Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation
Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation
复制标题
DOI：
10.1073/pnas.1112047108
复制
发表时间：
2011-10-11
影响因子：
11.1
通讯作者：
Sablin, Elena P.
中科院分区：
文献类型：
--
作者：
Benod, Cindy;Vinogradova, Maia V.;Sablin, Elena P.
核受体肝受体同源物1 （LRH-1）是基因转录的重要调控因子，控制发育中的胰腺细胞分化并维持成人胆固醇稳态。最近的全基因组关联研究将LRH-1基因及其上游调控区域的突变与胰腺癌的发展联系起来。在这项工作中，我们发现与正常胰腺导管上皮细胞相比，LRH-1转录在人胰腺癌细胞中被激活高达30倍。这种激活与体内人胰腺导管腺癌中LRH-1蛋白表达的显著增加相关。受体特异性siRNA选择性阻断LRH-1可显著抑制胰腺癌细胞体外增殖。这种抑制在一定程度上是由于受体的转录靶标控制细胞生长、增殖和分化的衰减。此前，研究表明LRH-1有助于肠道肿瘤的形成。本研究证明了LRH-1在胰腺癌发生发展中的重要作用，提示LRH-1受体可能是治疗胰腺导管腺癌的一个可行的治疗靶点。
An essential regulator of gene transcription, nuclear receptor liver receptor homologue 1 (LRH-1) controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults. Recent genome-wide association studies linked mutations in the LRH-1 gene and its up-stream regulatory regions to development of pancreatic cancer. In this work, we show that LRH-1 transcription is activated up to 30-fold in human pancreatic cancer cells compared to normal pancreatic ductal epithelium. This activation correlates with markedly increased LRH-1 protein expression in human pancreatic ductal adenocarcinomas in vivo. Selective blocking of LRH-1 by receptor specific siRNA significantly inhibits pancreatic cancer cell proliferation in vitro. The inhibition is tracked in part to the attenuation of the receptor's transcriptional targets controlling cell growth, proliferation, and differentiation. Previously, LRH-1 was shown to contribute to formation of intestinal tumors. This study demonstrates the critical involvement of LRH-1 in development and progression of pancreatic cancer, suggesting the LRH-1 receptor as a plausible therapeutic target for treatment of pancreatic ductal adenocarcinomas.