Surfactant Protein D as a Potential Biomarker and Therapeutic Target in Ovarian Cancer.

Juhi Kumar,Georgios Sotiriadis,Jayanta Chatterjee,Emmanouil Karteris,Marcia Hall,Jeyarooban Jeyaneethi,Valamarthy Murugaiah,Fatimah S Alhamlan,Anuvinder Kaur,Isotta Sturniolo,Uday Kishore

doi:10.3389/fonc.2019.00542

Abstract

Surfactant protein D (SP-D) is an important innate immune molecule that is involved in clearing pathogens and regulating inflammation at pulmonary as well as extra-pulmonary sites. Recent studies have established the role of SP-D as an innate immune surveillance molecule against lung and pancreatic cancer, but little is known about its involvement in signaling pathways it can potentially activate in ovarian cancer. We focused our study on ovarian cancer by performing bioinformatics analysis (Oncomine) of datasets and survival analysis (Kaplan-Meier plotter), followed by immunohistochemistry using ovarian cancer tissue microarrays. SP-D mRNA was found to be expressed widely in different types of ovarian cancer irrespective of stage or grade. These in silico data were further validated by immunohistochemistry of clinical tissues. High transcriptional levels of SP-D were associated with unfavorable prognosis (overall and progression-free survival). We also detected SP-D protein in Circulating Tumor Cells of three ovarian cancer patients, suggesting that SP-D can also be used as a potential biomarker. Previous studies have shown that a recombinant fragment of human SP-D (rfhSP-D) induced apoptosis in pancreatic cancer cells via Fas-mediated pathway. In this study, we report that treatment of SKOV3 cells (an ovarian cancer cell line) with rfhSP-D led to a decrease in cell motility and cell proliferation. This was followed by an inhibition of the mTOR pathway activity, increase in caspase 3 cleavage, and induction of pro-apoptotic genes Fas and TNF-α. These data, suggesting a likely protective role of rfhSP-D against ovarian cancer, together with the observation that the ovarian cancer microenvironment overexperesses SP-D leading to poor prognosis, seems to suggest that the tumor microenvironment components manipulate the protective effect of SP-D in vivo.

Highlights

Surfactant protein D (SP-D) is an innate immune molecule involved in clearing a range of pathogens and apoptotic/necrotic cells at pulmonary as well as extra-pulmonary mucosal sites [1, 2]
A recent study using a bioinformatic approach and RT-qPCR validation indicated that SP-D is overexpressed in ovarian cancer patients compared to healthy controls [18]
We performed an extended bioinformatics analysis in order to investigate whether SP-D is differentially expressed in various types of ovarian cancer and whether it can serve as a potential prognostic marker for the disease

Summary

Introduction

Surfactant protein D (SP-D) is an innate immune molecule involved in clearing a range of pathogens and apoptotic/necrotic cells at pulmonary as well as extra-pulmonary mucosal sites [1, 2]. In mouse models of Aspergillus fumigatusinduced allergic hypersensivity, immunopathological parameters of type I and III hypersensitivity improved considerably following therapeutic delivery of full-length human SP-D and its recombinant fragment containing trimeric neck and lectin domains (rfhSP-D) [5]. Recent studies have focused on lung cancer, as it is the primary production site of SPD where it plays a crucial role in surfactant and immunological homeostasis. SP-D can downregulate the EGF pathway by directly binding to EGFR and inhibit cell proliferation, invasion and metastasis of the A549 lung cancer cell line [12]. A recombinant fragment of human SP-D (rfhSP-D) induced apoptosis in vitro via Fas-mediated pathway [16]. RfhSP-D inhibited TGF-β expression in a range of pancreatic cancer cell lines, thereby reducing their invasive potential by suppressing the Epithelial-to-Mesenchymal Transition [17]

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Conclusion