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Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9.

ABSTRACT: BACKGROUND:Novel therapies tailored to the molecular composition of esophageal squamous cell carcinoma (ESCC) are needed to improve patient survival. We investigated the regulatory network of long intergenic non-protein coding RNA, regulator of reprogramming (linc-ROR) and sex-determining region Y-box 9 (SOX9), and their therapeutic relevance in ESCC. METHODS:Linc-ROR and SOX9 expression were examined in ESCC specimens, cell lines, and cultured tumorspheres. We investigated the effects of linc-ROR on SOX9 expression and malignant phenotypes by CCK8, colony formation, Transwell, and sphere-forming assay. The linc-ROR/SOX9 interaction mediated by multiple microRNAs (miRNAs) was confirmed by bioinformatic analysis, luciferase assay, and RNA-binding protein immunoprecipitation, transient overexpression or antagonizing endogenous candidate miRNAs. The effect of linc-ROR depletion on tumor growth was assessed by xenograft assay. RESULTS:A positive correlation between linc-ROR and SOX9 expression was found in clinical ESCC specimens (r = 0.562, P = 0.036), cell lines, and tumorspheres. Silencing of linc-ROR significantly inhibited cell proliferation, motility, chemoresistance, and self-renewal capacity. Mechanistically, linc-ROR modulating the derepression of SOX9 by directly sponging multiple miRNAs including miR-15b, miR-33a, miR-129, miR-145, and miR-206. Antagonizing these miRNAs counteracted with linc-ROR silencing, whereas the repression of SOX9 abrogated malignant phenotypes induced by the cocktail of miRNA inhibitors. Moreover, linc-ROR disruption was sufficient to attenuate tumor growth and cancer stem cell marker expression in vivo. CONCLUSIONS:Our results demonstrate that the linc-ROR-miRNA-SOX9 regulatory network may represent a novel therapeutic target for ESCC.

SUBMITTER: Wang L

PROVIDER: S-EPMC5727696 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9.

Wang Lianghai L Yu Xiaodan X Zhang Zhiyu Z Pang Lijuan L Xu Jiang J Jiang Jinfang J Liang Weihua W Chai Yuhang Y Hou Jun J Li Feng F

Journal of experimental & clinical cancer research : CR 20171213 1

<h4>Background</h4>Novel therapies tailored to the molecular composition of esophageal squamous cell carcinoma (ESCC) are needed to improve patient survival. We investigated the regulatory network of long intergenic non-protein coding RNA, regulator of reprogramming (linc-ROR) and sex-determining region Y-box 9 (SOX9), and their therapeutic relevance in ESCC.<h4>Methods</h4>Linc-ROR and SOX9 expression were examined in ESCC specimens, cell lines, and cultured tumorspheres. We investigated the ef ...[more]

PMID: 29237490

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. Due to its high morbidity and mortality rates, it is urgent to find a molecular target that contributes to esophageal carcinogenesis and progression. In this research, we aimed to investigate the functions of Latent transforming growth factor β binding protein 1(LTBP1) in ESCC progression and elucidate the underlying mechanisms.MethodsThe tandem mass tag-based quantitative proteomic approach was applied to screen the differentially expressed proteins (DEPs) between 3 cases of ESCC tumor samples and paired normal tissues. Then the DEPs were validated in human ESCC tissues using western blot assays and GEPIA database respectively. The expression level of LTBP1 was detected in 152 cases of ESCC tissues and paired normal tissues. Loss-of-function assays were performed to detect the function of LTBP1 in vivo and in vitro. Immunofluorescence and Western blot assays were used to detect the expression of apoptosis, epithelial-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) markers.ResultsA total of 39 proteins were screened to be up-regulated (ratio > 2.0) in all three ESCC tissues. The results of immunohistochemistry assays indicated that the expression level of LTBP1 was higher in ESCC tissues than that in paired normal tissues (p < 0.001). Overexpression of LTBP1 was positively associated with lymphatic metastasis in ESCC (p = 0.002). Down-regulation of LTBP1 inhibited the invasion and migration as well as metastatic abilities in vitro and in vivo. It was also observed the down-regulation of LTBP1 not only decreased the mesenchymal phenotypes but also inhibited TGFβ-induced EMT in ESCC cells. We further found that down-regulation of LTBP1 enhanced ESCC cells' sensitivity to 5-FU treatment. Inhibition of LTBP1 expression could also attenuate induction of CAFs transformation and restrain fibroblast express fibronectin (FN1) in ESCC cells.ConclusionOverexpression of LTBP1 was associated with lymph node metastasis in ESCC. Our results indicated that LTBP1 not only increased the malignant behaviors of ESCC cells but also induced EMT and CAFs transformation. Our studies suggested an oncogenic role of LTBP1 in ESCC progression and it may serve as a potential therapeutic target for ESCC patients.

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Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9.

Publications

Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9.

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