Unknown,Transcriptomics,Genomics,Proteomics

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RNA binding protein TIA1 cytoplasmic expression as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma (ESCC).

ABSTRACT: T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein modulating many regulatory aspects of target mRNA metabolism. Despite several reports referring to the role of TIA1 in carcinogenesis, little is known about the significance of its expression and function in human cancers including esophageal squamous cell carcinoma (ESCC). In the present study, we found that ectopic localization of overexpressed TIA1 in the cytoplasm was observed in a cohort of 143 ESCC patients using immunohistochemistry, and the cytoplasmic TIA1 was an independent prognosticator for worse overall survival. Moreover, we revealed that TIA1 was overexpression in many ESCC cell lines, and silencing of TIA1 in those cells inhibited cell growth with an accumulation of cells in G0âG1 and sub-G1 phases. The human TIA1 gene generates two major protein isoforms, TIA1a and TIA1b. Expression of TIA1a isoform tended to be higher than that of TIA1b in ESCC cells, and TIA1a was expressed both in the nucleus and cytoplasm but TIA1b was expressed mainly in the nucleus. Further studies revealed that each isoform showed opposite effects on cell proliferation through ectopically introducing each gene: TIA1a promotes anchorage-dependent and independent cell proliferation, whereas TIA1b inhibits cell proliferation and/or induces cell death. The ribonucleoprotein immunoprecipitation followed by a microarray analysis or massive-parallel sequencing identified a set of TIA1-associating mRNAs including enriched cell cycle-associated genes. Among them, SKP2 and CCNA2 mRNA were shown to be interacted with TIA1 protein through their different regions, and SKP2 and CCNA2 protein levels were positively regulated by TIA1 through suppression of mRNA decay and translational induction, respectively. These findings provide new insights into the previously unknown role of TIA1 and its isoforms as tumor-promoting molecules regulating a set of downstream oncogenic proteins, and implicate their potential application as a useful marker of malignant potential and a therapeutic target in ESCC. To investigate the target molecules regulated by TIA1 in esophageal squamous cell carcinoma cell line (KYSE180), the expression levels of mRNAs (total) and transcripts captured by RIP with TIA1 antibody (TIA1_RIP) were analyzed using microarray.

ORGANISM(S): Homo sapiens

SUBMITTER: Kiyoshi Masuda

PROVIDER: E-GEOD-71342 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein modulating many regulatory aspects of target mRNA metabolism. Despite several reports referring to the role of TIA1 in carcinogenesis, little is known about the significance of its expression and function in human cancers including esophageal squamous cell carcinoma (ESCC). In the present study, we found that ectopic localization of overexpressed TIA1 in the cytoplasm was observed in a cohort of 143 ESCC patients using immunohistochemistry, and the cytoplasmic TIA1 was an independent prognosticator for worse overall survival. Moreover, we revealed that TIA1 was overexpression in many ESCC cell lines, and silencing of TIA1 in those cells inhibited cell growth with an accumulation of cells in G0–G1 and sub-G1 phases. The human TIA1 gene generates two major protein isoforms, TIA1a and TIA1b. Expression of TIA1a isoform tended to be higher than that of TIA1b in ESCC cells, and TIA1a was expressed both in the nucleus and cytoplasm but TIA1b was expressed mainly in the nucleus. Further studies revealed that each isoform showed opposite effects on cell proliferation through ectopically introducing each gene: TIA1a promotes anchorage-dependent and independent cell proliferation, whereas TIA1b inhibits cell proliferation and/or induces cell death. The ribonucleoprotein immunoprecipitation followed by a microarray analysis or massive-parallel sequencing identified a set of TIA1-associating mRNAs including enriched cell cycle-associated genes. Among them, SKP2 and CCNA2 mRNA were shown to be interacted with TIA1 protein through their different regions, and SKP2 and CCNA2 protein levels were positively regulated by TIA1 through suppression of mRNA decay and translational induction, respectively. These findings provide new insights into the previously unknown role of TIA1 and its isoforms as tumor-promoting molecules regulating a set of downstream oncogenic proteins, and implicate their potential application as a useful marker of malignant potential and a therapeutic target in ESCC.

Project description:Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers with high mortality rate. Smoking is one of the established risk factors of ESCC. However, there is limited data on molecular alterations associated with cigarette smoke exposure in esophageal cells. Understanding the effects of cigarette smoke on esophageal squamous epithelial cells at a molecular level would lead to a better understanding of the pathobiology of ESCC which has implications for identification of early biomarkers and therapeutic targets. To investigate the effect of cigarette smoke exposure, we developed a cell line model where Het1A cells (non-neoplastic human esophageal epithelial cells) were chronically treated with cigarette smoke condensate (CSC) for 2 months, 4 months, 6 months and 8 months. We carried out comparative proteomic, phosphoproteomic and whole exome sequencing analyses on CSC treated and untreated cells. Increased cell proliferation and invasion of Het1A cells was observed after chronic exposure to cigarette smoke. Using quantitative proteomic and phosphoproteomic analyses, we identified 56 proteins and 296 phosphoproteins that showed differential expression. Bioinformatics analysis of differentially expressed proteins and phosphoproteins showed enrichment of molecules involved in DNA damage response pathway. Whole exome sequencing (WES) of CSC treated and untreated cells also revealed mutations and copy number alterations in genes associated with DNA damage response. By correlating WES, proteomic and phosphoproteomic results, we observed potential loss of function in HMGN2 and MED1 that were reported as potential tumor suppressors and are known to play important role in DNA damage response. We also observed decreased expression of HMGN2 in tissue section of ESCC. Overexpression of HMGN2 and MED1 lead to decreased proliferative and invasive ability of CSC treated cells. These findings suggest that cigarette smoke affects genes and proteins associated with DNA damage response pathways which might play a vital role in development of ESCC.

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RNA binding protein TIA1 cytoplasmic expression as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma (ESCC).

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