative control. A series of experiments including CCK-8, flow cytometry, transwell, and wound healing assay were adopted to evaluate the effects of lncRNA SNHG16 on cell growth and metastasis. Besides, the nude mouse xenograft tumor model was established to draw tumor growth curve and measure tumor volume during treatments. TUNEL staining was used to determine the apoptosis rate of tissues. The expression of lncRNA SNHG16 in GC tissue, significantly associated with invasion depth, lymph node metastasis, TNM stage and histological differentiation (all P< 0.05), was upregulated compared with adjacent tissues. Transfected with siRNA of lncRNA SNHG16 inhibited GC MGC-803 cell proliferation, and arrested cells in the G0/G1 phase, and then promoted apoptosis rate with reduced cell invasion and shortened migration distance. Additionally, the nude mice xenograft presented lower tumor growth rate and weight loss alongside elevated apoptosis rate of tumor tissues. LncRNA SNHG16 is highly expressed in GC, while suppression of SNHG16 expression can inhibit proliferation, weaken invasion and migration of GC cells, and enhance apoptosis, to be a novel target for GC clinical treatment.
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Qi L, Liu F, Zhang F, Zhang S, Lv L, Bi Y, Yu Y. lncRNA NEAT1 competes against let-7a to contribute to non-small cell lung cancer proliferation and metastasis. Biomed Pharmacother 2018; 103:1507-1515. [DOI: 10.1016/j.biopha.2018.04.053] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 04/08/2018] [Accepted: 04/09/2018] [Indexed: 01/26/2023] Open
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Zhang Y, Wang LJ, Li WF, Zhang X, Yang XJ. The prognostic value of HOTAIR for predicting long-term prognosis of patients with gastrointestinal cancers. Medicine (Baltimore) 2018; 97:e11139. [PMID: 29952959 PMCID: PMC6039682 DOI: 10.1097/md.0000000000011139] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Increased expression of HOX transcription antisense RNA (HOTAIR) has been reported to be associated with unfavorable prognosis in cancer patients. Several studies have evaluated the significance of HOTAIR in the development and progression of gastrointestinal cancers (GICs). METHODS Systematic literature retrieval was performed by searching keywords in several electronic databases, including PubMed, Embase, Web of Science, CNKI, Springer, Google Scholar, and GEO. Relevant articles on association between HOTAIR expression levels and prognosis in patients with GIC were collected and screened with eligible criteria. The RevMan 5.2 software and Stata SE12.0 software was applied. RESULTS A total of 1297 patients from 15 eligible articles were included in this meta-analysis. The results revealed that increased expression of HOTAIR was significantly associated with shorter overall survival (OS) in GIC patients [hazard ratio (HR) = 1.93, 95% CI: 1.64-2.26], as well as poorer disease-free survival (DFS) (HR = 2.79; 95% CI: 1.38-5.63). Additionally, the pooled odds ratio (OR) indicated that increased HOTAIR was associated with clinicopathological parameters, including lymph node metastasis (OR = 2.48, 95% CI: 1.71-3.61), distant metastasis (OR = 4.34, 95% CI: 2.12-8.91), poor tumor differentiation (OR = 2.90, 95% CI: 1.45-5.80), lymphovascular invasion (OR = 2.86, 95% CI: 1.83-4.46), high depth of tumor invasion (OR = 2.07, 95% CI: 1.36-3.16), and poor clinical stage (OR = 2.72, 95% CI: 1.70-4.35). In survival analysis through the Kaplan-Meier plotter database, enhanced level of HOTAIR was associated with better OS and DFS in gastric cancer patients. CONCLUSIONS High expression level of HOTAIR was related to poor clinical outcome of GIC patients. The HOTAIR could be applied as potential biomarker for assessing the prognosis. Further well-designed studies should be performed to verify the clinical applications of HOTAIR in GIC.
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Affiliation(s)
- Yi Zhang
- Department of General Surgery, the First People's Hospital of Neijiang, Neijiang, Sichuan Province
| | - Li-juan Wang
- Department of Nephrology, ShangRao People 's Hospital, ShangRao
| | - Wei-feng Li
- Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P. R. China
| | - Xu Zhang
- Department of General Surgery, the First People's Hospital of Neijiang, Neijiang, Sichuan Province
| | - Xian-jin Yang
- Department of General Surgery, the First People's Hospital of Neijiang, Neijiang, Sichuan Province
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Vaziri F, Tarashi S, Fateh A, Siadat SD. New insights of Helicobacter pylori host-pathogen interactions: The triangle of virulence factors, epigenetic modifications and non-coding RNAs. World J Clin Cases 2018; 6:64-73. [PMID: 29774218 PMCID: PMC5955730 DOI: 10.12998/wjcc.v6.i5.64] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 02/09/2018] [Accepted: 03/07/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a model organism for understanding host-pathogen interactions and infection-mediated carcinogenesis. Gastric cancer and H. pylori colonization indicates the strong correlation. The progression and exacerbation of H. pylori infection are influenced by some factors of pathogen and host. Several virulence factors involved in the proper adherence and attenuation of immune defense to contribute the risk of emerging gastric cancer, therefore analysis of them is very important. H. pylori also modulates inflammatory and autophagy process to intensify its pathogenicity. From the host regard, different genetic factors particularly affect the development of gastric cancer. Indeed, epigenetic modifications, MicroRNA and long non-coding RNA received more attention. Generally, various factors related to pathogen and host that modulate gastric cancer development in response to H. pylori need more attention due to develop an efficacious therapeutic intervention. Therefore, this paper will present a brief overview of host-pathogen interaction especially emphases on bacterial virulence factors, interruption of host cellular signaling, the role of epigenetic modifications and non-coding RNAs.
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Affiliation(s)
- Farzam Vaziri
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Samira Tarashi
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Abolfazl Fateh
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
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32
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ncRNA-disease association prediction based on sequence information and tripartite network. BMC SYSTEMS BIOLOGY 2018; 12:37. [PMID: 29671405 PMCID: PMC5907179 DOI: 10.1186/s12918-018-0527-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background Current technology has demonstrated that mutation and deregulation of non-coding RNAs (ncRNAs) are associated with diverse human diseases and important biological processes. Therefore, developing a novel computational method for predicting potential ncRNA-disease associations could benefit pathologists in understanding the correlation between ncRNAs and disease diagnosis, treatment, and prevention. However, only a few studies have investigated these associations in pathogenesis. Results This study utilizes a disease-target-ncRNA tripartite network, and computes prediction scores between each disease-ncRNA pair by integrating biological information derived from pairwise similarity based upon sequence expressions with weights obtained from a multi-layer resource allocation technique. Our proposed algorithm was evaluated based on a 5-fold-cross-validation with optimal kernel parameter tuning. In addition, we achieved an average AUC that varies from 0.75 without link cut to 0.57 with link cut methods, which outperforms a previous method using the same evaluation methodology. Furthermore, the algorithm predicted 23 ncRNA-disease associations supported by other independent biological experimental studies. Conclusions Taken together, these results demonstrate the capability and accuracy of predicting further biological significant associations between ncRNAs and diseases and highlight the importance of adding biological sequence information to enhance predictions.
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Elsayed ET, Salem PE, Darwish AM, Fayed HM. Plasma long non-coding RNA HOTAIR as a potential biomarker for gastric cancer. Int J Biol Markers 2018; 33:1724600818760244. [PMID: 29683069 DOI: 10.1177/1724600818760244] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) Hox transcript antisense intergenic RNA ( HOTAIR) has been suggested to be implicated in gastric cancer tumorigenesis and progression; however, little is known about the role of the plasma HOTAIR in gastric cancer diagnosis and prognosis. OBJECTIVE The current study was aimed at investigating the clinical relevance of plasma long non-coding HOTAIR as a non-invasive diagnostic biomarker in gastric cancer. METHODS Plasma HOTAIR expression was measured in 50 patients with newly diagnosed gastric cancer and 50 age- and sex-matched healthy controls using quantitative reverse transcription polymerase chain reaction. RESULTS Plasma level of HOTAIR was significantly higher in gastric cancer patients compared with healthy controls ( P < 0.001). By using receiver operating characteristic curve analysis, it was found that plasma HOTAIR could diagnose gastric cancer with 88% sensitivity and 84% specificity. Furthermore, increased HOTAIR expression was associated with advanced tumor stages, higher grades, and metastasis. CONCLUSION Plasma HOTAIR might serve as a potential non-invasive biomarker for diagnosis of gastric cancer.
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Affiliation(s)
- Eman T Elsayed
- 1 Clinical Pathology Department, Alexandria University, Egypt
| | - Perihan E Salem
- 2 Internal Medicine Department, Alexandria University, Egypt
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Min L, Mu X, Tong A, Qian Y, Ling C, Yi T, Zhao X. The association between HOTAIR polymorphisms and cancer susceptibility: an updated systemic review and meta-analysis. Onco Targets Ther 2018; 11:791-800. [PMID: 29497311 PMCID: PMC5818844 DOI: 10.2147/ott.s151454] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES This work aims to explore whether HOX transcript antisense intergenic RNA (HOTAIR) polymorphisms are associated with cancer susceptibility. MATERIALS AND METHODS A comprehensive search was conducted for literature published from January 2007 to July 2017. The pooled odds ratios (ORs) and the corresponding 95% CIs were calculated using the Revman 5.2 software. Eighteen articles of 36 case-control studies were enrolled including six HOTAIR polymorphisms and 10 cancer types. RESULTS The results showed that cancer risk was elevated in recessive mutation of rs12826786 (TT vs CC+CT: OR =1.55, 95% CI =1.19, 2.03; TT+CT vs CC: OR =1.23, 95% CI =1.04, 1.46; TT vs CC: OR =1.67, 95% CI =1.24, 2.24; T vs C: OR =1.24, 95% CI =1.09, 1.40) and rs920778 (TT vs CC+CT: OR =1.73, 95% CI =1.30, 2.30; TT+CT vs CC: OR =1.40, 95% CI =1.16, 1.70; TT vs CC: OR =1.83, 95% CI =1.25, 2.68; T vs C: OR =1.37, 95% CI =1.18, 1.59), while the results for polymorphisms of rs7958904, rs4759314, rs874945, and rs1899663 were insignificant. The stratified results for Chinese population were consistent with the overall group analysis. CONCLUSION Our meta-analysis showed that HOTAIR polymorphisms of rs12826786 and rs920778 were correlated with increased cancer risk, while rs7958904, rs4759314, rs874945, and rs1899663 were not. More studies with different types of cancer are needed to confirm the findings.
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Affiliation(s)
- Ling Min
- Department of Gynecology and Obstetrics, Key laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Xiyan Mu
- Department of Gynecology and Obstetrics, Key laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - An Tong
- Department of Gynecology and Obstetrics, Key laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Yanping Qian
- Department of Gynecology and Obstetrics, Key laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Chen Ling
- Department of Gynecology and Obstetrics, Key laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Tao Yi
- Department of Gynecology and Obstetrics, Key laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Key laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
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Zhang Y, Zhou Y, Xu T, Tian W, Yang C, Wang X, Zhong S, Ran Q, Yang H, Zhu S. Clinical Value of Long Noncoding RNA HOTAIR as a Novel Biomarker in Digestive Cancers: A Meta-Analysis. Technol Cancer Res Treat 2018; 17:1533034618756783. [PMID: 29444619 PMCID: PMC5818090 DOI: 10.1177/1533034618756783] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/04/2017] [Accepted: 11/22/2017] [Indexed: 01/16/2023] Open
Abstract
HOX transcript antisense intergenic RNA has been reported to serve as an important prognostic biomarker in several types of cancers. However, the clinical value of HOX transcript antisense intergenic RNA in digestive cancers remains unclear. Therefore, we tried to investigate the clinical role of expression of HOX transcript antisense intergenic RNA as a prognostic indicator in digestive cancers by a meta-analysis. Literature collection was performed by searching the PubMed, Embase, Web of Science, and Cochrane Library databases (up to October 7, 2017). A quantitative meta-analysis was conducted to assess the eligible articles on the prognostic value of HOX transcript antisense intergenic RNA in digestive cancers. The pooled hazard ratios or odds ratios with 95% confidence intervals were used to evaluate the association between expression of HOX transcript antisense intergenic RNA and clinical outcomes. A total of 1844 patients from 22 studies were included in this meta-analysis. The results found a significant association between expression of HOX transcript antisense intergenic RNA and poor overall survival in digestive cancers (pooled hazard ratio = 2.19, 95% confidence interval, 1.86-2.57, P < .001). Furthermore, subgroup analysis showed that tumor type, region, Newcastle-Ottawa scale, and sample size did not alter the predictive value of HOX transcript antisense intergenic RNA as an independent factor for patients' survival. In addition, we also revealed that the clinicopathological characteristics such as differentiation, lymph node metastasis, tumor node metastasis (TNM) stage, and distant metastasis were positively related to expression of HOX transcript antisense intergenic RNA digestive cancers. In conclusion, our results suggested high expression of HOX transcript antisense intergenic RNA was correlated with poor clinical outcomes and may serve as a novel prognostic biomarker for patients with digestive cancers.
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Affiliation(s)
- Yun Zhang
- Southwest Medical University, Luzhou, Sichuan, China
| | - Yu Zhou
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Tian Xu
- Organ Transplant Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Wei Tian
- Southwest Medical University, Luzhou, Sichuan, China
| | - Chong Yang
- Organ Transplant Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Xiaoxiao Wang
- Organ Transplant Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Shan Zhong
- Organ Transplant Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Qin Ran
- Organ Transplant Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Hongji Yang
- Southwest Medical University, Luzhou, Sichuan, China
- Organ Transplant Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Shikai Zhu
- Organ Transplant Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
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Wu Y, Ding J, Sun Q, Zhou K, Zhang W, Du Q, Xu T, Xu W. Long noncoding RNA hypoxia-inducible factor 1 alpha-antisense RNA 1 promotes tumor necrosis factor-α-induced apoptosis through caspase 3 in Kupffer cells. Medicine (Baltimore) 2018; 97:e9483. [PMID: 29369172 PMCID: PMC5794356 DOI: 10.1097/md.0000000000009483] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Kupffer cells (KCs) play a crucial role in the pathogenesis of acute-on-chronic liver failure (ACLF) which is characterized by acute and severe disease in patients with preexisting liver disease and shows high mortality. Long noncoding RNAs (lncRNAs) are recently found to be involved in gene regulation. However, the mechanisms of how KCs are regulated by inflammatory factors, tumor necrosis factor-α (TNF-α), and whether lncRNAs are involved in the process remain largely unknown. Hence, we investigated the role of lncRNAs in the cytotoxicity of TNF-α on KCs.lncRNA array (The lncRNAs in the array are apoptosis-related lncRNAs reported in some research papers.) was used to identify lncRNAs related with liver fibrosis. Annexin V/protease inhibitor (PI) staining was used for detection of cell apoptosis. Real time-polymerase chain reaction was utilized for analysis of mRNA levels of lncRNA hypoxia-inducible factor 1 alpha-antisense RNA 1 (HIF1A-AS1) and apoptosis-related genes. Western blot was implied to the determination of lymphoid enhancer factor-1 (LEF-1).In this study, we found that HIF1A-AS1 could be upregulated by TNF-α by lncRNA array analysis and knockdown of HIF1A-AS1 significantly rescued cell apoptosis induced by TNF-α. Moreover, inhibition of HIF1A-AS1 markedly reduced mRNA level of caspase 3 which can be significantly enhanced by TNF-α. Furthermore, HIF1A-AS1 showed binding sites for LEF-1 and siRNA-mediated downregulation of LEF-1 decreased HIF1A-AS1 level in KCs treated with TNF-α.This study elucidates a new role of HIF1A-AS1 in TNF-α-induced cell apoptosis and provides potential therapeutic targets for ACLF.
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Li E, Zhao Z, Ma B, Zhang J. Long noncoding RNA HOTAIR promotes the proliferation and metastasis of osteosarcoma cells through the AKT/mTOR signaling pathway. Exp Ther Med 2017; 14:5321-5328. [PMID: 29285059 PMCID: PMC5740751 DOI: 10.3892/etm.2017.5248] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 07/27/2017] [Indexed: 11/05/2022] Open
Abstract
It has been proven that long non-coding (lnc)RNAs serve an important role in the tumorigenesis and development of several types of human malignancy. Previous studies have demonstrated that the lncRNA Hox transcript antisense intergenic RNA (HOTAIR) is involved in the development various types of cancer, including osteosarcoma (OS). However, the underlying mechanisms by which it has an affect are still largely unknown. In the present study, it was observed that the expression of HOTAIR was significantly upregulated in OS tissues compared to matched adjacent normal tissues, using reverse transcription-quantitative polymerase chain reaction analysis. HOTAIR was silenced using specific small interfering RNA (siRNA/siR), siR-HOTAIR, in order to investigate its role in regulating OS cell proliferation, apoptosis, migration and invasion. siR-HOTAIR inhibited the proliferation of MG-63 cells due to the induction of G1 phase arrest. In addition, the results of in vitro assays demonstrated that the suppression of HOTAIR in MG-63 OS cells significantly reduced migration and invasion. The silencing of HOTAIR also significantly decreased the expression of matrix metalloproteinase (MMP) 2 and MMP9, but increased E-cadherin expression through regulating the RAC α serine/threonine protein kinase-mammalian target of rapamycin signaling pathway. The results indicated that siR-HOTAIR may be a potential OS therapy.
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Affiliation(s)
- Enqi Li
- Department of Orthopaedic Trauma, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Zhe Zhao
- Department of Surgery of Traditional Chinese Medicine, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Baotong Ma
- Department of Orthopaedic Trauma, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Jinli Zhang
- Department of Orthopaedic Trauma, Tianjin Hospital, Tianjin 300211, P.R. China
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Wang M, Yang YO, Jin Q, Shang L, Zhang J. Function of miR-25 in the invasion and metastasis of esophageal squamous carcinoma cells and bioinformatical analysis of the miR-106b-25 cluster. Exp Ther Med 2017; 15:440-446. [PMID: 29250158 DOI: 10.3892/etm.2017.5358] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 09/06/2017] [Indexed: 01/07/2023] Open
Abstract
MicroRNAs (miRNAs/miRs) are a class of small, non-coding RNA molecules that serve a key function in carcinogenesis and tumor progression. Recent evidence indicates that miRNAs may act as powerful regulators of migration and invasion. The present study aimed to investigate the effect of miR-25 on the invasion and metastasis of KYSE-150 and EC109 esophageal squamous cell carcinoma (ESCC) cells, and predict the mechanism of this effect by bioinformatically analyzing the miR-106b-25 cluster. In order to alter the expression of miR-25 in the two cell lines, a miR-25 inhibitor or mimic were transfected into the cells, which were then studied via Transwell migration and invasion assays. Subsequently, the target genes of the miR-106b-25 cluster were predicted using miRanda, PicTar, TargetScan and miRTarbase, and the functions of the target genes were predicted via Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Then, a protein-protein interaction (PPI) network was produced using the Search Tool for the Retrieval of Interacting Genes. The results revealed that overexpressing miR-25 led to significantly increased cell migration and invasion in KYSE150 and EC109 cells. Suppressing miR-25 resulted in significantly decreased cell migration and invasion in KYSE150 cells, while the result was not significant in EC109 cells. Target genes of the miR-106b-25 cluster were significantly enriched in the biological process regulation of cellular metabolic process and several cancer-associated pathways, such as those for glioma and melanoma. The PPI network revealed that PTEN, TP53, MDM2, E2F1, PRMT5, MCM2, RB1, CDKN1A, SHAD7 and EZH2 may serve core roles within the network and associate with one another during the pathogenesis of ESCC. These results indicate that a high expression of miR-25 promotes the invasion and metastasis of ESCC cells, while the influence of low expression of miR-25 differs with cells with different degrees of differentiation. Invasion and metastasis are not effected in cells with poor differentiation, while they were decreased in well differentiated cells. Furthermore, PTEN, TP53, MDM2, E2F1, PRMT5, MCM2, RB1, CDKN1A, SHAD7 and EZH2 may be targeted by the miR-106b-25 cluster, and act together to regulate the development of ESCC.
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Affiliation(s)
- Meng Wang
- Medical Department, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Yangyang Ou Yang
- Department of Gastroenterology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Qingtao Jin
- Department of Gastroenterology, Jiaxiang People's Hospital, Jining, Shandong 272400, P.R. China
| | - Linlin Shang
- Department of Pharmacy, Jining No. 2 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Jian Zhang
- Department of Gastroenterology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
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Chen WM, Chen WD, Jiang XM, Jia XF, Wang HM, Zhang QJ, Shu YQ, Zhao HB. HOX transcript antisense intergenic RNA represses E-cadherin expression by binding to EZH2 in gastric cancer. World J Gastroenterol 2017; 23:6100-6110. [PMID: 28970725 PMCID: PMC5597501 DOI: 10.3748/wjg.v23.i33.6100] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 04/13/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To clarify the mechanisms of HOX transcript antisense intergenic RNA (HOTAIR) in gastric cancer (GC) migration and invasion.
METHODS Quantitative real-time polymerase chain reaction (qPCR) was used to detect the expression level of HOTAIR in GC tissues. The correlation of its expression with clinicopathological features was analyzed. Area under receiver operating characteristic curve (AUCROC) was constructed to evaluate the diagnostic value of HOTAIR. Wound-healing assay and Transwell assay were performed to detect the biological effects of HOTAIR in GC cells. qPCR, western blot and immunohistochemistry were used to evaluate the mRNA and protein expression of E-cadherin. RNA-binding protein immunoprecipitation was used for the analysis of EZH2 interactions with HOTAIR. Chromatin immunoprecipitation assay was performed to investigate direct interactions between EZH2 and E-cadherin.
RESULTS The expression of HOTAIR was up-regulated in GC tumorous tissues compared with the para-tumorous tissues (P < 0.001). Its over-expression was correlated with tumor-node-metastasis (TNM) stage (P = 0.024), tumor invasion (P = 0.018), lymph node metastasis (P = 0.023), and poor prognosis (P < 0.001). Multivariate Cox regression analysis confirmed expression of HOTAIR as an independent predictor of overall survival (P = 0.033), together with TNM stage (P = 0.002) and lymph node metastasis (P = 0.002). The AUCROC was up to 0.709 (95%CI: 0.623-0.785, P < 0.001). Knockdown of HOTAIR by siRNA in GC cells suppressed the migration and invasion of GC cells. Significantly negative correlation between HOTAIR and E-cadherin was found in GC tissues and cell lines, and HOTAIR contributed to the regulation of E-cadherin through binding to EZH2 with the E-cadherin promoter.
CONCLUSION HOTAIR may play a pivotal role in tumor cell migration and invasion. It can be used as a potential diagnostic and prognostic biomarker for GC.
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MESH Headings
- Antigens, CD
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cadherins/genetics
- Cadherins/metabolism
- Cell Line, Tumor
- Cell Movement/genetics
- Chromatin Immunoprecipitation
- Enhancer of Zeste Homolog 2 Protein/genetics
- Enhancer of Zeste Homolog 2 Protein/metabolism
- Female
- Follow-Up Studies
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Humans
- Immunohistochemistry
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Invasiveness/genetics
- Neoplasm Staging
- Prognosis
- Promoter Regions, Genetic
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Real-Time Polymerase Chain Reaction
- Stomach Neoplasms/genetics
- Stomach Neoplasms/mortality
- Stomach Neoplasms/pathology
- Up-Regulation
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Affiliation(s)
- Wen-Ming Chen
- Department of Oncology, Jining NO.1 People’s Hospital, Jining 272011, Shandong Province, China
| | - Wei-Dong Chen
- Department of Oncology, Jining NO.1 People’s Hospital, Jining 272011, Shandong Province, China
| | - Xue-Mei Jiang
- Traditional Chinese Medicine Hospital of Jining City, Jining 272011, Shandong Province, China
| | - Xue-Feng Jia
- Department of Oncology, Jining NO.1 People’s Hospital, Jining 272011, Shandong Province, China
| | - Hong-Mei Wang
- The Special Hospital Serving the Municipal Officials of Jining City, Jining 272011, Shandong Province, China
| | - Qiu-Jie Zhang
- Department of Oncology, Jining NO.1 People’s Hospital, Jining 272011, Shandong Province, China
| | - Yong-Qian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu Province, China
| | - Hai-Bo Zhao
- Department of Oncology, Jining NO.1 People’s Hospital, Jining 272011, Shandong Province, China
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Li J, Wang J, Zhong Y, Guo R, Chu D, Qiu H, Yuan Z. HOTAIR: a key regulator in gynecologic cancers. Cancer Cell Int 2017; 17:65. [PMID: 28649178 PMCID: PMC5480152 DOI: 10.1186/s12935-017-0434-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 05/27/2017] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) play critical roles in the initiation and progression of human cancers. HOX transcript antisense RNA (HOTAIR) is an lncRNA localized to the mammalian HOXC gene cluster; it can interact with polycomb repressive complex 2 and the lysine-specific histone demethylase/CoREST/REST complex, and it manipulates the expression of various genes. HOTAIR promotes tumor invasion and metastasis by silencing tumor suppressors, and activating oncogenes and signaling pathways. HOTAIR is deregulated in many human cancers; despite its critical roles in health and disease, the underlying mechanisms governing HOTAIR function are unknown. In this review, we summarize the recent findings on the roles of HOTAIR in gynecologic cancers.
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Affiliation(s)
- Jing Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Jing Wang
- Department of Obstetrics and Gynecology, Yantai Yuhuangding Hospital Affiliated to the Medical College of Qingdao University, Yantai, 264000 China
| | - Yan Zhong
- Department of Gynecological Oncology, Linyi Tumor Hospital, Linyi, 276001 China
| | - Ruixia Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Danxia Chu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Haifeng Qiu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Zhongfu Yuan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
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Min SN, Wei T, Wang XT, Wu LL, Yu GY. Clinicopathological and prognostic significance of homeobox transcript antisense RNA expression in various cancers: A meta-analysis. Medicine (Baltimore) 2017; 96:e7084. [PMID: 28591050 PMCID: PMC5466228 DOI: 10.1097/md.0000000000007084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Increased expression of the homeobox (HOX) transcript antisense RNA (HOTAIR) has been reported in multiple types of malignancies and enhances the proliferation and migration of cancer cells. However, the association between HOTAIR expression and tumor progression and prognosis remains controversial. We performed a meta-analysis to clarify the association between the expression of HOTAIR and the clinicopathological features and prognosis in different cancers. METHODS A systematic search of the PubMed, Web of Science, EMBASE, and Ovid databases was conducted, up to September 2016, for eligible studies involving HOTAIR expression and malignancies. The odds ratios (ORs), hazard ratios (HRs), and corresponding 95% confidence intervals (CIs) were calculated using fixed- or random-effect models. Any publication bias was evaluated using Begg and Egger tests, and adjusted using the trim and fill method if a bias existed. RESULTS A total of 4116 patients from 44 studies were included in our meta-analysis. The results showed that high HOTAIR expression was associated with an advanced clinical tumor stage (OR = 3.90, 95% CI = 3.02-5.03, P < .001), lymph node metastasis (OR = 3.11, 95% CI = 2.15-4.49, P < .001), poor differentiation of the tumor (OR = 1.56, 95% CI = 1.01-2.41, P = .03), and worse prognosis (HR = 2.16, 95% CI = 1.73-2.69, P < .001) in different cancer types. HOTAIR expression was more predictive in monitoring the clinical tumor stage of patients and there was no significant heterogeneity or publication bias found in the analysis. CONCLUSION Our meta-analysis suggests that HOTAIR is positively correlated with tumor development and negatively correlated with clinical outcome. Thus, an increase in HOTAIR expression may be a potential biomarker for tumor progression and evaluation of prognosis.
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Affiliation(s)
- Sai-Nan Min
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing
| | - Tai Wei
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing
| | - Xiang-Ting Wang
- School of Life Science, University of Science and Technology of China, Hefei
| | - Li-Ling Wu
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Guang-Yan Yu
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing
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Yu D, Zhang C, Gui J. RNA-binding protein HuR promotes bladder cancer progression by competitively binding to the long noncoding HOTAIR with miR-1. Onco Targets Ther 2017; 10:2609-2619. [PMID: 28553126 PMCID: PMC5440069 DOI: 10.2147/ott.s132728] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The elevated expressions of RNA-binding protein HuR and long noncoding HOX transcript antisense RNA (HOTAIR) are observed in numerous cancers. And HuR often exerts its promotive effects on tumorigenesis via binding to AU-rich elements in target transcripts and thus regulating the expression of target transcripts. However, the roles and related mechanisms of HuR/HOTAIR in bladder cancer progression have never been formally tested. Here, we found that the expression level of HuR was higher in clinical bladder cancer samples than in normal adjacent samples, mirroring that of HOTAIR, and their expression showed strong correlation. Knockdown of HuR/HOTAIR in bladder cancer inhibited cell proliferation, migration, invasion, and promoted cell apoptosis. Notably, HuR interacted and stabilized HOTAIR mRNA and knockdown of HuR decreased HOTAIR expression. Additionally, HOTAIR was identified as a potential target of miR-1 in bladder cancer cells. Interestingly, overexpression of HOTAIR enhanced HuR expression and increased cytoplasmic accumulation of HuR, thus enhancing HOTAIR expression in turn. But mutation of miR-1 binding site in HOTAIR canceled the effects of HOTAIR on HuR expression. Overall, we identified a regulatory loop between HOTAIR and HuR during the progression of bladder cancer, which could be exploited to curb bladder cancer progression.
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Affiliation(s)
- Dapeng Yu
- Department of Urinary Surgery, the Jining No 1 People's Hospital, Jining
| | - Chao Zhang
- Department of Urinary Surgery, the Qujing No 1 People's Hospital, Qujing, People's Republic of China
| | - Junqing Gui
- Department of Urinary Surgery, the Qujing No 1 People's Hospital, Qujing, People's Republic of China
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The long noncoding RNA HOTAIR activates the Hippo pathway by directly binding to SAV1 in renal cell carcinoma. Oncotarget 2017; 8:58654-58667. [PMID: 28938586 PMCID: PMC5601682 DOI: 10.18632/oncotarget.17414] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Accepted: 03/14/2017] [Indexed: 12/05/2022] Open
Abstract
The long noncoding RNA HOTAIR promotes the development and progression of several tumors. Here, the clinical significance and role of HOTAIR in renal cell carcinoma (RCC) tumorigenesis were explored. The results showed that increased expression of HOTAIR predicted a poor prognosis of RCC after surgery. HOTAIR promoted RCC cell proliferation and growth in vitro and in vivo. The expressions of HOTAIR and Salvador homolog 1 (SAV1) were inversely correlated in clinical RCC samples. HOTAIR downregulated SAV1 by directly binding to the SAV1 protein and enhanced histone H3K27 methylation. Loss of function of SAV1 activated the Hippo pathway. HOTAIR could be a potential therapeutic target in RCC.
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44
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Ülger Y, Dadaş E, Yalinbaş Kaya B, Sümbül AT, Genç A, Bayram S. The analysis of lncRNA HOTAIR rs12826786 C>T polymorphism and gastric cancer susceptibility in a Turkish population: lack of any association in a hospital-based case-control study. Ir J Med Sci 2017; 186:859-865. [PMID: 28342055 DOI: 10.1007/s11845-017-1596-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 03/14/2017] [Indexed: 01/28/2023]
Abstract
BACKGROUND The HOX transcript antisense intergenic RNA (HOTAIR), a well-known long noncoding RNA (lncRNA), has been widely identified to participate in pathogenesis of multiple cancers. An aberrant up-regulation and biological functions have been observed in gastric cancer (GC). A common single nucleotide polymorphism (SNP) (rs12826786 C>T) at the HOTAIR has been reported to influence HOTAIR expression, but its association with GC has yet to be investigated in Turkish population. AIM The aim of the present study was to investigate whether HOTAIR rs12826786 C>T polymorphism could be involved in the risk of GC susceptibility in Turkish population. METHODS We genotyped HOTAIR rs12826786 C>T polymorphism in 312 Turkish individuals including 105 GC patients and 207 healthy controls matched on age and gender by a Real-Time Polymerase Chain Reaction (PCR) with the TaqMan assay. RESULTS No statistically significant differences were found in the allele or genotype distributions of the HOTAIR rs12826786 C>T polymorphism among GC and healthy control subjects (P > 0.05). CONCLUSIONS Our results demonstrate that the HOTAIR rs12826786 C>T polymorphism has not been in any major role in genetic susceptibility to gastric carcinogenesis, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.
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Affiliation(s)
- Y Ülger
- Department of Gastroenterology, Education and Research Hospital, Adıyaman University, 02040, Adıyaman, Turkey
| | - E Dadaş
- Faculty of Medicine, Department of Thoracic Surgery, Adıyaman University, 02040, Adıyaman, Turkey
| | - B Yalinbaş Kaya
- Department of Gastroenterology, Isparta State Hospital, 32100, Isparta, Turkey
| | - A T Sümbül
- Faculty of Medicine, Department of Medical Oncology, Başkent University, 01250, Adana, Turkey
| | - A Genç
- Vocational School of Health Services, Adıyaman Univesity, 02040, Adıyaman, Turkey
| | - S Bayram
- Department of Nursing, Adıyaman School of Health, Adıyaman University, 02040, Adıyaman, Turkey.
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Wu X, Zhou J, Wu Z, Chen C, Liu J, Wu G, Zhai J, Liu F, Li G. miR-101-3p Suppresses HOX Transcript Antisense RNA (HOTAIR)-Induced Proliferation and Invasion Through Directly Targeting SRF in Gastric Carcinoma Cells. Oncol Res 2017; 25:1383-1390. [PMID: 28251884 PMCID: PMC7841108 DOI: 10.3727/096504017x14879366402279] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
miR-101-3p has been identified as a tumor suppressor in several cancers, but its exact role in gastric adenocarcinoma is still largely unknown. In this study, we found that, compared with the RGM-1 human normal gastric epithelial cells, miR-101-3p was significantly downregulated in all six human gastric adenocarcinoma cell lines, including BGC-823, MNK-45, MGC-803, SGC-7901, AGS, and HGC-27. Overexpression of miR-101-3p suppressed both the proliferation and invasion of AGS gastric adenocarcinoma cells, and knockdown of miR-101-3p displayed the opposite effect. In addition, miR-101-3p could directly target and suppress the expression of the serum response factor (SRF) gene, which is a transcription factor of HOTAIR, a well-characterized tumor promoter lncRNA. miR-101-3p negatively regulated SRF-mediated transcription of HOTAIR. Moreover, silencing of either SRF or HOTAIR could counteract the promotion of gastric adenocarcinoma cell proliferation and invasion by miR-101-3p inhibition. Our findings indicate that miR-101-3p suppresses HOTAIR-induced proliferation and invasion through directly targeting SRF in gastric carcinoma cells.
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Lee NK, Lee JH, Ivan C, Ling H, Zhang X, Park CH, Calin GA, Lee SK. MALAT1 promoted invasiveness of gastric adenocarcinoma. BMC Cancer 2017; 17:46. [PMID: 28077118 PMCID: PMC5225525 DOI: 10.1186/s12885-016-2988-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 12/09/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Gastric cancer is the second leading cause of cancer globally, and the mechanism of its pathogenesis is still largely unknown. Recently, non-coding RNAs have been recognized to promote metastasis in various cancers, including gastric cancer. METHODS We found that metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is upregulated in gastric cancer tissue compared to adjacent normal tissue, as determined by microarray and subsequent qRT-PCR, then investigated the impact of MALAT1 on apoptosis, cell proliferation, and the cell cycle to dissect the carcinogenesis of gastric cancer, and examined mechanisms of invasion and metastasis. Expression of MALAT1 and U6 was determined by SYBR qRT-PCR in nine-teen gastric cancer cell lines and fifty fresh samples of cancer tissue and adjacent tissues. Downregulation of MALAT1 was accomplished with two different siRNAs. Cell proliferation was determined after treatment with these siRNAs. FACS using PI/Annexin-V staining was carried out. To analyze the invasiveness, a scratch wound-healing assay and a Matrigel invasion assay were performed. Cancer related gene expression assay was done after transfection of siR- MALAT1. RESULTS The expression of MALAT1 was significantly elevated in various gastric cancer cell lines and gastric cancer tissues compared to normal cell lines and tissues (p < 0.01). siR-MALAT1 significantly reduced viable AGS cell numbers and induced apoptosis (p < 0.05). Deep invasion of tumor (advanced T stages) was more common in the high MALAT1-level group (p = 0.039). siR-MALAT1 significantly decreased AGS cell invasiveness and migration. siR-MALAT1 reduced expression of snail and N-cadherin, and elevated E-cadherin. The Wnt/β-catenin related genes were significantly decreased by transfection of siRNA MALAT1. MALAT1 is involved in gastric carcinogenesis via inhibition of apoptosis and promotes invasiveness via the epithelial-to-mesenchymal transition. CONCLUSIONS In our study, we found that deregulation of MALAT1 could be involved in both tumorigenesis and invasiveness in gastric cancer cells.
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Affiliation(s)
- Na Keum Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Jung Hwa Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Cristina Ivan
- Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Hui Ling
- Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Xinna Zhang
- Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Chan Hyuk Park
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - George A Calin
- Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
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Lee NK, Lee JH, Kim WK, Yun S, Youn YH, Park CH, Choi YY, Kim H, Lee SK. Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors. Oncotarget 2016; 7:75307-75318. [PMID: 27659532 PMCID: PMC5342742 DOI: 10.18632/oncotarget.12171] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 09/12/2016] [Indexed: 12/12/2022] Open
Abstract
HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 cells, we demonstrated that HOTAIR repressed apoptosis, was associated with cell cycle progression, and controlled the invasion and migration of GIST cells. Using a gene expression microarray and lists of HOTAIR-associated candidate genes, we suggested that protocadherin 10 (PCDH10) is a key molecule. PCDH10 expression was significantly decreased in GIST-T1 and GIST882 cells, possibly as a consequence of hypermethylation. We observed that HOTAIR induced PCDH10 methylation in a SUZ12-dependent manner. In this study, we found that the malignant character of GISTs was initiated and amplified by PCDH10 in a process regulated by HOTAIR. In summary, our findings imply that PCDH10 and HOTAIR may be useful markers of disease progression and therapeutic targets.
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Affiliation(s)
- Na Keum Lee
- Yonsei Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Jung Hwa Lee
- Yonsei Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Won Kyu Kim
- Department of pathology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Seongju Yun
- Department of pathology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Young Hoon Youn
- Yonsei Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Chan Hyuk Park
- Yonsei Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Yun Young Choi
- Yonsei Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Hogeun Kim
- Department of pathology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
| | - Sang Kil Lee
- Yonsei Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, South Korea
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Song W, Zou SB. Prognostic role of lncRNA HOTAIR in esophageal squamous cell carcinoma. Clin Chim Acta 2016; 463:169-173. [PMID: 27810266 DOI: 10.1016/j.cca.2016.10.035] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 10/27/2016] [Accepted: 10/29/2016] [Indexed: 11/20/2022]
Abstract
BACKGROUND HOX transcript antisense intergenic RNA (HOTAIR) may be implicated in cancer development and progression. Clinical studies have suggested that HOTAIR may be related to poor prognosis in esophageal squamous cell carcinoma (ESCC). This study was designed to clarify the prognostic role of HOTAIR in ESCC. METHODS MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the China National Knowledge Infrastructure (CNKI) databases were searched to identify studies evaluating the prognostic significance of HOTAIR in ESCC. Pooled hazard ratios (HRs) for overall survival (OS), lymph node metastasis (LNM), and cancer stage were calculated using fixed-effects/random-effects models. RESULTS A total of 510 patients from five studies were included. Meta-analysis revealed that high HOTAIR expression was significantly correlated with poor OS (HR, 2.37; 95% CI, 1.80-3.11; P<0.00001) and positive LNM (RR, 1.96; 95% CI, 1.07-3.60; P=0.03). CONCLUSION Elevated lncRNA HOTAIR indicated a poor prognosis for patients with ESCC, and it may also have predictive potential for ESCC metastasis.
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Affiliation(s)
- Wei Song
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No.1 Minde Road, Nanchang, China
| | - Shu-Bing Zou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No.1 Minde Road, Nanchang, China.
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Zhang FF, Luo YH, Wang H, Zhao L. Metastasis-associated long noncoding RNAs in gastrointestinal cancer: Implications for novel biomarkers and therapeutic targets. World J Gastroenterol 2016; 22:8735-8749. [PMID: 27818589 PMCID: PMC5075548 DOI: 10.3748/wjg.v22.i39.8735] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 07/05/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs), a newly discovered class of ncRNA molecules, have been widely accepted as crucial regulators of various diseases including cancer. Increasing numbers of studies have demonstrated that lncRNAs are involved in diverse physiological and pathophysiological processes, such as cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Aberrant expression of lncRNAs frequently occurs in gastrointestinal cancer and plays emerging roles in cancer metastasis. In this review, we focus on and outline the regulatory functions of recently identified metastasis-associated lncRNAs, and evaluate the potential roles of lncRNAs as novel diagnostic biomarkers and therapeutic targets in gastrointestinal cancer.
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50
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Qiu H, Wang X, Guo R, Liu Q, Wang Y, Yuan Z, Li J, Shi H. HOTAIR rs920778 polymorphism is associated with ovarian cancer susceptibility and poor prognosis in a Chinese population. Future Oncol 2016; 13:347-355. [PMID: 27690631 DOI: 10.2217/fon-2016-0290] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM The aim of this study was to determine if HOTAIR rs920778 polymorphism is associated with ovarian cancer susceptibility and prognosis. MATERIALS & METHODS The data were obtained from two independent groups including 329 ovarian cancer patients and 680 cancer-free, age-matched women. Blood samples were collected and genomic DNA was extracted for genotyping. RESULTS TT genotype and T allele of HOTAIR rs920778 were significantly associated with a decreased ovarian cancer risk (p = 0.0004 and p < 0.0001, respectively), which associated with advanced tumor stage, lymph node metastasis and poor prognosis. Moreover, TT and TC carriers obtained a much shorter survival (p = 0.026). CONCLUSION These findings propose that HOTAIR rs920778 polymorphism influences ovarian cancer susceptibility and prognosis, and further studies are warranted in other populations.
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Affiliation(s)
- Haifeng Qiu
- Department of Obstetrics & Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.,Ovarian & Cervical Disease Clinical Treatment Center of Henan Province, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Xiujuan Wang
- Department of Obstetrics & Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.,Ovarian & Cervical Disease Clinical Treatment Center of Henan Province, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Ruixia Guo
- Department of Obstetrics & Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.,Ovarian & Cervical Disease Clinical Treatment Center of Henan Province, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Qiuli Liu
- Department of Obstetrics & Gynecology, the Affiliated Hospital of Jiangnan University & the Fourth's People's Hospital of Wuxi, Wuxi, 214062, China
| | - Yuan Wang
- Department of Obstetrics & Gynecology, the Affiliated Hospital of Jiangnan University & the Fourth's People's Hospital of Wuxi, Wuxi, 214062, China
| | - Zhongfu Yuan
- Department of Obstetrics & Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.,Ovarian & Cervical Disease Clinical Treatment Center of Henan Province, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Jing Li
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Huirong Shi
- Department of Obstetrics & Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.,Ovarian & Cervical Disease Clinical Treatment Center of Henan Province, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
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