Dataset Information

MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model.

ABSTRACT: Lung epithelial-mesenchymal transition (EMT) plays an important role in silicosis fibrosis. The reverse process of EMT is mesenchymal-epithelial transition (MET), which is viewed as an anti-EMT therapy and is a good target toward fibrosis. MicroRNAs (miRNAs) have emerged as potent regulators of EMT and MET programs, and, hence, we tested the miRNA expression using microarray assay and investigated their roles in silica-induced EMT in lung epithelial cells. We found that miRNA-29b (miR-29b) was dynamically downregulated by silica and influenced the promotion of MET in RLE-6TN cells. Furthermore, delivery of miR-29b to mice significantly inhibited silica-induced EMT, prevented lung fibrosis, and improved lung function. Together, our results clearly demonstrated that miR-29b acted as a novel negative regulator of silicosis fibrosis-inhibited lung fibrosis, probably by promoting MET and by suppressing EMT in the lung. These findings may represent a new potential therapeutic target for treating silicosis fibrosis.

SUBMITTER: Sun J

PROVIDER: S-EPMC6282658 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model.

Sun Jingping J Li Qiuyue Q Lian Ximeng X Zhu Zhonghui Z Chen Xiaowei X Pei Wanying W Li Siling S Abbas Ali A Wang Yan Y Tian Lin L

Molecular therapy. Nucleic acids 20181106

Lung epithelial-mesenchymal transition (EMT) plays an important role in silicosis fibrosis. The reverse process of EMT is mesenchymal-epithelial transition (MET), which is viewed as an anti-EMT therapy and is a good target toward fibrosis. MicroRNAs (miRNAs) have emerged as potent regulators of EMT and MET programs, and, hence, we tested the miRNA expression using microarray assay and investigated their roles in silica-induced EMT in lung epithelial cells. We found that miRNA-29b (miR-29b) was d ...[more]

PMID: 30529807

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Project description:Simple Summary Chemotherapeutic agents including cisplatin promote tumor metastasis while inhibiting tumor growth, which still represents a major obstacle for some patients in clinical practices. This study demonstrated that cisplatin induced epithelial-mesenchymal transition and tumor metastasis in lung adenocarcinoma. Further bioinformatic analysis showed that DCBLD2 may play a key role in metastasis after platinum chemotherapy. In terms of mechanism, DCBLD2 stabilized β-catenin through phosphorylation and inactivation of GSK3β, leading to the disintegration of the destruction complex of β-catenin. The accumulated β-catenin transported to the nucleus and promoted the expression of metastasis-related genes. In addition, cisplatin markedly enhanced DCBLD2 (Discoidin, CUB and LCCL domain containing 2) expression via ERK/AP-1 axis. Importantly, DCBLD2-specific siRNAs encapsulated by nanoparticles strikingly inhibited cisplatin-induced metastasis in tumor-bearing mice. Taken together, DCBLD2 mediates cisplatin-induced metastasis and DCBLD2 inhibition is a promising treatment option for preventing chemotherapy-induced metastasis. Abstract Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor metastasis while inhibiting tumor growth, which is a critical issue for certain patients 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 (Discoidin, CUB and LCCL domain containing 2) is a key gene that mediates cisplatin-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 enhanced DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently inhibit cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cisplatin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.

Dataset Information

MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model.

Publications

MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model.

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