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DCST1-AS1 Promotes TGF-?-Induced Epithelial-Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1.

ABSTRACT: Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype, and the primary systemic treatment strategy involves conventional chemotherapy. DC-STAMP domain containing 1-antisense 1 (DCST1-AS1) is a long non-coding RNA that promotes TNBC migration and invasion. Studying the role of DCST1-AS1 in promoting epithelial-mesenchymal transition (EMT) and chemoresistance will provide a new strategy for TNBC therapy. In the present study, we found that DCST1-AS1 regulates the expression or secretion of EMT-related proteins E-cadherin, snail family zinc finger 1 (SNAI1), vimentin, matrix metallopeptidase 2 (MMP2), and matrix metallopeptidase 9 (MMP9). Interference with DCST1-AS1 impaired TGF-?-induced TNBC cell invasion and migration. DCST1-AS1 directly binds to ANXA1 in BT-549 cells and affects the expression of ANXA1. DCST1-AS1 enhances TGF-?/Smad signaling in BT-549 cells through ANXA1 to promote EMT. The combination of DCST1-AS1 and ANXA1 also contributes to enhancement of the resistance of BT-549 cells to doxorubicin and paclitaxel. In conclusion, DCST1-AS1 promotes TGF-?-induced EMT and enhances chemoresistance in TNBC cells through ANXA1, and therefore represents a potentially promising target for metastatic breast cancer therapy.

SUBMITTER: Tang L

PROVIDER: S-EPMC7080863 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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DCST1-AS1 Promotes TGF-β-Induced Epithelial-Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1.

Tang Li L Chen Yuli Y Chen Huanhuan H Jiang Pan P Yan Linping L Mo Dongping D Tang Xun X Yan Feng F

Frontiers in oncology 20200312

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype, and the primary systemic treatment strategy involves conventional chemotherapy. DC-STAMP domain containing 1-antisense 1 (DCST1-AS1) is a long non-coding RNA that promotes TNBC migration and invasion. Studying the role of DCST1-AS1 in promoting epithelial-mesenchymal transition (EMT) and chemoresistance will provide a new strategy for TNBC therapy. In the present study, we found that DCST1-AS1 ...[more]

PMID: 32226772

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Project description:Background: DC-STAMP domain containing 1-antisense 1 (DCST1-AS1) is a long noncoding RNA (lncRNA) that is up-regulated in triple-negative breast cancer (TNBC) tissues. Here, we attempt to investigate the oncogenic property of DCST1-AS1. Methods: LncRNA microarrays were used to detect differentially expressed lncRNA in cancerous tissues. Fluorescence in situ hybridization assay was used to detect the distribution of DCST1-AS1 in BT-549 and MDA-MB-231 cells. Lentiviral systems, inhibitors, siRNA and overexpression plasmids were used for gain- and loss-of-function experiments. Colony formation assay, wound healing assay, CCK8 assay, transwell assay, and flow cytometry assay were used to study the function of DCST1-AS1. Luciferase assay was used to verify the binding of MYC to the promoter region and the binding of miR-873-5p to DCST1-AS1. RNA immunoprecipitation assay was used to verify that argonaute 2 binds to both miR-873-5p and DCST1-AS1. Western blotting was used to measure changes in protein expression. Results: Consistent with the microarray results, we found that DCST1-AS1 was up-regulated in both TNBC tissue samples and cell lines. DCST1-AS1 was positively correlated with distant metastasis and histopathological grades. DCST1-AS1 is distributed in both nucleus and cytoplasm. Knockdown of DCST1-AS1 inhibits TNBC cell proliferation and metastasis, while overexpression of DCST1-AS1 promotes TNBC cell proliferation and metastasis. We confirmed that DCST1-AS1 expression in TNBC cells is regulated by MYC. Furthermore, we found that DCST1-AS1 is negatively correlated with miR-873-5p in TNBC tissues and is a direct target gene of miR-873-5p. Argonaute 2 is involved in the binding of DCST1-AS1 and miR-873-5p and promotes the degradation of DCST1-AS1. The interaction of DCST1-AS1 with miR-873-5p ultimately up-regulated the expression of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), MYC, CD44 and lymphoid enhancer binding factor 1 (LEF1). Conclusions: DCST1-AS1 is activated by MYC and is degraded by binding to miR-873-5p, thereby upregulating the expression of miR-873-5p downstream proteins IGF2BP1, MYC, LEF1 and CD44. MYC, DCST1-AS1 and miR-873-5p form a positive regulatory loop to promote TNBC cell proliferation and metastasis.

Dataset Information

DCST1-AS1 Promotes TGF-?-Induced Epithelial-Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1.

Publications

<i>DCST1-AS1</i> Promotes TGF-β-Induced Epithelial-Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1.

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