Dataset Information

Musashi-2 (MSI2) supports TGF-? signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis.

ABSTRACT: Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ?16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras(LA1/+);P53(R172H?G/+) (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-? receptor 1 (TGF?R1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGF?RI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial-mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGF?R1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.

SUBMITTER: Kudinov AE

PROVIDER: S-EPMC4922167 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis.

Kudinov Alexander E AE Deneka Alexander A Nikonova Anna S AS Beck Tim N TN Ahn Young-Ho YH Liu Xin X Martinez Cathleen F CF Schultz Fred A FA Reynolds Samuel S Yang Dong-Hua DH Cai Kathy Q KQ Yaghmour Khaled M KM Baker Karmel A KA Egleston Brian L BL Nicolas Emmanuelle E Chikwem Adaeze A Andrianov Gregory G Singh Shelly S Borghaei Hossein H Serebriiskii Ilya G IG Gibbons Don L DL Kurie Jonathan M JM Golemis Erica A EA Boumber Yanis Y

Proceedings of the National Academy of Sciences of the United States of America 20160606 25

Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras(LA1/+);P53(R172HΔG/+) (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCL ...[more]

PMID: 27274057

Similar Datasets

Project description:BackgroundLung cancer is a leading cause of cancer-related mortality worldwide and non-small-cell lung carcinoma (NSCLC) is responsible for almost 80% of lung cancer-related deaths. Identifying novel molecules that can repress the invasiveness and metastasis of lung cancer will facilitate the development of new antilung cancer strategies. The aim of this study is to determine the roles of NUAK1 (a downstream of Akt) and miR-204 in the invasiveness and metastasis of NSCLC and to reveal the correlation between NUAK1 and miR-204.MethodsThe expression of NUAK1 in primary human NSCLC tissues was evaluated by immunohistochemistry. Real-time PCR was employed to measure the expression level of miR-204. The effect of NUAK1 and miR204 on the prognosis of NSCLC patients was evaluated by log-rank test. The siRNA transfection was used to manipulate the expression levels of NUAK1 and miR204 in cancer cells. Chemotaxis assay, Scratch assay, and Matrigel invasion assay were performed to evaluate the migration and invasion of cells. Cellular F-actin measurement was used to measure F-actin polymerisation in lung cancer cells. Western blot was used to detect the expression levels of corresponding proteins. The Luciferase assay and RNA immunoprecipitation were used to confirm the actual binding site of miR-204 to 3'UTR of NUAK1.ResultsIncreased expression of NUAK1 is correlated with the invasiveness and metastasis of human NSCLC. Knockdown of NUAK1 inhibited cell migration and invasion. In addition, this study showed that NUAK1 influenced mTOR phosphorylation and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E-binding protein1 (4E-BP1), two downstream targets of mTOR in NSCLC cells. At the same time, decreased expression of miR-204 promoted NSCLC progression and, contrarily, manipulated upregulation of miR-204-inhibited cell migration and invasion. There is clinical relevance between miR-204 downregulation and NUAK1 upregulation in human NSCLC. Furthermore, we found that miR-204 inhibited NSCLC tumour invasion by directly targeting and downregulating NUAK1 expression. Finally, our data suggested that the downregulation of miR-204 was due to hypermethylation of its promoter region.ConclusionsOur results indicate that NUAK1 is excessively expressed in NSCLC and plays important roles in NSCLC invasion. The miR-204 acts as a tumour suppressor by inhibiting NUAK1 expression in NSCLC. Both NUAK1 and miR-204 may serve as potential targets of NSCLC therapy.

Dataset Information

Musashi-2 (MSI2) supports TGF-? signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis.

Publications

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets