Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

Abstract

Krüppel-like factor 4 (KLF4) is a transcription factor and plays a vital role in cancer initiation and development. However, the role of Krüppel-like factor 4 in the metastasis of non-small cell lung cancer (NSCLC) is not clear. Here, we demonstrated that the expression of Krüppel-like factor 4 was significantly decreased in human non-small cell lung cancer tissues compared with that in normal tissues using Western blot. We performed immunohistochemical staining and observed the decreased expression of Krüppel-like factor 4 in human lung cancer tissues, and metastatic tumor tissues located in the trachea and main bronchus. We also found that the Ecadherin expression was decreased, while vimentin expression was increased in human NSCLC tissues and metastatic tumor tissues located in the trachea and main bronchus. Additionally, enforced expression of Krüppel-like factor 4 in mouse lungs significantly inhibited the metastasis of circulating Lewis lung carcinoma cells to the lungs by attenuating mesenchymal-epithelial transition (MET). Furthermore, cell scratch assays and Matrigel invasion assays revealed that overexpression of Krüppel-like factor 4 inhibited the migration and invasion of non-small cell lung cancer cell lines A549, H1299, H226, and H1650 cells. Moreover, overexpression of Krüppel-like factor 4 attenuated TGF-b1-induced epithelial-mesenchymal transition (EMT) in A549, and inhibited the phosphorylation of c-Jun-NH2-terminal kinase (JNK), an important pathway in metastasis in non-small cell lung cancer. Our in vivo and in vitro findings illustrate that Krüppel-like factor 4 inhibited metastasis and migration of non-small cell lung cancer, and indicate that Krüppel-like factor 4 could be a potential therapeutic target for the treatment of non-small cell lung cancer.

Impact of KLF4 on Cell Proliferation and Epithelial Differentiation in the Context of Cystic Fibrosis

“…Noticeably, KLF4 KO impact on KLF2 expression is also dependent on the CFTR status ( Figure 3), and KLF2 has been shown to mediate EMT [46]. Consistently, KLF4 has been shown to prevent EMT in human corneal epithelia [47] as well as in some types of lung cancers [48]. In fact, in some contexts, it has been shown that KLF4 actively promotes mesenchymal-to-epithelial transition, i.e., MET [49].…”

Transcription Factor KLF4: A Potential Biomarker of Non-small Cell Lung Cancertranscription Factor KLF4: A Potential Biomarker of Non-small Cell Lung Cancer

“…Fadous-Khalife et al reported that KLF4 expression is related to the clinicopathological characteristics of lung cancer patients and is a potential biomarker of lung cancer [10] , but its research has some shortcomings such as the small number of included tissue samples. Our preliminary basic research found that KLF4 can inhibit the metastasis of NSCLC [11] . In order to further study the expression of KLF4 in NSCLC and its clinicopathological correlation with NSCLC, this study intends to include surgical tissue samples from 155 patients with NSCLC, and draw conclusions by KLF4 immunohistochemical staining and statistical analysis.…”

Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types

“…KLF4 is an important suppressor of lung cancer [ 67 , 68 , 69 , 70 ]. It inhibits migration, invasion and metastasis of non-small cell lung cancer (NSCLC) cells by attenuating TGF-β1-induced EMT and inhibiting the c-Jun-NH 2 -terminal kinase signaling pathway [ 68 ]. However, as the Authors of the latter study acknowledge, the mechanistic explanation for the observed phenomena is lacking [ 68 ].…”

“…KLF4 is an important suppressor of lung cancer [67][68][69][70]. It inhibits migration, invasion and metastasis of non-small cell lung cancer (NSCLC) cells by attenuating TGF-β1-induced EMT and inhibiting the c-Jun-NH 2 -terminal kinase signaling pathway [68].…”