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HOTAIR Contributes to the Carcinogenesis of Gastric Cancer Via Zhang et al. Cell Death and Disease (2020) 11:780 https://doi.org/10.1038/s41419-020-02946-4 Cell Death & Disease ARTICLE Open Access HOTAIR contributes to the carcinogenesis of gastric cancer via modulating cellular and exosomal miRNAs level Jie Zhang1, Wei-qing Qiu1,HongyiZhu1,HuaLiu1, Jian-hua Sun1, Yuanwen Chen1, Huojian Shen1, Chang-lin Qian1 and Zhi-yong Shen1 Abstract Gastric cancer (GC) is one of the most leading malignancies. Long noncoding RNA is related to GC. In this study, 11 miRNAs in the exosomes and six lncRNAs in the tissues was examined by qRT-PCR. Correlation analysis was used to analyze the relationship between miRNAs in exosome and lncRNAs in the tissues. Four miRNAs level in GC tissues were examined by qRT-PCR. MTT was used to determine cell viability. Flow cytometry was used to quantify the apoptotic cells. Transwell assay was used to examine the migration and invasion capacity. Dual-luciferase assay was used to examine the interaction between HOTAIR and miR-30a or -b. Capillary formation was used to determine the capillary formation capacity. Weak negative correlations were found between HOTAIR and miR-30a or -b in GC tissue samples. Interestingly, strong negative correlations were identified between the HOTAIR level in GC tissue samples and the miR- 30a or -b levels in plasma exosomes. HOTAIR knockdown GC cells exhibited decreased migration, invasion, proliferation, and upregulated apoptosis, which released more miR-30a and -b into the exosomes. KRAS was upregulated when co-cultured with exosomes from HOTAIR overexpressed cells, and promoted GC cells proliferation, 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; migration, and invasion. Meanwhile, HUVEC cells expressed increased VEGF-A and formatted more capillaries. Subsequently, we identified a 10mer target site of miR-30a or -b in HOTAIR sequence, and the overexpression of HOTAIR induced the degradation of miR-30a or -b, indicating a ceRNA role of HOTAIR. We report the negative correlation between the plasma miRNAs level and GC tissue HOTAIR expression for the first time and unveiled the ceRNA role of HOTAIR in GC. HOTAIR functions as an onco-lncRNA regulating the level of miR-30a and -b in both GC cells and exosomes. These findings may give insight into understanding the mechanism of GC pathogenesis and provide new biomarkers for clinical diagnosis. Introduction Furthermore, a large number of patients are diagnosed Gastric cancer (GC), also known as stomach cancer, is with advanced gastric cancer and have a poor prognosis. – one of the most common cancer in the world1 3. Due to Thus, more sensitive markers for GC early stage diagnosis, the advancement of medical technology, the mortality of tumor grading, prognostic evaluation after treatment is gastric cancer have gradually decreased, but there are still urgently needed. nearly 700,000 confirmed mortalities annually worldwide4. MicroRNAs (miRNAs) are a group of gene expression negative regulators, which repress gene expression at post-transcriptional level by binding to the 3′-untrans- Correspondence: Chang-lin Qian ([email protected])or Zhi-yong Shen ([email protected]) lated region (UTR) region of target mRNA directly. 1Department of General Surgery, South Campus, Ren Ji Hospital, School of MiRNAs are involved in gene function modulation during Medicine, Shanghai Jiao Tong University, 201112 Shanghai, China many different biological processes, such as proliferation, These authors contributed equally: Jie Zhang, Wei-qing Qiu These authors jointly supervised this work: Chang-lin Qian, Zhi-yong Shen apoptosis, and differentiation. It has been verified that Edited by G. Calin © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Zhang et al. Cell Death and Disease (2020) 11:780 Page 2 of 15 miRNA expression profile is altered during the initiation, interaction between miRNA and HOTAIR induces progression, and metastasis of human cancers and it is instability of miRNAs was still unknown. believed that miRNAs may function both as tumor sup- In this study, the level of 11 candidate miRNAs in the pressors and oncogenes in cancer development5,6. miR- plasma exosomes and the expression of four lnRNAs in NAs alteration has also been found in the serum samples the GC tissue samples were detected in 87 GC patients. of GC patients, which has the potential to be used as Negative correlation was found between the expression of biomarker for GC diagnosis and classification. 3 miRNAs and HOTAIR. We also identified HOTAIR Exosomes are a kind of extracellular vesicle (EV), the functions as a ceRNA modulate the tumor micro- diameter of which ranging from 40–100 nm, secreted by environment by control the level exosomal miRNAs. cells, and transfer signal molecule to targeted cells. Tumor-derived exosomes containing key regulators Materials and methods modulating the process of tumor migration, metastases, Patients and samples angiogenesis, and so on. Meanwhile, a group of miRNAs A total of 87 specimens of primary gastric adenocarci- was found packaged by exosomes and exosomal miRNAs’ noma, corresponding adjacent nontumorous gastric tissue level in serum has been confirmed relates to the devel- and plasma samples were obtained between 2012 and opment and prognosis of cancers7,8. 2014 at Renji Hospital, Shanghai Jiao Tong University Recent genetic study indicates that more than 70% of School of Medicine. Tissue samples were immediately the human genome is transcribed to RNA, but only about snap-frozen in liquid nitrogen and stored in a refrigerator 1% is protein coding, suggesting that a large group of at −80 °C. About 0.1 g tumor and adjacent control tissues RNAs function as gene expression regulators regulating a were selected for RNA extraction followed by qRT-PCR. – relatively small amount of effectors9 11. Long noncoding Control plasma samples were obtained from 87 age and RNA (lncRNAs) is a group of more than 200 nt non- sex matched healthy participants. Tumor staging was protein coding RNA molecules, that have been identified determined according to the tumor–node–metastasis as key regulators of diverse cellular processes including classification system of the American Joint Committee on development, differentiation, and cell fate as well as dis- Cancer, 7th edition23. Follow-up was performed every ease pathogenesis12,13. lncRNAs can serve as enhancers or 6 months by specially trained staff according to standard repressors directly modulating target genes expression; epidemiologic procedures. All samples were Random and they can also function as molecular decoys, scaffold selected. Patients and controls were acquired with and signal mediators14. informed consent, under the protocol approved by Renji HOX antisense intergenic RNA(HOTAIR) is 2158 Hospital, Shanghai Jiao Tong University School of Med- nucleotides long non-protein coding RNA, which is icine research ethics committee. The clinical character- transcribed from the antisense strand of the HOXC gene istics were shown in Table 1 and Table S1. cluster15. HOTAIR has been found as a oncogene over- expressed in both solid tumors and hematologic malig- Plasmid construction nancies. In gastric cancer, HOTAIR expression was higher For HOTAIR overexpression, full length of 2364 in tumor when compared with the adjacent noncancerous HOTAIR sequence was amplified by RT-PCR and cloned tissues, and was significantly correlated with lymph node into pcDNA3.1 vector between Kpn I and EcoR I sites. For metastasis, TNM stage, and invasion16,17. High HOTAIR dual-luciferase assay, wild-type or mutant HOTAIR expression was also used as a predictor of poor overall sequence was cloned into pmirGLO vector, following survival in patients with GC18. HOTAIR was shown to firefly luciferase coding region. directly bind to and inhibit miR-126, thereby promoting To construct KRAS reporter vector, a 521 nucleotides the expression of vascular endothelial growth factor A segment of human KRAS 3′UTR containing the miR-30a/ (VEGF-A) and PI3-K regulatory subunit beta19. HOTAIR b target site was cloned into pmirGLO vector between binds to the multiprotein chromatin modifying complex Xho I and Xba I sites. PRC2, which is responsible for H3K27me3, an epigenetic To construct VEGF-A reporter vector, full length of hallmark of repressed chromatin, thereby repressing fur- 1.9 kb VEGF-A 3′UTR sequence was cloned into pmir- ther the expression of miR-34a in GC16. GLO vector, between Xho I and Xba I sites. It is reported in human cells and fruit fly that, the extensive base pairing between miRNAs and cognate Exosome isolation target mRNAs promotes miRNA decay20. However, EVs were extracted from cell culture supernatant or in vitro and in vivo assays with Caenorhabditis elegans plasma sample using Puro Exo exosome isolation kit showed that targets can also protect miRNAs from active (101Bio, USA) following the manufacture’s instruction. degradation21,22. HOTAIR has been reported relates to Briefly, plasma sample was centrifuge at 3000 × g for abnormal miRNAs level in tumors, but whether the 10 min at 20 °C to remove cells and debris, followed by Official journal of the Cell Death Differentiation Association Zhang et al. Cell Death and Disease (2020) 11:780 Page 3 of 15 Table 1 The association of exosome miR-30a and -b level with clinicopathological features.
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