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鉴定调节间皮瘤细胞中钙视网膜蛋白表达的顺式和反式作用元件。

Identification of cis- and trans-acting elements regulating calretinin expression in mesothelioma cells.

作者信息

Kresoja-Rakic Jelena, Kapaklikaya Esra, Ziltener Gabriela, Dalcher Damian, Santoro Raffaella, Christensen Brock C, Johnson Kevin C, Schwaller Beat, Weder Walter, Stahel Rolf A, Felley-Bosco Emanuela

机构信息

Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital Zürich, Zürich, Switzerland.

Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Zürich, Switzerland.

出版信息

Oncotarget. 2016 Apr 19;7(16):21272-86. doi: 10.18632/oncotarget.7114.

DOI:10.18632/oncotarget.7114
PMID:26848772
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5008284/
Abstract

Calretinin (CALB2) is a diagnostic marker for epithelioid mesothelioma. It is also a prognostic marker since patients with tumors expressing high calretinin levels have better overall survival. Silencing of calretinin decreases viability of epithelioid mesothelioma cells. Our aim was to elucidate mechanisms regulating calretinin expression in mesothelioma. Analysis of calretinin transcript and protein suggested a control at the mRNA level. Treatment with 5-aza-2'-deoxycytidine and analysis of TCGA data indicated that promoter methylation is not likely to be involved. Therefore, we investigated CALB2 promoter by analyzing ~1kb of genomic sequence surrounding the transcription start site (TSS) + 1 using promoter reporter assay. Deletion analysis of CALB2 proximal promoter showed that sequence spanning the -161/+80bp region sustained transcriptional activity. Site-directed analysis identified important cis-regulatory elements within this -161/+80bp CALB2 promoter. EMSA and ChIP assays confirmed binding of NRF-1 and E2F2 to the CALB2 promoter and siRNA knockdown of NRF-1 led to decreased expression of calretinin. Cell synchronization experiment showed that calretinin expression was cell cycle regulated with a peak of expression at G1/S phase. This study provides the first insight in the regulation of CALB2 expression in mesothelioma cells.

摘要

钙视网膜蛋白（CALB2）是上皮样间皮瘤的诊断标志物。它也是一种预后标志物，因为肿瘤中钙视网膜蛋白水平高的患者总体生存率更高。钙视网膜蛋白的沉默会降低上皮样间皮瘤细胞的活力。我们的目的是阐明间皮瘤中调节钙视网膜蛋白表达的机制。对钙视网膜蛋白转录本和蛋白质的分析表明在mRNA水平存在调控。用5-氮杂-2'-脱氧胞苷处理并分析TCGA数据表明启动子甲基化不太可能参与其中。因此，我们通过使用启动子报告基因测定法分析转录起始位点（TSS）+1周围约1kb的基因组序列来研究CALB2启动子。CALB2近端启动子的缺失分析表明，跨越-161/+80bp区域的序列维持转录活性。定点分析确定了该-161/+80bp CALB2启动子内重要的顺式调控元件。电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）测定证实了NRF-1和E2F2与CALB2启动子的结合，并且NRF-1的小干扰RNA（siRNA）敲低导致钙视网膜蛋白表达降低。细胞同步化实验表明钙视网膜蛋白的表达受细胞周期调控，在G1/S期表达达到峰值。本研究首次深入了解了间皮瘤细胞中CALB2表达的调控机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/694043faecea/oncotarget-07-21272-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/f1644c2c593e/oncotarget-07-21272-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/c4b3e706f9ce/oncotarget-07-21272-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/2cb60c7cb890/oncotarget-07-21272-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/20015a17cddf/oncotarget-07-21272-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/2bb4890429c9/oncotarget-07-21272-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/694043faecea/oncotarget-07-21272-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/f1644c2c593e/oncotarget-07-21272-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/c4b3e706f9ce/oncotarget-07-21272-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/2cb60c7cb890/oncotarget-07-21272-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/20015a17cddf/oncotarget-07-21272-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/2bb4890429c9/oncotarget-07-21272-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/318f/5008284/694043faecea/oncotarget-07-21272-g006.jpg

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