title: Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer.
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.
authors.affiliation: Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Pathology, China Medical University and Hospital, Taichung, Taiwan 404, Taiwan.|Department of Pathology, China Medical University and Beigang Hospital, Yunlin, Taiwan 651, Taiwan.
authors.forename: Chia-Ing
authors.initials: CI
authors.lastname: Jan
authors.affiliation: Department of Molecular and Cellular Biology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Wen-Chieh
authors.initials: WC
authors.lastname: Pi
authors.affiliation: Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 833, Taiwan.
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-San, Tao-Yuan 333, Taiwan.|Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 333, Taiwan.
authors.forename: Tong-Hong
authors.initials: TH
authors.lastname: Wang
authors.affiliation: The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Karni
authors.affiliation: Department of Molecular and Cellular Biology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Tzu-Chien V
authors.initials: TC
authors.lastname: Wang
mesh_terms: D017398:Alternative Splicing; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis*; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1 / Q000378:metabolism*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020033:Protein Isoforms; D015398:Signal Transduction / Q000502:physiology
chemical_list: C120664:DNAJA3 protein, human; D050956:HSP40 Heat-Shock Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D020033:Protein Isoforms; C439768:hnRNP A2; C000619656:hnRNPA1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; NSCLC; Tid1; hnRNP A1; hnRNP A2