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Long noncoding RNA NEAT1 drives aggressive endometrial cancer progression via miR-361-regulated networks involving STAT3 and tumor microenvironment-related genes

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Title: Long noncoding RNA NEAT1 drives aggressive endometrial cancer progression via miR-361-regulated networks involving STAT3 and tumor microenvironment-related genes
Authors: Dong, Peixin Browse this author →KAKEN DB
Xiong, Ying Browse this author
Yue, Junming Browse this author
Xu, Daozhi Browse this author
Ihira, Kei Browse this author
Konno, Yosuke Browse this author →KAKEN DB
Kobayashi, Noriko Browse this author
Todo, Yukiharu Browse this author →KAKEN DB
Watari, Hidemichi Browse this author →KAKEN DB
Keywords: NEAT1
Endometrial cancer metastasis
Tumor microenvironment
Issue Date: 8-Jul-2019
Publisher: BioMed Central
Journal Title: Journal of Experimental & Clinical Cancer Research
Volume: 38
Start Page: 295
Publisher DOI: 10.1186/s13046-019-1306-9
Abstract: Background: High-grade endometrioid and serous endometrial cancers (ECs) are an aggressive subtype of ECs without effective therapies. The reciprocal communication between tumor cells and their surrounding microenvironment drives tumor progression. Long noncoding RNAs (lncRNAs) are key mediators of tumorigenesis and metastasis. However, little is known about the role of lncRNAs in aggressive EC progression and tumor microenvironment remodeling. Methods: We performed an array-based lncRNA analysis of a parental HEC-50 EC cell population and derivatives with highly invasive, sphere-forming, and paclitaxel (TX)-resistant characteristics. We characterized the roles of the lncRNA NEAT1 in mediating aggressive EC progression in vitro and in vivo and explored the molecular events downstream of NEAT1. Results: We identified 10 lncRNAs with upregulated expression (NEAT1, H19, PVT1, UCA1, MIR7-3HG, SNHG16, HULC, RMST, BCAR4 and LINC00152) and 10 lncRNAs with downregulated expression (MEG3, GAS5, DIO3OS, MIR155HG, LINC00261, FENDRR, MIAT, TMEM161B-AS1, HAND2-AS1 and NBR2) in the highly invasive, sphere-forming and TX-resistant derivatives. NEAT1 expression was markedly upregulated in early-stage EC tissue samples, and high NEAT1 expression predicted a poor prognosis. Inhibiting NEAT1 expression with small hairpin RNAs (shRNAs) diminished cellular proliferation, invasion, sphere formation, and xenograft tumor growth and improved TX response in aggressive EC cells. We showed that NEAT1 functions as an oncogenic sponge for the tumor suppressor microRNA-361 (miR-361), which suppresses proliferation, invasion, sphere formation and TX resistance by directly targeting the oncogene STAT3. Furthermore, miR-361 also suppressed the expression of multiple prometastatic genes and tumor microenvironment-related genes, including MEF2D, ROCK1, WNT7A, VEGF-A, PDE4B, and KPNA4. Conclusions: NEAT1 initiates a miR-361-mediated network to drive aggressive EC progression. These data support a rationale for inhibiting NEAT1 signaling as a potential therapeutic strategy for overcoming aggressive EC progression and chemoresistance.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 董 培新

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