Abstract
Although the transcription factor Krüppel-like factor 5 (KLF5) plays important roles in both inflammation and cancer, the mechanism by which this factor promotes cervical carcinogenesis remains unclear. In this study, we demonstrated a potential role for tumour necrosis factor receptor superfamily member 11a (TNFRSF11a), the corresponding gene of which is a direct binding target of KLF5, in tumour cell proliferation and invasiveness. Coexpression of KLF5 and TNFRSF11a correlated significantly with tumorigenesis in cervical tissues (P < 0.05) and manipulation of KLF5 expression positively affected TNFRSF11a mRNA and protein expression. Functionally, KLF5 promoted cancer cell proliferation, migration and invasiveness in a manner dependent partly on TNFRSF11a expression. Moreover, in vivo functional TNFRSF11a-knockdown mouse studies revealed suppression of tumorigenicity and liver metastatic potential. Notably, tumour necrosis factor (TNF)-α induced KLF5 expression by activating the p38 signalling pathway and high KLF5 and TNFRSF11a expression increased the risk of death in patients with cervical squamous cell carcinoma. Our results demonstrate that KLF5 and TNFRSF11a promote cervical cancer cell proliferation, migration and invasiveness.
Highlights
Cervical cancer (CC) is a major cause of cancer-related deaths in women worldwide, accounting 250,000 deaths each year[1]
To determine whether both molecules were responsible for cervical tumorigenesis, we examined their expression in cervical tissues using immunofluorescence (IF) and haematoxylin–eosin staining
We analysed the levels of Krüppel-like factor 5 (KLF5) and TNFRSF11a mRNA in 45 cervical intraepithelial neoplasia (CIN) II-III samples (Fig. 1c) and 110 cervical squamous cell carcinoma (CSCC) samples (Fig. 1d) and observed that a significant correlation of TNFRSF11A with KLF5 expression in the latter
Summary
Cervical cancer (CC) is a major cause of cancer-related deaths in women worldwide, accounting 250,000 deaths each year[1]. Several reports have suggested links between the aggressive nature of human cervical carcinoma and a number of molecular abnormalities, including the inactivation of various tumour suppressor genes and activation of various oncogenes[4,5] This lack of sufficient genetic and epigenetic data regarding the pathogenesis of CC and the paucity of effective targets has hindered the development of novel targeted therapies[6,7,8]. (c) Stable KLF5 overexpression in HeLa cells significantly promoted cell growth compared with stable GFP expression during a 96 h period, as measured by the CCK-8 assay. In (i) and (j), representative photomicrographs of a Transwell assay show the respective quantification of HeLa cell migration and invasion after the above-described treatments.
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