ABSTRACT
BACKGROUND: 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. 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. METHODS: EVs 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. RESULTS: We 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. CONCLUSIONS: Our 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.
Subject(s)
Carcinoma, Ovarian Epithelial/metabolism , DNA Helicases/metabolism , Extracellular Vesicles/metabolism , Ovarian Neoplasms/metabolism , Peritoneal Neoplasms/secondary , Poly-ADP-Ribose Binding Proteins/metabolism , RNA Helicases/metabolism , RNA Recognition Motif Proteins/metabolism , RNA, Long Noncoding/genetics , Animals , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/pathology , Cell Line, Tumor , DNA Helicases/genetics , Extracellular Vesicles/pathology , Female , Heterografts , Humans , Mice , Mice, SCID , Neoplasm Metastasis , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/pathology , Poly-ADP-Ribose Binding Proteins/genetics , RNA Helicases/genetics , RNA Recognition Motif Proteins/genetics , RNA, Antisense/genetics , RNA, Antisense/metabolismABSTRACT
OBJECTIVE: To investigate the detailed roles and mechanisms of tumor-derived exosomes in progression and metastasis of ovarian cancer in vitro. METHODS: Exosomes were isolated by differential centrifugation method; the morphology, size and biological markers of exosomes were separately defined by transmission electron microscopy, nanoS90 and Western blotting; Trans-well chambers assay was used to assess the ability of migration and invasion of recipient cells uptaking the exosomes from HO8910PM cells. The downstream molecule was screened by mass spectrometry.CD44 was identified by western blotting and the function of CD44 was identified by trans-well chambers assay and CCK8 assay. RESULTS: Exosomes derived from HO8910PM cells could be transferred to HO8910 cells and promote cell migration and invasion in the recipient cells of ovarian cancer. And CD44 could be transferred to the HO8910 cells through exosomes from HO8910PM cells and influence the migration and invasion ability of HO8910 cells. CONCLUSION: The more aggressive subpopulation can transfer a metastatic phenotype to the less one via secreting exosomes within a heterogeneous tumor. CD44 may be a potential therapeutic approach for ovarian cancer.
Subject(s)
Carcinoma, Ovarian Epithelial/genetics , Cell Movement/genetics , Exosomes/metabolism , Hyaluronan Receptors/metabolism , Ovarian Neoplasms/genetics , Carcinoma, Ovarian Epithelial/metabolism , Carcinoma, Ovarian Epithelial/secondary , Cell Line, Tumor , Female , Humans , Hyaluronan Receptors/genetics , Mass Spectrometry , Microscopy, Electron, Transmission , Neoplasm Metastasis/genetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , PhenotypeABSTRACT
Chemotherapy resistance is one of the biggest challenges in treatment of ovarian cancer. Mounting evidence shows that the exosomes shedding from tumor cells are considered to be involved in chemotherapy resistance of ovarian cancer by enhanced exosomal export of drugs, transferring RNAs or proteins and interfering with the bioactivity of therapeutic anti-tumor antibodies. In this review, we display the correlation between exosomes and chemotherapy resistance of ovarian cancer, the mechanism of exosomes involved in chemotherapy resistance of ovarian cancer, and discuss the potential clinical values of exosomes in chemotherapy resistance of ovarian cancer.