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Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling.

ABSTRACT: SH3GL2 (Src homology 3 (SH3) domain GRB2-like 2) is mainly expressed in the central nervous system and regarded as a tumour suppressor in human glioma. However, the molecular mechanism of the SH3GL2 protein involved in malignant behaviours of human glioma has not been elucidated. In this study, we tried to investigate the role of SH3GL2 in glioma cell migration and invasion and explore its underlined molecular mechanism. Firstly, we discovered that the protein level of SH3GL2 was widely decreased in the human glioma patients, especially in high-grade glioma tissues. Then, we determined the role of SH3GL2 in migration and invasion of glioma cells upon SH3GL2 knocking down and overexpressing. It was showed that knocking down of SH3GL2 promoted the migration and invasion of glioma cells, whereas overexpression of SH3GL2 inhibited them. Further study on molecular mechanism disclosed that silencing of SH3GL2 obviously activated the STAT3 (signal transducer and activator of transcription 3) signalling thereby promoting the expression and secretion of MMP2. On the contrary, overexpression of SH3GL2 had opposite effect. Taken together, the above results suggest that SH3GL2 suppresses migration and invasion behaviours of glioma cells through negatively regulating STAT3/MMP2 signalling and that loss of SH3GL2 may intensify the STAT3/MMP2 signalling thereby contributing to the migration and invasion of glioma cells.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC5661104 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling.

Zhu Yufu Y Zhang Xiang X Wang Lei L Ji Zhe Z Xie Manyi M Zhou Xinyu X Liu Zhiyi Z Shi Hengliang H Yu Rutong R

Journal of cellular and molecular medicine 20170504 11

SH3GL2 (Src homology 3 (SH3) domain GRB2-like 2) is mainly expressed in the central nervous system and regarded as a tumour suppressor in human glioma. However, the molecular mechanism of the SH3GL2 protein involved in malignant behaviours of human glioma has not been elucidated. In this study, we tried to investigate the role of SH3GL2 in glioma cell migration and invasion and explore its underlined molecular mechanism. Firstly, we discovered that the protein level of SH3GL2 was widely decrease ...[more]

PMID: 28470949

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Project description:Background:Thymosin ?1 (T?1) is one of the most commonly used immunomodulators for metastatic non-small-cell lung cancer (NSCLC) patients in many countries. Despite the identification of the direct suppression on cancer cell proliferation, little is known about its effect on metastasis and metastasis-related signaling such as matrix metalloproteinases (MMPs) and programmed cell death ligand 1 (PD-L1). Materials and methods:NSCLC cells with distinguishing PD-L1 expression levels were treated with T?1. siRNAs were used to knockdown PD-L1. Cell migration and invasion abilities were evaluated by wound-healing and transwell assays. The xenograft model by BALB/c nude mice was constructed to test the inhibitory effect of T?1 on metastasis in vivo. The expression levels of metastasis-related signaling pathways and key molecules were assessed by Western blot (WB) and quantitative reverse transcriptase PCR (qRT-PCR). Results:T?1 significantly suppressed cell migration and invasion in PD-L1 high-expressing H1299, NL9980, and L9981 cells but not in PD-L1 low-expressing A549 or SPC-A-1 cells. This difference was demonstrated by mouse model in vivo as well. Knocking down of PD-L1 significantly impaired the inhibition of cell migration and invasion caused by T?1 treating in PD-L1 high-expressing cells. Besides, T?1 inhibited the activation and translocation of STAT3 and the expression of MMP2 in PD-L1 high-expressing NSCLC cells. Moreover, the treatment of STAT3 activator colivelin could partly reverse the T?1-induced MMP2 suppression and the migration phenotype. Conclusion:T?1 significantly suppresses migration and invasion in PD-L1 high-expressing NSCLC cells compared with PD-L1 low-expressing NSCLC cells in vitro and in vivo, through the downregulation of STAT3-MMP2 signaling. These different responses to T?1, together with the depiction of T?1-induced signaling changes, suggest a potential benefit of T?1 for PD-L1-positive NSCLC patients, enlightening the combination of T?1 with target therapy or immune checkpoint inhibitors.

Dataset Information

Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling.

Publications

Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling.

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