Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma.
Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma.
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DOI：
10.18632/oncotarget.7937
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发表时间：
2016-03-29
期刊：
影响因子：
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通讯作者：
Imoto I
中科院分区：
文献类型：
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作者：
Hamada J;Shoda K;Masuda K;Fujita Y;Naruto T;Kohmoto T;Miyakami Y;Watanabe M;Kudo Y;Fujiwara H;Ichikawa D;Otsuji E;Imoto I
t细胞胞内抗原-1 （TIA1）是一种rna结合蛋白，参与mRNA代谢的许多调控方面。在这里，我们报道了以前未知的TIA1的促肿瘤活性，这似乎与它在食管鳞状细胞癌（ESCC）中的亚型特异性分子分布和一组癌症相关转录物的调控有关。在143例ESCC患者的队列中，肿瘤细胞胞质中异位TIA1的免疫组织化学过表达是总生存率较差的独立预后因素。敲低TIA1可抑制ESCC细胞的增殖。通过外源性引入TIA1a和TIA1b两种主要亚型，只有定位于细胞核和细胞质的TIA1a促进了锚定依赖性和锚定非依赖性ESCC细胞的增殖。核糖核蛋白免疫沉淀，随后进行微阵列分析或大规模平行测序，鉴定出一组tia1结合mrna，包括SKP2和CCNA2。TIA1分别通过抑制mRNA衰变和诱导翻译提高SKP2和CCNA2蛋白水平。我们的研究结果揭示了TIA1在食管肿瘤发生中的一种新的致癌功能，并暗示其可作为ESCC预后评估的标志和治疗靶点。
T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein involved in many regulatory aspects of mRNA metabolism. Here, we report previously unknown tumor-promoting activity of TIA1, which seems to be associated with its isoform-specific molecular distribution and regulation of a set of cancer-related transcripts, in esophageal squamous cell carcinoma (ESCC). Immunohistochemical overexpression of TIA1 ectopically localized in the cytoplasm of tumor cells was an independent prognosticator for worse overall survival in a cohort of 143 ESCC patients. Knockdown of TIA1 inhibited proliferation of ESCC cells. By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation. Ribonucleoprotein immunoprecipitation, followed by microarray analysis or massive-parallel sequencing, identified a set of TIA1-binding mRNAs, including SKP2 and CCNA2. TIA1 increased SKP2 and CCNA2 protein levels through the suppression of mRNA decay and translational induction, respectively. Our findings uncover a novel oncogenic function of TIA1 in esophageal tumorigenesis, and implicate its use as a marker for prognostic evaluation and as a therapeutic target in ESCC.