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Long noncoding RNA CASC2 suppresses esophageal squamous cell carcinoma progression by increasing SOCS1 expression.

ABSTRACT: Objective:Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related deaths worldwide. Emerging evidence suggests the involvement of long noncoding RNAs (lncRNAs) in tumorigenesis. LncRNA Cancer Susceptibility Candidate 2 (CASC2) has been demonstrated to act as a tumor suppressor contributing to the development and progression of several cancers. However, the functional significance and underlying mechanism of CASC2 in ESCC progression has not been well elucidated. Methods:The expression levels of CASC2 in ESCC tissues were detected by qRT-PCR. CASC2 overexpression and knockdown models were established and used to investigate the functional role of CASC2 in ESCC cells. RIP, RNA pull-down and dual-luciferase assay was used to detect the association between CASC2 and miR-155. The interaction between CASC2 and Suppressor Of Cytokine Signaling 1 (SOCS1) was assessed by RIP and RNA pull-down assays. Results:In the present study, we found that CASC2 was significantly downregulated in ESCC tissues and positively correlated with overall survival time of patients with ESCC. Functional assays demonstrated that CASC2 suppressed proliferation, migration and invasion, as well as enhanced drug sensitivity in ESCC cells. Mechanistically, CASC2 inhibited ESCC progression by upregulating the expression of SOCS1 via two different ways. CASC2 acted as competing endogenous RNA (ceRNA) for miR-155 to post-transcriptionally increase SOCS1 expression. On the other hand, CASC2 was capable of interacting with SOCS1 protein and suppressing its degradation. Conclusion:Conclusively, these results demonstrated that CASC2 could exert as a tumor suppressive lncRNA in ESCC progression via regulating SOCS1.

SUBMITTER: Sun K

PROVIDER: S-EPMC6842511 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Long noncoding RNA CASC2 suppresses esophageal squamous cell carcinoma progression by increasing SOCS1 expression.

Sun Ke K Zhang Guangping G Zhang Guangping G

Cell & bioscience 20191109

<h4>Objective</h4>Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related deaths worldwide. Emerging evidence suggests the involvement of long noncoding RNAs (lncRNAs) in tumorigenesis. LncRNA Cancer Susceptibility Candidate 2 (CASC2) has been demonstrated to act as a tumor suppressor contributing to the development and progression of several cancers. However, the functional significance and underlying mechanism of CASC2 in ESCC progression has not been well eluc ...[more]

PMID: 31728180

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Project description:BackgroundRecently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular carcinoma (HCC) remain unclear.MethodsThe expression of CASC2 and miR-367 in HCC specimens and cell lines were detected by real-time PCR. Western blotting and immunohistochemistry were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers in HCC. Transwell assays were used to determine migration and invasion of HCC cells. A mouse model for lung metastasis was established to evaluated HCC metastasis in vivo. The correlation among CASC2, miR-367 and F-box and WD repeat domain containing 7 (FBXW7) were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay.ResultsHere, CASC2 expression was significantly downregulated in HCC tissues, especially in aggressive and recurrent cases. In accordance, CASC2 underexpression was observed in HCC cell lines compared to LO2. In vitro and in vivo experiments revealed that CASC2 inhibited migration and invasion of HCC cells. Additionally, CASC2 repressed EMT process of HCC cells. Further studies demonstrated that CASC2 could function as a competing endogenous RNA (ceRNA) by sponging miR-367 in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-367 promoted migration, invasion and EMT progression of HCC cells. Moreover, further investigations disclosed that FBXW7 was a downstream target of miR-367 and CASC2 prohibited EMT progression and subsequently exerted its anti-metastatic effects via CASC2/miR-367/FBXW7 axis in HCC cells. Clinically, CASC2 underexpression and miR-367 overexpression were closely correlated with the metastasis-associated clinicopathologic features. Notably, CASC2 low-expressing and miR-367 high-expressing HCC patients showed the poorest clinical outcome.ConclusionsOverall, we conclude that the CASC2/miR-367/FBXW7 axis may be a ponderable and promising therapeutic target for HCC.

Project description:BackgroundLong noncoding RNAs (lncRNAs) are implicated in the oncogenesis and metastasis of multiple human cancers. Nonetheless, the precise molecular mechanisms underlying the oncogenic role of lncRNA in esophageal squamous cell carcinoma (ESCC) remains to be clarified.MethodsThe expression of GK intronic transcript 1 (GK-IT1) was analyzed using ESCC RNA-seq data from The Cancer Genome Atlas database. Quantitative real-time PCR was used to measure the expression of GK-IT1 in ESCC clinical samples and cells. The correlation between GK-IT1 expression and clinicopathological variables was examined using chi-squared tests. Kaplan-Meier survival and Cox regression analyses were employed to generate the survival curve and assess the prognostic value of GK-IT1. Functional experiments were utilized to explore the role of GK-IT1 in promoting cell migration, invasion, proliferation, and suppressing apoptosis and autophagy in ESCC. To understand the mechanism, an RNA pulldown assay, RNA immunoprecipitation, agarose gel electrophoresis, immunofluorescence, and co-immunoprecipitation assays were used.ResultsIn this study we identified an unreported lncRNA, termed GK-IT1 that was aberrantly overexpressed in ESCC tissues and cells. GK-IT1 was closely associated with advanced clinical stage, and it was an independent prognostic indicator of ESCC. Functional assays verified that GK-IT1 significantly promoted ESCC proliferation, invasion, and migration, and suppressed ESCC apoptosis and autophagy. Furthermore, tumorigenesis experiments in nude mice indicated that GK-IT1 promoted ESCC tumor growth and metastasis. Mechanistically, GK-IT1 competitively bound to mitogen-activated protein kinase 1 (MAPK1) to prevent the interaction between dual specificity phosphatase 6 (DUSP6) and MAPK1, thereby controlling the phosphorylation of MAPK1 and promoting ESCC progression.ConclusionOur study revealed that GK-IT1 competed with DUSP6 to attenuate the interaction between DUSP6 and MAPK1, leading to activation of the ERK/MAPK pathway, thereby promoting progression of ESCC. Our research indicated that GK-IT1 served as a novel potential target for the diagnosis and treatment of ESCC.

Project description:BackgroundEsophageal cancer, especially esophageal squamous cell carcinoma (ESCC), is a common malignant tumor of the digestive tract. Bufalin is an effective anti-tumor compound. However, little is known about the regulatory mechanisms of Bufalin in ESCC. To investigate the effect and molecular mechanism of Bufalin on the proliferation, migration and invasion of ESCC cells will provide a more reliable basis for the application of Bufalin in clinical tumor therapy.MethodsFirst, the half-inhibitory concentration (IC50) of Bufalin was evaluated by Cell Counting Kit-8 (CCK-8) assays. In vitro, the effects of Bufalin on the proliferation of the ECA109 cells was measured using CCK-8 and 5-ethynyl-2'-deoxyuridine assays. Wound-healing and transwell assays were used to evaluate the effects of Bufalin on the migration and invasion of the ECA109 cells. Further, to determine the mechanisms underlying the Bufalin-mediated suppression of cell progression in ESCC, total RNA was extracted from negative control (NC) and Bufalin treated cells to perform RNA-sequencing (RNA-seq) to screen for abnormally expressed genes. In vivo, the ECA 109 cells were subcutaneously injected into BALB/c nude mice to determine the effects of Bufalin on tumor cell proliferation. The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3), signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3) protein expression levels in the ECA109 cells were detected by Western blot.ResultsThe CCK-8 assays showed that the IC50 of Bufalin was 200 nM. The proliferation, migration, and invasion ability of the ECA109 cells was significantly inhibited in the Bufalin group in a concentration-dependent manner. In vivo, the Xenograft tumor model showed that Bufalin decreased the tumor volume and weight of the subcutaneous tumors. The RNA-seq results showed that the expression of PIAS3 was upregulated in the Bufalin group. Additionally, down-regulation of PIAS3 decreased the inhibition of STAT3, thereby increasing p-STAT3 expression. Finally, PIAS3 knockdown reversed the inhibitory effects of Bufalin on the proliferation, migration, and invasion of the ECA109 cells.ConclusionsBufalin may inhibit the proliferation, migration, and invasion of the ECA109 cells through the PIAS3/STAT3 signaling pathway.

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Long noncoding RNA CASC2 suppresses esophageal squamous cell carcinoma progression by increasing SOCS1 expression.

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Long noncoding RNA CASC2 suppresses esophageal squamous cell carcinoma progression by increasing SOCS1 expression.

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