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Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial-mesenchymal transition in lung adenocarcinoma.

ABSTRACT: Non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma, is the leading cause of death from lung malignancies and has a poor prognosis due to metastasis. Suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown to be involved in growth control. Here, we show that SOCS2 were significantly downregulated in tumour foci in NSCLC patients. The expression levels of SOCS2 significantly correlated with clinical stage, lymph node metastasis, histological subtype and survival time. In particular, the decreased expression of SOCS2 significantly associated with advanced pathological stage, lymph node metastasis and shorter overall survival in lung adenocarcinoma patients. In vivo animal results showed that overexpressed SOCS2 attenuated the metastatic characteristics of lung adenocarcinoma, including by inhibiting the epithelial-mesenchymal transition (EMT). Further functional studies indicated that insulin-like growth factor 1 (IGF1)-driven migratory and invasive behaviours of lung adenocarcinoma cells can be partially suppressed by exogenous SOCS2 expression. Investigations into the mechanism of action revealed that SOCS2 inhibits EMT by inactivating signal transducer and activator of transcription 3 (STAT3) and STAT5 via the competitive binding of SOCS2 to the STAT binding sites on IGF1R. Altogether, our results reveal an important role for SOCS2 dysregulation in the pathogenicity of lung adenocarcinoma, suggest its potential use as a biomarker for diagnosing lung adenocarcinoma, and paves the way to develop novel therapy targets as the axis of SOCS2-IGF1R-STAT in lung adenocarcinoma.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC5861121 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial-mesenchymal transition in lung adenocarcinoma.

Zhou Yue Y Zhang Zhilei Z Wang Ning N Chen Jizheng J Zhang Xu X Guo Min M John Zhong Li L Wang Qian Q

Cell death & disease 20180401 4

Non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma, is the leading cause of death from lung malignancies and has a poor prognosis due to metastasis. Suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown to be involved in growth control. Here, we show that SOCS2 were significantly downregulated in tumour foci in NSCLC patients. The expression levels of SOCS2 significantly correlated with clinical stage, lymph ...[more]

PMID: 29559623

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Project description:BackgroundLung cancer is the most common and lethal malignancy worldwide. TCTP is highly expressed in various cancers including lung cancer. Epithelial-mesenchymal transition (EMT) could increase cancer cell invasion. Whether TCTP's expression is associated with EMT in lung adenocarcinoma is largely unknown.MethodsSeveral Gene Expression Omnibus datasets were used to analyze the correlation between TCTP expression and overall survival of lung adenocarcinoma patients by Kaplan-Meier survival analysis. Then, 24 surgically removed fresh lung adenocarcinoma tissue samples and paired paracancer tissue samples were used to analyze the correlation between TCTP expression and tumor stage by immunohistochemical analysis. Furthermore, stable cell lines were generated using lentiviral transduction systems to knock down or overexpress TCTP in A549 cells. Cell migration and invasion were measured by scratch and transwell assays, and EMT marker proteins such as α-SMA, ZEB1, and E-cadherin were quantitated by Western blot. The expression levels of miR-200a, miR-141, and miR-429 were determined by real-time quantitative PCR, and their target genes were predicted by an online database miRTarBase. The interaction between TCTP and these genes was analyzed by String database and visualized by Cytoscape.ResultsTCTP was highly expressed in tumor tissues compared to paracancer tissues. The expression of TCTP was associated with shorter overall survival. TCTP knockdown experiment in A549 cells suggested that TCTP knockdown could decrease the migration and invasion of lung cancer cells, and the expression level of ZEB1 and α-SMA, but increase the expression of E-cadherin and p53. Vice versa, overexpression of TCTP could increase the migration and invasion of cancer cells, and the expression level of ZEB1 and α-SMA, but decrease the expression of E-cadherin and p53. Furthermore, we found the expression of miR-200a, miR-141, and miR-429 was associated with TCTP expression.ConclusionTCTP promotes EMT in lung adenocarcinoma, and this effect may be associated with miR-200 family members like miR-200a, miR-141, and miR-429.

Dataset Information

Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial-mesenchymal transition in lung adenocarcinoma.

Publications

Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial-mesenchymal transition in lung adenocarcinoma.

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