Elevated expression of pancreatic adenocarcinoma upregulated factor (PAUF) is associated with poor prognosis and chemoresistance in epithelial ovarian cancer

Chel Hun Choi,Sang Seok Koh,Kris Ylaya,Eun Joo Chung,Jae-Hoon Kim,Joon Seon Song,Stephen M Hewitt,Young Seob Kim,Joon-Yong Chung,Tae Heung Kang,Seokho Kim

doi:10.1038/s41598-018-30582-8

Abstract

Pancreatic adenocarcinoma upregulated factor (PAUF) is a ligand of toll-like receptors (TLRs) and has been reported to be involved in pancreatic tumor development. However, the significance of PAUF expression in epithelial ovarian cancer remains unclear. We aimed to investigate the possible clinical significance of PAUF in epithelial ovarian cancer. We examined the link between PAUF and TLR4 in ovarian cancer cell lines. Recombinant PAUF induced cell activation and proliferation in ovarian cancer cell lines, whereas PAUF knockdown inhibited these properties. Subsequently, we assessed PAUF and TLR4 expression by immunohistochemistry on tissue microarray of 408 ovarian samples ranging from normal to metastatic. PAUF expression positively correlated with TLR4 expression. Overexpression of PAUF was associated with high-grade tumor (p = 0.014) and chemoresistant tumor (p = 0.017). Similarly, high expression of TLR4 correlated with advanced tumor stage (p = 0.002) and chemoresistant tumor (p = 0.001). Multivariate analysis indicated that PAUFhigh, TLR4high, and PAUFhigh/TLR4high expression are independent prognostic factor for progression-free survival, while TLR4high and PAUFhigh/TLR4high expression were independent prognostic factors for overall survival. Our results suggest that PAUF has a role in ovarian cancer progression and is a potential prognostic marker and novel chemotherapeutic target for ovarian cancer.

Highlights

Ovarian cancer is the leading cause of gynecologic cancer-related deaths in the United States, accounting for 13,850 deaths annually[1]
Given that Pancreatic adenocarcinoma up-regulated factor (PAUF) activates toll-like receptors (TLRs)-mediated extracellular signal-regulated kinase (ERK) signaling in pancreatic cancer, we examine its role in ovarian cancer
Since PAUF is an endogenous ligand for TLR4, we investigated whether PAUF could induce cancer cell activation and cancer proliferation via TLR4 using PAUF and TLR4 expressing ovarian cancer cell lines (A2780 and SKOV3)

Summary

Introduction

Ovarian cancer is the leading cause of gynecologic cancer-related deaths in the United States, accounting for 13,850 deaths annually[1]. Prior studies demonstrated that inflammatory mediators and cytokines produced by activated immune cells promote ovarian tumorigenesis and cancer progression[11,12]. Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel tumor-specific protein[21] that plays an important role in carcinogenesis and metastasis in several types of cancer[21,22,23]. It has been associated with poor outcomes in cervical cancer[23]. We hypothesized that the PAUF/TLR4 signaling pathway may play a role in the development of ovarian cancer and potentially a novel target for treatment. We assessed the clinical applicability of PAUF and TLR4 expression as a prognostic and predictive biomarker in ovarian cancers

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Conclusion