The RNA binding protein SORBS2 suppresses metastatic colonization of ovarian cancer by stabilizing tumor-suppressive immunomodulatory transcripts

Linjie Zhao,Bonnie Lau,Lian Xu,Qilian Yang,Wei Wang,Xin Wang,Yuquan Wei,Wayne Bond Lau,Qiuhong Shen,Xiaobing Le,Chenlu Wang,Zhengnan Yang,Nan Zhou ,Xuelin Zhou ,Su Yao ,Tao Yi,Shuang Huang,Xia Zhao,Jinjin Wang,Min Feng,Shengtao Zhou

doi:10.1186/s13059-018-1412-6

Abstract

BackgroundOvarian cancer constitutes one of the most lethal gynecologic malignancies for females. Currently, early detection strategies and therapeutic options for ovarian cancer are far from satisfactory, leading to high diagnosis rates at late stages and disease relapses. New avenues of therapy are needed that target key processes in ovarian cancer progression. While a variety of non-coding RNAs have been proven to regulate ovarian cancer metastatic progression, the functional roles of RNA-binding proteins (RBPs) in this process are less well defined.ResultsIn this study, we identify that the RBP sorbin and SH3 domain containing 2 (SORBS2) is a potent suppressor of ovarian cancer metastatic colonization. Mechanistic studies show that SORBS2 binds the 3′ untranslated regions (UTRs) of WFDC1 (WAP four-disulfide core domain 1) and IL-17D (Interleukin-17D), two secreted molecules that are shown to act as metastasis suppressors. Enhanced expression of either WFDC1 or IL-17D potently represses SORBS2 depletion-mediated cancer metastasis promotion. By enhancing the stability of these gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment.ConclusionsOur data illustrate a novel post-transcriptional network that links cancer progression and immunomodulation within the tumor microenvironment through SORBS2-mediated transcript stabilization.

Highlights

Ovarian cancer constitutes one of the most lethal gynecologic malignancies for females
Integrated analysis identifies sorbin and SH3 domain containing 2 (SORBS2) as a key RNA-binding proteins (RBPs) that suppresses ovarian cancer metastasis To identify key RBPs required for ovarian cancer development and progression, we cross-referenced a list of RBPs in the published literature to compile a comprehensive list of 1345 genes encoding all known human RBPs
We found that only SORBS2 and MEX3D gene knock down significantly increased the metastatic colonization capacity of ovarian cancer (Fig. 1c)

Summary

Introduction

Ovarian cancer constitutes one of the most lethal gynecologic malignancies for females. Jiménez-Sánchez et al [7] recently presented an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Through immunogenomic approaches, they found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8+ and CD4+ T cells and exhibited oligoclonal expansion of specific T-cell subsets. Currently it is still unclear whether RNA binding protein (RBP)based post-transcriptional regulation of mRNAs could link ovarian cancer metastasis and immune functions

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