Wei Yongchang, Liu Guohong, Wu Balu, Yuan Yufen, Pan Yunbao
Department of Clinical Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Cell Physiol Biochem. 2018;47(5):2126-2135. doi: 10.1159/000491523. Epub 2018 Jul 5.
BACKGROUND/AIMS: MicroRNAs (miRNAs) regulate the expressions of cancer-related genes, and are involved in the development and progression of various human cancers. Here, we performed further analyses to determine whether let-7d is functionally linked to Jab1 in breast cancer.
In situ hybridization and immunohistochemical analyses were used to determine the level of let-7d and Jab1 in breast cancer clinical specimens and its correlation with clinicopathological data. Let-7d overexpressing breast cancer cell lines combined with mouse models bearing cell-derived xenografts were used to assess the functional role of let-7d both in vitro and in vivo.
In this study, we found that let-7d was downregulated in breast cancer tissues, coupled with the elevations of Jab1 protein expressions, compared with paired adjacent noncancerous breast tissues. Let-7d overexpression significantly suppressed the proliferation and invasion in MCF-7 and MDA-MB-231 cells. Dual luciferase reporter assay indicated that Jab1 was the direct target of let-7d. Stepwise studies from in vitro and in vivo experiments indicated that let-7d overexpression inhibited cell growth and decreased Jab1 expressions in breast cancer cells and nude mice tumor tissues. Statistical analyses demonstrated that breast cancer patients with low levels of let-7d or high levels of Jab1 had a significant correlation with worse prognosis.
These findings provide novel insights into molecular mechanism of let-7d and Jab1 in tumor development and progression of breast cancer, and thus let-7d/Jab1 are novel potential therapeutic targets for breast cancer patients.
背景/目的：微小RNA（miRNA）可调节癌症相关基因的表达，并参与多种人类癌症的发生和发展。在此，我们进行了进一步分析，以确定在乳腺癌中let-7d是否与Jab1存在功能联系。
采用原位杂交和免疫组化分析来确定乳腺癌临床标本中let-7d和Jab1的水平及其与临床病理数据的相关性。利用过表达let-7d的乳腺癌细胞系结合携带细胞来源异种移植物的小鼠模型，在体外和体内评估let-7d的功能作用。
在本研究中，我们发现与配对的相邻非癌性乳腺组织相比，let-7d在乳腺癌组织中表达下调，同时Jab1蛋白表达升高。let-7d过表达显著抑制MCF-7和MDA-MB-231细胞的增殖和侵袭。双荧光素酶报告基因检测表明Jab1是let-7d的直接靶点。体外和体内实验的逐步研究表明，let-7d过表达抑制乳腺癌细胞和裸鼠肿瘤组织中的细胞生长并降低Jab1表达。统计分析表明，let-7d水平低或Jab1水平高的乳腺癌患者与较差的预后显著相关。
这些发现为let-7d和Jab1在乳腺癌肿瘤发生和发展中的分子机制提供了新的见解，因此let-7d/Jab1是乳腺癌患者新的潜在治疗靶点。
