Oncology/Endocrine
Interferon alpha-inducible protein 27 promotes epithelial–mesenchymal transition and induces ovarian tumorigenicity and stemness

https://doi.org/10.1016/j.jss.2014.06.055Get rights and content

Abstract

Background

Interferon alpha-inducible protein 27 (IFI27) is an interferon alpha-inducible protein, which was found to be upregulated in some cancers, such as breast cancer, squamous cell carcinoma, hepatocellular carcinoma, and serous ovarian carcinoma. However, the role of IFI27 in ovarian cancer remains to be elucidated. This study was designed to investigate the role of IFI27 in ovarian cancer tumorigenicity.

Materials and methods

The expression of IFI27 was examined in ovarian cancer tissues and cell lines by real time quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The cell migration and invasion was investigated by wound healing and transwell invasion assay. The epithelial–mesenchymal transition markers were detected by Western blotting and the stemness was evaluated by sphere formation. The tumor growth was examined in the athymic mice model.

Results

We found that IFI27 is overexpressed in ovarian cancer and associated with patients' survival. Interestingly, we further observed that the expression of IFI27 was associated with the expression of mesenchymal marker vimentin in ovarian cancer. Overexpression of IFI27 induces epithelial–mesenchymal transition and promotes epithelial ovarian cancer cells migration and invasion, tumorigenicity, stemness, and drug resistance. Moreover, overexpression of IFI27 is associated with loss of miR-502 in ovarian cancer. Reexpression of miR-502 inhibits IFI27-induced tumorigenicity, migration, and drug resistance.

Conclusions

These data suggested that IFI27 may be a potential target for developing novel diagnosis strategies and therapeutic interventions.

Introduction

Epithelial ovarian cancer (EOC) accounts for over 90% of all ovarian malignancies and is the fifth most common type of cancer in females and the leading cause of mortality for gynecologic malignancies [1]. Although the recent progress in surgery, chemotherapy, and radiotherapy strategies has significantly improved the quality of life and median survival of EOC patients, the overall prognosis and cure rate has not improved appreciably [2]. Most deaths (∼70%) are of patients presenting with advanced-stage and high-grade serous ovarian cancer [3]. The treatment of ovarian cancer may include aggressive surgery followed by radiation therapy and/or platinum-based chemotherapy. After therapy, platinum resistance may occur in approximately 25% of patients within 6 months [4]. The Cancer Genome Atlas researchers have examined comprehensively genomic and epigenomic abnormalities on clinically annotated high-grade serous ovarian cancer samples to identify molecular abnormalities that influence pathophysiology, affect outcome, and constitute therapeutic targets [3]. The understanding of the molecular pathogenesis and heterogeneity of EOC hold promise for the development of novel therapies against these tumors.

However, it is still unclear how these genetic changes precisely cause the critical clinical characteristics like metastasis and recurrence of ovarian cancer, and thereby underlying mechanisms involved in the development and progression of ovarian cancer remain poorly understood. Ovarian cancer is a highly metastatic disease and understanding of the molecular changes associated with metastasis could lead to the identification of targets for novel therapeutic interventions. The conversion of an epithelial cell to a mesenchymal cell, epithelial–mesenchymal transition (EMT), plays a key role both in the embryonic development and cancer invasion and metastasis. The molecular profiling of primary and metastatic ovarian cancer patient samples has suggested the role of EMT in ovarian cancer metastasis [5]. Interferon alpha-inducible protein 27 (IFI27) is an interferon alpha-inducible protein found to be upregulated in lesional and non-lesional psoriatic skin and some cancers, such as breast cancer [6], squamous cell carcinoma (SCC) [7], hepatocellular carcinoma (HCC) [8], and serous ovarian carcinoma [9]. However, the role of IFI27 in ovarian cancer remains to be elucidated.

In this study, we examined the expression of IFI27 in a panel of ovarian cancer tissue samples and cell lines. We found that IFI27 is overexpressed in ovarian cancer and associated with patients' survival. Interestingly, we further observed that the expression of IFI27 was associated with the expression of mesenchymal marker vimentin in ovarian cancers. Overexpression of IFI27 induces EMT and promotes EOC cells migration and invasion, tumorigenicity, stemness, and drug resistance. These data suggested that IFI27 may be a potential target for developing novel diagnosis strategies and therapeutic interventions.

Section snippets

Reagents and cell culture

The human ovarian cancer cell lines were cultured in modified RPMI-1640 (OVCAR-3), McCoy's 5a medium (SK-OV-3), or Dulbecco Eagle medium (Invitrogen, Carlsbad, CA) with 10% fetal bovine serum (FBS) and 100 U/mL of penicillin and 100 μg/mL of streptomycin (GIBCO, Grand Island, NY). The OV-90 cell line was maintained in OSE media consisting of 50:50 medium 199:105 (Sigma–Aldrich, St. Louis, MO) supplemented with 15% FBS. The BioCoat Matrigel invasion chambers were products of BD Biosciences

IFI27 is overexpressed in ovarian cancer and associated with patients' survival

To investigate the expression and role of IFI27 in ovarian cancer development, we first analyzed the expression of IFI27 in paired ovarian tumor tissue samples and histologically normal tissues from 30 ovarian cancer patients by real time qRT-PCR. The relative expression level of IFI27 was normalized by the expression of internal control HPRT1 using relative quantification (2−ΔCt) [10]. The results showed that the median expression level of IFI27 was significantly higher in human ovarian tumor

Discussion

In this study, we examined the expression of IFI27 in a panel of ovarian cancer tissue samples and found that IFI27 is significantly overexpressed in most of ovarian cancer tissues compared with matched non-tumor tissues. Kaplan–Meier analysis showed that high-level IFI27 expression was significantly associated with a poor DFS. Interestingly, we observed a significant correlation of the expression of IFI27 and mesenchymal marker vimentin in ovarian cancer tissue samples. We further investigate

Acknowledgment

This work was supported by grants from the National Natural Science Foundation of China (81201994).

Authors' contributions: S.L., Y.X., and H.X. contributed to the conception and design of the study. S.L., Y.X., W.Z., J.G., M.W., G.Z., X.Y., X.T., and H.X. collected, analyzed, and interpreted the data. S.L. and Y.X. wrote the article. X.T. and H.X. obtained the funding, provided critical revisions, and approved the final version of the article.

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