High expression of PDIA4 promotes malignant cell behavior and predicts reduced survival in cervical cancer

Abstract

The protein disulfide isomerase (PDI) gene family plays important roles in the maintenance of several cellular functions. Previous studies have showed that protein disulfide isomerase family A member 4 (PDIA4) is aberrantly expressed in several types of cancer, and correlates with prognosis of patients. However, the role of PDIA4 in cervical cancer remains unclear. In the present study, the expression pattern of PDIA4 from both public database and immunohistochemical analysis in cervical samples was analyzed. Cell Counting Kit-8 and Transwell assays were performed to determine the effect of PDIA4 on cervical cancer cell proliferation and migration. Gene set enrichment analysis (GSEA) was used to provide the associated enriched pathways of PDIA4 in regulating cervical tumorigenesis. It was observed that mRNA expression and protein level of PDIA4 were upregulated in cervical cancer tissues. High expression of PDIA4 was significantly associated with poor overall survival (P= 0.0095) and relapse-free survival (P= 0.0019) in The Cancer Genome Atlas cohort. Knockdown of PDIA4 inhibited cervical cancer cell proliferation and migration. Moreover, PDIA4 affected the expression of proliferation-related molecules (cyclin D1 and PCNA) and migration-related molecules (E-cadherin and Vimentin). Additionally, GSEA revealed that PDIA4 was significantly associated with gene signatures involving glycan biosynthesis, glycosaminoglycan degradation and protein export. In conclusion, the present findings highlighted the importance of PDIA4 in cervical oncogenesis, and suggested that targeting PDIA4 may be a potential therapeutic application for cervical cancer.

Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival

“…There is no known direct link between autophagy and endothelial function; however, matrix proteoglycans like Decorin and Perlecan provide an indirect link [37] as both of these proteoglycans can regulate angiogenesis and autophagy [38,39]. Xing et al found that loss of PDIA-4 in cervical cancer cells significantly impaired cell proliferation and cell migration [40]. Additionally, it was found that the knockdown of PDIA-4 resulted in significantly lower cell proliferation in glioma cells [41].…”

Effects of Fractionated Radiation Exposure on Vimentin Expression in Cervical Cancers: Analysis of Association with Cancer Stem Cell Response and Short-Term Prognosis

“…The prognostic value of vimentin expression determined in tumor cells by immunohistochemistry before treatment was previously shown using univariate and multivariate analyses of overall and disease-free survival of patients with squamous cell CC and adenocarcinoma of the uterine cervix [ 40 , 41 , 42 , 43 ]. In addition, there have been growing data on the association of other EMT markers, including the transcription factors Snail, Slug, Twist, ZEB1, etc., and EMT-related molecules with poor prognosis of long-term clinical outcome [ 43 , 44 , 45 , 46 ]; at the same time, inhibitors or negative modulators of EMT were found to be factors of favorable prognosis of CC patients [ 47 , 48 ]. Taking into account these data, it made sense to analyze the informativeness of the vimentin expression assessment in non-invasive material of scrapings from the cervix before treatment to predict the clinical outcome.…”

Protein Disulfide Isomerase 4 is an Essential Regulator of Endothelial Function and Survival

“…Similarly, we, for the first time, report that loss of PDIA-4 is associated with impaired endothelial function, with reduced angiogenic potential, cell migration, and cell proliferation. Xing et al found that loss of PDIA-4 in cervical cancer cells significantly impaired cell proliferation and cell migration [44]. Additionally, it was found that the knockdown of PDIA-4 resulted in significantly lower cell proliferation in glioma cells [45].…”