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DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma

ABSTRACT: Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor me-tastasis while inhibiting tumor growth, which is a critical issue in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 is a key gene that mediates cispla-tin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin aggravated DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently in-hibits cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cispla-tin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168498 | GEO | 2021/03/09

REPOSITORIES: GEO

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Project description:Increasing evidence has shown that chemoresistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long noncoding RNAs (lncRNAs) play pivotal roles in tumour metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin resistance induced EMT and metastasis are not well understood. In this study, a Chemotherapy Induced Long non-coding RNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells.Upregulation of CILA1 promotes EMT, invasiveness and chemoresistance in TSCC cells, whereas the inhibition of CILA1 expression induces MET and chemosensitivity and inhibis the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/ β-catenin signalling pathway.High CILA1 expression levels and low levesl of phosphorylated β-catenin were closely associated with cisplatin-resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for Increasing evidence has shown that chemoresistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long noncoding RNAs (lncRNAs) play pivotal roles in tumour metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin resistance induced EMT and metastasis are not well understood. In this study, a Chemotherapy Induced Long non-coding RNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells.Upregulation of CILA1 promotes EMT, invasiveness and chemoresistance in TSCC cells, whereas the inhibition of CILA1 expression induces MET and chemosensitivity and inhibis the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/ β-catenin signalling pathway.High CILA1 expression levels and low levesl of phosphorylated β-catenin were closely associated with cisplatin-resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for the chemosensitivity of TSCC tumours and a therapeutic target for TSCC treatment.

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DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma

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