LncRNA SPOCD1-AS from ovarian cancer extracellular vesicles remodels mesothelial cells to promote peritoneal metastasis via interacting with G3BP1

Conghui Wang,Yongfang Yue,Jiaying Wang,Mingyue Li,Xiaodong Cheng,Xing Xie,Xinyu Wang,Xiameng Shen,Weiguo Lu

doi:10.1186/s13046-021-01899-6

Abstract

BackgroundMetastasis is the key cause of death in ovarian cancer patients. To figure out the biological nature of cancer metastasis is essential for developing effective targeted therapy. Here we investigate how long non-coding RNA (lncRNA) SPOCD1-AS from ovarian cancer extracellular vesicles (EVs) remodel mesothelial cells through a mesothelial-to-mesenchymal transition (MMT) manner and facilitate peritoneal metastasis.MethodsEVs purified from ovarian cancer cells and ascites of patients were applied to mesothelial cells. The MMT process of mesothelial cells was assessed by morphology observation, western blot analysis, migration assay and adhesion assay. Altered lncRNAs of EV-treated mesothelial cells were screened by RNA sequencing and identified by qRT-PCR. SPOCD1-AS was overexpressed or silenced by overexpression lentivirus or shRNA, respectively. RNA pull-down and RNA immunoprecipitation assays were conducted to reveal the mechanism by which SPOCD1-AS remodeled mesothelial cells. Interfering peptides were synthesized and applied. Ovarian cancer orthotopic implantation mouse model was established in vivo.ResultsWe found that ovarian cancer-secreted EVs could be taken into recipient mesothelial cells, induce the MMT phenotype and enhance cancer cell adhesion to mesothelial cells. Furthermore, SPOCD1-AS embedded in ovarian cancer-secreted EVs was transmitted to mesothelial cells to induce the MMT process and facilitate peritoneal colonization in vitro and in vivo. SPOCD1-AS induced the MMT process of mesothelial cells via interacting with G3BP1 protein. Additionally, G3BP1 interfering peptide based on the F380/F382 residues was able to block SPOCD1-AS/G3BP1 interaction, inhibit the MMT phenotype of mesothelial cells, and diminish peritoneal metastasis in vivo.ConclusionsOur findings elucidate the mechanism associated with EVs and their cargos in ovarian cancer peritoneal metastasis and may provide a potential approach for metastatic ovarian cancer therapeutics.

Highlights

Metastasis is the key cause of death in ovarian cancer patients
We identified an uncharacterized Long non-coding RNAs (lncRNAs) in ovarian cancer cell-derived extracellular vesicles (EVs) to modulate mesenchymal transition (MMT) phenotypes of mesothelial cells, promoting cancer cell adhesion to mesothelial cells in vitro and facilitating peritoneal metastasis in vivo, and confirmed a signaling pathway that participated in MMT process induced by the lncRNA and a specific peptide to block the effect of lncRNA
The results showed that MeT5A cells treated with cancer EVs for 72 h acquired an evident spindle-like morphology, similar as cells treated with TGF-β1 plus IL-1β, while the control cells did not show such change (Fig. 1e)

Summary

Introduction

Metastasis is the key cause of death in ovarian cancer patients. To figure out the biological nature of cancer metastasis is essential for developing effective targeted therapy. We investigate how long non-coding RNA (lncRNA) SPOCD1-AS from ovarian cancer extracellular vesicles (EVs) remodel mesothelial cells through a mesothelial-to-mesenchymal transition (MMT) manner and facilitate peritoneal metastasis. A monolayer of mesothelial cells covers the peritoneal surface and acts as the first barrier of cancer cell intraperitoneal implantation. In certain circumstances, such as inflammatory or injury stimulation, mesothelial cells may undergo a mesothelial-mesenchymal transition (MMT) process to obtain a myofibroblast-like phenotype, leading to tissue fibrosis and peritoneal adhesions [3,4,5]. Recent studies have found that MMT of mesothelial cells participate in the process of cancer cells adhesion to and colonization of the peritoneum [6,7,8], but the involved mechanisms remain elusive. Whether cancer derived EVs remodel the peritoneal environment via altering the phenotype of mesothelial cells is poorly understood

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