Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer
Journal
Oncotarget
Journal Volume
7
Journal Issue
13
Pages
16760-16772
Date Issued
2016
Author(s)
Abstract
The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various cancers, including head and neck cancer and non-small cell lung cancer (NSCLC). However, the molecular mechanism responsible for regulating the alternative splicing of Tid1 is not yet known. Two splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2, participate in alternative splicing and are known to be overexpressed in lung cancers. In this work, we examined if hnRNP A1 and A2 could regulate the alternative splicing of Tid1 to modulate tumorigenesis in NSCLC. We report that RNAi-mediated depletion of both hnRNP A1/A2 (but not single depletion of either) increased Tid1-L expression, inhibited cell proliferation and attenuated EGFR signaling. Analyses of the expression levels of hnRNP A1, hnRNP A2, EGFR and Tid1-L in NSCLC tissues revealed that hnRNP A1 and A2 are positively correlated with EGFR, but negatively correlated with Tid1-L. NSCLC patients with high-level expression of hnRNP A1, hnRNP A2 and EGFR combined with low-level expression of Tid1-L were associated with poor overall survival. Taken together, our results suggest that hnRNP A1 or A2 are both capable of facilitating the alternative splicing of exon 11 in the Tid1 pre-mRNA, thereby suppressing the expression of Tid1-L and allowing EGFR-related signaling to facilitate NSCLC tumorigenesis.
Subjects
EGFR; hnRNP A1; hnRNP A2; NSCLC; Tid1
SDGs
Other Subjects
epidermal growth factor receptor; heterogeneous nuclear ribonucleoprotein; heterogeneous nuclear ribonucleoprotein A1; heterogeneous nuclear ribonucleoprotein A2; unclassified drug; DNAJA3 protein, human; EGFR protein, human; epidermal growth factor receptor; heat shock protein 40; heterogeneous nuclear ribonucleoprotein A1; heterogeneous nuclear ribonucleoprotein group A B; hnRNP A2; HNRPA1 protein, human; isoprotein; alternative RNA splicing; anchorage independent growth; apoptosis; Article; cancer tissue; cell proliferation; clinical article; controlled study; exon; gene expression regulation; hnRNP A1 gene; hnRNP A2 gene; human; human cell; human tissue; lung carcinogenesis; non small cell lung cancer; oncogene; overall survival; RNA interference; signal transduction; Tid1 L gene; Tid1 S gene; upregulation; biosynthesis; Kaplan Meier method; lung tumor; metabolism; mortality; non small cell lung cancer; pathology; physiology; signal transduction; Alternative Splicing; Carcinoma, Non-Small-Cell Lung; Gene Expression Regulation, Neoplastic; Heterogeneous Nuclear Ribonucleoprotein A1; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; HSP40 Heat-Shock Proteins; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Protein Isoforms; Receptor, Epidermal Growth Factor; Signal Transduction
Publisher
Impact Journals LLC
Type
journal article