Human KLF5 adenoviral particles

Although the transcription factor Krüppel-like factor 5 (KLF5) plays an important role in both inflammation and cancer, the mechanism by which this factor promotes cervical carcinogenesis remains unclear. Here, researchers demonstrate a potential role for tumor necrosis factor receptor superfamily member 11a (TNFRSF11a), whose corresponding gene is a direct binding target of KLF5, in tumor cell proliferation and invasiveness. Co-expression of KLF5 and TNFRSF11a significantly correlated with tumorigenesis in cervical tissues, and manipulation of KLF5 expression had a positive effect on TNFRSF11a mRNA and protein expression. Functionally, KLF5 promoted cancer cell proliferation, migration, and invasiveness in a manner that was partially dependent on TNFRSF11a expression. Furthermore, in vivo studies in functional TNFRSF11a knockdown mice showed suppressed tumorigenicity and liver metastatic potential. Notably, tumor necrosis factor (TNF)-α induces KLF5 expression by activating the p38 signaling pathway, and high KLF5 and TNFRSF11a expression increases the risk of death in patients with cervical squamous cell carcinoma. These findings suggest that KLF5 and TNFRSF11a promote cervical cancer cell proliferation, migration, and invasion.

KLF5 has been reported to exert pro-oncogenic activity by regulating gene transcription and stimulating cancer cell progression. TNF-α is an indispensable cytokine that modulates the local microenvironment, thereby promoting CC progression. To further investigate whether KLF5 is an effector of TNFRSF11a and whether KLF5 plays a role in TNF-α-induced CC cell functions, the researchers overexpressed KLF5 in HeLa cells by infection with a specific adenovirus (Ad-KLF5). As shown in Figures 1a and b, KLF5 overexpression led to a sustained upregulation of TNFRSF11a protein and mRNA in HeLa cells. HeLa cell proliferation was further tested using the CCK-8 assay, and migration and invasion were tested using the Transwell assay. The results showed that TNF-α significantly induced HeLa cell proliferation (Figure 1c). Furthermore, treatment with TNF-α and/or Ad-KLF5 resulted in increased migration and invasion in Transwell assays compared with HeLa cells expressing green fluorescent protein (Ad-GFP) alone, indicating increased metastatic potential (Figure 1d, e). These results suggest that KLF5 affects TNFRSF11a expression, thereby promoting TNF-α-induced CC cell migration and invasion.

Figure 1. KLF5 mediates tumour necrosis factor (TNF)-α-induced cervical cancer cell migration and invasion. (Ma D, et al., 2017)