Bai Xiaoyan, Jiang Xiao, Liu Yuting, Wang Yiting, Jiang Xuewei, Song Guang, Qiu Hongmei, Zhang Qinggao
Medical College, Dalian University Dalian, China.
Department of Gastroenterology and Hepatology, Dalian Municipal Central Hospital Dalian, China.
Am J Cancer Res. 2021 Jul 15;11(7):3660-3673. eCollection 2021.
Aberrant expression of Krüppel-like factor 9 (KLF9) is frequently found in some types of cancer and is implicated in cancer initiation and progression. However, the effects of KLF9 on cancer metastases and the underlying mechanisms still need to be understood. Here, we found that KLF9 evidently inhibited the capabilities of migration and invasion of breast cancer cells. The expression of KLF9 was markedly decreased in breast cancer patients compared with benign tumors, and was positively correlated with the expression of E-cadherin in the tissues of breast cancer patients. Mechanistically, chromatin immunoprecipitation combined with site-directed mutagenesis-luciferase assay revealed that KLF9 activated the promoter by binding to GT-box elements located +84 bp and -143 bp from the in the promoter, leading to elevated expression of E-cadherin mRNA and protein. experiments confirmed that KLF9 strongly inhibited the lung metastasis of breast cancer and increased mouse E-cadherin expression in 4T1 mouse breast cancer cells. Taken together, our findings demonstrated that KLF9 could suppress breast cancer invasion and metastasis by upregulating E-cadherin, which provided new insight into aggressive treatment of breast cancer by targeting the KLF9/E-cadherin axis.
在某些类型的癌症中经常发现Krüppel样因子9（KLF9）的异常表达，并且其与癌症的发生和发展有关。然而，KLF9对癌症转移的影响及其潜在机制仍有待进一步了解。在此，我们发现KLF9明显抑制乳腺癌细胞的迁移和侵袭能力。与良性肿瘤相比，乳腺癌患者中KLF9的表达明显降低，并且与乳腺癌患者组织中E-钙黏蛋白的表达呈正相关。机制上，染色质免疫沉淀结合定点诱变-荧光素酶分析表明，KLF9通过与位于E-钙黏蛋白启动子转录起始位点上游+84 bp和-143 bp处的GT-box元件结合来激活启动子，导致E-钙黏蛋白mRNA和蛋白表达升高。体内实验证实，KLF9强烈抑制乳腺癌的肺转移，并增加4T1小鼠乳腺癌细胞中E-钙黏蛋白的表达。综上所述，我们的研究结果表明，KLF9可通过上调E-钙黏蛋白来抑制乳腺癌的侵袭和转移，这为通过靶向KLF9/E-钙黏蛋白轴积极治疗乳腺癌提供了新的见解。
