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RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma.

ABSTRACT: RNA-binding proteins provide a new layer of posttranscriptional regulation of RNA during cancer progression. We identified RNA-binding motif protein 47 (RBM47) as a target gene of transforming growth factor (TGF)-? in mammary gland epithelial cells (NMuMG cells) that have undergone the epithelial-to-mesenchymal transition. TGF-? repressed RBM47 expression in NMuMG cells and lung cancer cell lines. Expression of RBM47 correlated with good prognosis in patients with lung, breast and gastric cancer. RBM47 suppressed the expression of cell metabolism-related genes, which were the direct targets of nuclear factor erythroid 2-related factor 2 (Nrf2; also known as NFE2L2). RBM47 bound to KEAP1 and Cullin 3 mRNAs, and knockdown of RBM47 inhibited their protein expression, which led to enhanced binding of Nrf2 to target genomic regions. Knockdown of RBM47 also enhanced the expression of some Nrf2 activators, p21/CDKN1A and MafK induced by TGF-?. Both mitochondrial respiration rates and the side population cells in lung cancer cells increased in the absence of RBM47. Our findings, together with the enhanced tumor formation and metastasis of xenografted mice by knockdown of the RBM47 expression, suggested tumor-suppressive roles for RBM47 through the inhibition of Nrf2 activity.

SUBMITTER: Sakurai T

PROVIDER: S-EPMC5036161 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma.

Sakurai T T Isogaya K K Sakai S S Morikawa M M Morishita Y Y Ehata S S Miyazono K K Koinuma D D

Oncogene 20160229 38

RNA-binding proteins provide a new layer of posttranscriptional regulation of RNA during cancer progression. We identified RNA-binding motif protein 47 (RBM47) as a target gene of transforming growth factor (TGF)-β in mammary gland epithelial cells (NMuMG cells) that have undergone the epithelial-to-mesenchymal transition. TGF-β repressed RBM47 expression in NMuMG cells and lung cancer cell lines. Expression of RBM47 correlated with good prognosis in patients with lung, breast and gastric cancer ...[more]

PMID: 26923328

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Project description:Lung cancer is the leading cause of cancer-associated mortality worldwide. In China, in particular, lung cancer mortality has markedly increased and is likely to continue to rise. RNA-binding proteins are pivotal to the development and progression of a variety of cancer types, including non-small cell lung cancer (NSCLC). RNA-binding motif protein 47 (RBM47) has been found to act as a tumor suppressor in breast cancer and NSCLC. However, to the best of our knowledge, RBM47 expression in NSCLC tissues has yet to be investigated. Analysis via the online database, Gene Expression Omnibus, revealed that RBM47 was upregulated in NSCLC and associated with pathological type, suggesting that RBM47 may play different roles in lung adenocarcinoma and lung squamous cell carcinoma. In the present study, the expression of RBM47 was examined by immunohistochemistry in 175 pairs of tumor and adjacent non-cancerous tissues resected from patients with NSCLC. The results indicated that the expression of RBM47 was significantly increased in NSCLC samples compared with that in the matched non-cancerous samples. Furthermore, RBM47 expression was higher in Xuanwei compared with that in non-Xuanwei NSCLC, suggesting that RBM47 is a more sensitive biomarker in Xuanwei NSCLC, and that it may serve as a candidate therapeutic target. In addition, RBM47 expression was associated with the pathological type, however not with the age, sex, lymph node metastasis, pT stage or pathological Tumor-Node-Metastasis stage of the patients. The increased expression level of RBM47 may indicate a worse overall survival rate for patients with NSCLC. In addition, multivariate survival analysis showed that the Xuanwei area is associated with poor prognosis for patients with NSCLC. In conclusion, the present study revealed that the upregulation of RBM47 accelerated the malignant progression of NSCLC, indicating that RBM47 may be a potential biomarker for NSCLC progression and a therapeutic target for NSCLC.

Project description:Therapies for lung adenocarcinoma (LUAD) are mainly limited by drug resistance, metastasis or recurrence related to cancer stem cells (CSCs) with high proliferation and self-renewing. This research validated that miR-31 was over-expressed in LUAD by the analysis of generous clinical samples data. And the results of clinical data analysis showed that high expression of miR-31 was more common in patients with worse prognosis. The genes differentially expressed in LUAD tissues compared with normal tissues and A549CD133+ cells (LUAD CSCs) compared with A549 cells were separately screened from Gene Expression Profiling Interactive Analysis and GEO datasets. The target genes that may play a role in the regulation of lung adenocarcinoma was screened by comparison between the differential genes and the target genes of miR-31. The functional enrichment analysis of GO Biological Processes showed that the expression of target genes related to cell proliferation was increased, while the expression of target genes related to cell invasion and metastasis was decreased in LUAD tissues and A549CD133+ cells. The results suggested that miR-31 may have a significant inhibitory effect on the differentiation, invasion, metastasis and adhesion of LUAD CSCs, which was verified in vivo and in vitro experiments. Knock down of miR-31 accelerated xenograft tumor growth and liver metastasis in vivo. Likewise, the carcinogenicity, invasion and metastasis of A549CD133+ CSCs were promoted after miR-31 knockdown. The study validated that miR-31 was up regulated in LUAD and its expression may affect the survival time of patients with lung adenocarcinoma, which indicated that miR-31 may have potential value for diagnosis and prognosis of LUAD. However, the inhibitory effect of miR-31 on tumorigenesis, invasion and metastasis of lung adenocarcinoma CSCs suggested its complexity in the regulation of lung adenocarcinoma, which may be related to its extensive regulation of various target genes.

Dataset Information

RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma.

Publications

RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma.

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