Abstract
Objectives: It has been reported that keratinocyte differentiation factor 1 (KDF1) was related to proliferation, differentiation, and cell cycle. However, the role of KDF1 has not been reported in ovarian cancer. The present study investigated the function and the potential mechanism of KDF1 in ovarian cancer. Methods: We evaluated the prognostic value in ovarian cancer based on data from the Cancer Genome Atlas (TCGA) database. The Kruskal–Wallis test, Wilcoxon signed-rank test, and logistic regression were used to evaluate the relationship between KDF1 expression and clinicopathologic features. The Cox regression and the Kaplan–Meier method were adopted to evaluate prognosis-related factors. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) gene enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were performed to identify the key biological process related to KDF1. Then the expression of KDF1 in ovarian cancer tissues was validated by streptavidin–peroxidase (SP) immunohistochemistry. The proliferation and invasion ability of KDF1 were determined by EdU and Transwell assay, respectively, with KDF1 gene silencing and overexpression. The mRNA expression of KDF1 was determined by qPCR. The protein expression of KDF1 was determined using the Western blot. Methods: By performing differential expression analysis on the ovarian cancer data of the TCGA database, it was found that KDF1 is highly expressed in ovarian cancer patients and associated with poorer overall survival (OS) and progression-free survival (PFS) of ovarian cancer patients. The highly expressed KDF1 may reduce cell adhesion according to GO, KEGG, and GSEA results. After analysis combining the relevant clinical features, we found that the high expression of KDF1 is an independent prognostic factor of ovarian cancer and associated with platinum resistance and tumor metastasis in ovarian cancer. At the same time, the BioGRID database showed that there might be protein–protein interaction between KDF1 and E-cadherin. Then we further validated that the high expression of KDF1 had a close correlation with the stage and grade of ovarian cancer in ovarian cancer tissue chips. Silencing KDF1 inhibited the proliferation and invasion ability of SKOV3 cells. By contrast, ectopic expression of KDF1 promoted the proliferation and invasion ability of A2780 cells. We also found that KDF1 can interact with E-cadherin and regulate the expression of Wnt5A and β-catenin, hence activating Wnt/β-catenin pathway via in vitro and vivo experiments. Conclusions: Based on the bioinformatics analysis, in vitro experiments, and an in vivo study, it is indicated that KDF1 played an important role in ovarian cancer progression and might be a therapeutic target for patients with ovarian cancer.
Highlights
Ovarian cancer (OV) is the only gynecological tumor among the five leading causes of death in women
The different Keratinocyte differentiation factor 1 (KDF1) expression between OC and non-tumor tissue was investigated in three RNAseq datasets (GSE12470, GSE18520, and GSE66957), which were downloaded from the GEO database
Based on the cutoff criteria (|logFC|
Summary
Ovarian cancer (OV) is the only gynecological tumor among the five leading causes of death in women. According to the statistics report, there were 21,750 new cases and 13,940 deaths in the United States in 2020 (Siegel et al, 2020). According to the tumor-initiating cell type, ovarian cancer was divided into three categories: epithelial cancer, interstitial cancer, and germ cell cancer (Nguyen et al, 2019). Most patients with ovarian cancer are asymptomatic, and the volume of the ovary is relatively small, the anatomical position of which is deep in the pelvic cavity. Patients often cannot observe specific symptoms early, resulting in the difficulty of early screening of the disease. More than 70% newly diagnosed patients were at the advanced stage, resulting in a 5-year survival rate of less than 20%
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