MCPH1/BRIT1 和 BRCA1 肿瘤抑制基因与端粒酶剪接变异体在上皮性卵巢癌中的表达分析。

Expression analysis of the MCPH1/BRIT1 and BRCA1 tumor suppressor genes and telomerase splice variants in epithelial ovarian cancer.

机构信息

Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.

Leeds Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital Leeds, LS9 7TF, UK.

出版信息

Gene. 2018 Sep 25;672:34-44. doi: 10.1016/j.gene.2018.05.113. Epub 2018 May 31.

DOI:10.1016/j.gene.2018.05.113

PMID:29860064

Abstract

AIMS

The aim of this study was to explore the correlation of hTERT splice variant expression with MCPH1/BRIT1 and BRCA1 expression in epithelial ovarian cancer (EOC) samples.

BACKGROUND

Telomerase activation can contribute to the progression of tumors and the development of cancer. However, the regulation of telomerase activity remains unclear. MCPH1 (also known as BRIT1, BRCT-repeat inhibitor of hTERT expression) and BRCA1 are tumor suppressor genes that have been linked to telomerase expression.

METHODS

qPCR was used to investigate telomerase splice variants, MCPH1/BRIT1 and BRCA1 expression in EOC tissue and primary cultures.

RESULTS

The wild type α+/β+ hTERT variant was the most common splice variant in the EOC samples, followed by α+/β- hTERT, a dominant negative regulator of telomerase activity. EOC samples expressing high total hTERT demonstrated significantly lower MCPH1/BRIT1 expression in both tissue (p = 0.05) and primary cultures (p = 0.03). We identified a negative correlation between MCPH1/BRIT1 and α+/β+ hTERT (p = 0.04), and a strong positive association between MCPH1/BRIT1 and both α-/β+ hTERT and α-/β- hTERT (both p = 0.02). A positive association was observed between BRCA1 and α-/β+ hTERT and α-/β- hTERT expression (p = 0.003 and p = 0.04, respectively).

CONCLUSIONS

These findings support a regulatory effect of MCPH1/BRIT1 and BRCA1 on telomerase activity, particularly the negative association between MCPH1/BRIT1 and the functional form of hTERT (α+/β+).

摘要

目的

本研究旨在探讨端粒酶逆转录酶剪接变异体表达与微大头畸形蛋白 1/BRIT1 和乳腺癌 1 基因（BRCA1）在卵巢上皮性癌（EOC）组织中的相关性。

背景

端粒酶的激活可能导致肿瘤的进展和癌症的发生。然而，端粒酶活性的调节机制尚不清楚。微大头畸形蛋白 1（也称为 BRIT1，端粒酶表达的 BRCT 重复抑制剂）和 BRCA1 是肿瘤抑制基因，与端粒酶的表达有关。

方法

采用 qPCR 方法检测 EOC 组织和原代培养物中端粒酶剪接变异体、MCPH1/BRIT1 和 BRCA1 的表达。

结果

在 EOC 样本中，最常见的端粒酶剪接变异体是野生型α+/β+ hTERT 变异体，其次是α+/β- hTERT，这是一种端粒酶活性的显性负调控因子。在组织（p=0.05）和原代培养物（p=0.03）中，高总 hTERT 表达的 EOC 样本中，MCPH1/BRIT1 表达显著降低。我们发现 MCPH1/BRIT1 与α+/β+ hTERT 之间存在负相关（p=0.04），MCPH1/BRIT1 与α-/β+ hTERT 和α-/β- hTERT 之间存在强烈的正相关（均 p=0.02）。BRCA1 与α-/β+ hTERT 和α-/β- hTERT 表达呈正相关（分别为 p=0.003 和 p=0.04）。