State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Gastroenterology. 2012 Mar;142(3):521-530.e3. doi: 10.1053/j.gastro.2011.11.023. Epub 2011 Nov 19.
BACKGROUND & AIMS: Aberrant activation of the signal transducer and activator of transcription (Stat)3 and overexpression of polo-like kinase (PLK)1 each have been associated with cancer pathogenesis. The mechanisms and significance of dysregulation of Stat3 and PLK1 in carcinogenesis and cancer progression are unclear. We investigated the relationship between Stat3 and PLK1 and the effects of their dysregulation in esophageal squamous cell carcinoma (ESCC) cells.
We used immunoblot, quantitative reverse-transcription polymerase chain reaction, immunochemistry, chromatin immunoprecipitation, mobility shift, and reporter assays to investigate the relationship between Stat3 and PLK1. We used colony formation, fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and xenograft tumor assays to determine the effects of increased activation of Stat3 and PLK1 in proliferation and survival of ESCC cells.
Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3. PLK1 then potentiated the expression of Stat3; β-catenin was involved in PLK1-dependent transcriptional activation of Stat3. This mutual regulation between Stat3 and PLK1 was required for proliferation of esophageal cancer cells and resistance to apoptosis in culture and as tumor xenografts in mice. Furthermore, phosphorylation of Stat3 and overexpression of PLK1 were correlated in a subset of ESCC.
Stat3 and PLK1 control each other's transcription in a positive feedback loop that contributes to the development of ESCC. Increased activity of Stat3 and overexpression of PLK1 promote survival and proliferation of ESCC cells in culture and in mice.
信号转导子和转录激活子（Stat）3 的异常激活和 Polo 样激酶（PLK）1 的过表达都与癌症发病机制有关。Stat3 和 PLK1 失调在癌症发生和癌症进展中的机制和意义尚不清楚。我们研究了 Stat3 和 PLK1 之间的关系，以及它们在食管鳞状细胞癌（ESCC）细胞中失调的影响。
我们使用免疫印迹、定量逆转录聚合酶链反应、免疫组织化学、染色质免疫沉淀、迁移率变动分析和报告基因分析来研究 Stat3 和 PLK1 之间的关系。我们使用集落形成、荧光激活细胞分选、末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记和异种移植肿瘤测定来确定 Stat3 和 PLK1 激活增加对 ESCC 细胞增殖和存活的影响。
Stat3 直接激活食管癌细胞和小鼠胚胎成纤维细胞 NIH3T3 中 PLK1 的转录。PLK1 随后增强 Stat3 的表达；β-连环蛋白参与了 PLK1 依赖的 Stat3 转录激活。这种 Stat3 和 PLK1 之间的相互调节是食管癌细胞在培养中增殖和抵抗凋亡以及作为肿瘤异种移植在小鼠中存活所必需的。此外，Stat3 的磷酸化和 PLK1 的过表达在 ESCC 的一个亚集中相关。
Stat3 和 PLK1 在正反馈环中相互控制对方的转录，这有助于 ESCC 的发展。Stat3 和 PLK1 活性的增加促进了 ESCC 细胞在培养和小鼠中的存活和增殖。
