Zhu Zhonglin, Yu Zhilong, Wang Jianfeng, Zhou Lisheng, Zhang Jing, Yao Bin, Dou Jin, Qiu Zhengjun, Huang Chen
Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Gastrointestinal surgery, Jiangyin People's Hospital, Jiangsu, China.
Cell Physiol Biochem. 2018;46(1):238-252. doi: 10.1159/000488426. Epub 2018 Mar 21.
BACKGROUND/AIMS: Krüppel-like factor 4 (KLF4), a member of the KLF family of zinc finger transcription factors, has been identified as a tumor suppressor gene in a variety of tumors. However, the molecular mechanisms by which KLF4 inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in pancreatic cancer remain unclear.
KLF4 expression in pancreatic cancer was analyzed using public datasets (Oncomine and The Cancer Genome Atlas). The expression of KLF4, caveolin-1 (Cav-1), E-cadherin, and vimentin, and their correlations with clinicopathological characteristics were evaluated by immunohistochemistry in pancreatic cancer tissues. The biological functions and underlying mechanisms of KLF4 expression on EMT and metastasis were also investigated in vitro and in vivo.
Public datasets showed that KLF4 expression was significantly decreased in pancreatic cancer and correlated with the depth of invasion and disease stage. The expression of KLF4, Cav-1, E-cadherin, and vimentin protein in pancreatic cancer tissues was closely associated with pathological grade, disease stage, and metastasis. KLF4 expression was also positively correlated with E-cadherin expression and negatively correlated with vimentin expression, whereas Cav-1 expression was negatively associated with E-cadherin expression and positively correlated with vimentin expression. Knockdown of KLF4 expression promoted EMT and facilitated pancreatic cancer cell growth and metastasis in vitro and in vivo. In addition, immunohistochemistry (IHC) results indicated that KLF4 expression was negatively correlated with Cav-1 expression. Furthermore, down-regulating KLF4 expression increased Cav-1 and vimentin expression and decreased E-cadherin expression. Mechanistically, KLF4 could transcriptionally inhibit Cav-1 expression by binding directly to the promoter domain of Cav-1.
KLF4 inhibits pancreatic cancer EMT and metastasis by down-regulating Cav-1 expression, suggesting that the KLF4/Cav-1 signaling pathway may be a novel diagnostic and therapeutic target.
背景/目的：Krüppel样因子4（KLF4）是锌指转录因子KLF家族的成员，已被确定为多种肿瘤中的抑癌基因。然而，KLF4抑制胰腺癌上皮-间质转化（EMT）和转移的分子机制仍不清楚。
利用公共数据集（Oncomine和癌症基因组图谱）分析胰腺癌中KLF4的表达。通过免疫组织化学评估胰腺癌组织中KLF4、小窝蛋白-1（Cav-1）、E-钙黏蛋白和波形蛋白的表达及其与临床病理特征的相关性。还在体外和体内研究了KLF4表达对EMT和转移的生物学功能及潜在机制。
公共数据集显示，胰腺癌中KLF4表达显著降低，且与侵袭深度和疾病分期相关。胰腺癌组织中KLF4、Cav-1、E-钙黏蛋白和波形蛋白的蛋白表达与病理分级、疾病分期和转移密切相关。KLF4表达也与E-钙黏蛋白表达呈正相关，与波形蛋白表达呈负相关，而Cav-1表达与E-钙黏蛋白表达呈负相关，与波形蛋白表达呈正相关。敲低KLF4表达促进EMT，并在体外和体内促进胰腺癌细胞生长和转移。此外，免疫组织化学（IHC）结果表明KLF4表达与Cav-1表达呈负相关。此外，下调KLF4表达增加了Cav-1和波形蛋白表达，降低了E-钙黏蛋白表达。机制上，KLF4可通过直接结合Cav-1的启动子结构域转录抑制Cav-1表达。
KLF4通过下调Cav-1表达抑制胰腺癌EMT和转移，提示KLF4/Cav-1信号通路可能是一个新的诊断和治疗靶点。
