A shortcut from ovarian cancer development to metastasis <i>:</i> <i>MYC/FASN/SEMA7A</i> , a promising therapeutic axis.

Abstract

e17542 Background: Ovarian cancer is the leading cause of mortality among gynecologic malignancies. Trans coelomic metastasis is the most common and is responsible for the great morbidity and mortality in women with ovarian cancer. However, very little is known about the biology of trans coelomic metastasis. Here we analyzed the role of the MYC/FASN/SEMA7A axis in the progression of ovarian cancer trans coelomic metastasis. Methods: Bio-informatic analysis revealed the significant clinical importance of MYC and FASN expression in affecting survival including overall survival and progression free survival, as well as the relationship between MYC and FASN . Immunohistochemistry, real time-PCR and western blot analysis of MYC and FASN expression levels. Furthermore, flow cytometry and immunofluorescence were performed to observe the ratio of M1/M2 macrophages in tissues of ovarian cancer patients. Overexpression of MYC and FASN were generated via Lentivirus expression system in ovarian cancer cell lines. Cell proliferation, migration and invasion abilities were determined by CCK-8 assay, colony-formation assay, cell scratch assay and transwell assay, respectively. Transcriptional sequencing and mass spectrometry were used to analyze the key gene involved in trans coelomic metastasis of ovarian cancer. Results: Oncoprint for focal amplifications of MYC is 35% by CBioPortal database. Moreover, FASN was correlated positively with MYC expression. Survival analysis revealed that higher MYC and FASN mRNA levels appeared to be related to the poorer overall survival of ovarian cancer. Faster recurrence of ovarian cancer was observed in patients with higher MYC and FASN expression levels. Intriguingly, higher M2 macrophages ratio was observed in patients with metastasis and recurrence. Experimentally overexpressed MYC could promote FASN expression, as well as facilitating cell proliferation, migration and invasion abilities of ovarian cancer cell lines (SK-OV-3, OVCAR 3), reduction of MYC significantly inhibited these cell biological behaviors via activation of macrophages polarization. Furthermore, the inhibition of FASN could also reverse the negative effect of MYC overexpression. Moreover, transcriptional sequencing and mass spectrometry showed that up-regulation of MYC/FASN dramatically promoted M2 macrophages polarization via increasing overexpression of SEMA7A. Conclusions: In the present study, we identified a novel function of MYC/FASN/SEMA7A , by promoting M2 macrophages polarization in ovarian tumor tissues, serving a critical role on the progression and trans coelomic metastasis of ovarian carcinoma. It can be speculated that targeting MYC/FASN/SEMA7A might reduce the risk of ovarian cancer development and trans coelomic metastasis. However, detailed analysis is urgently needed to uncover the underlying molecular mechanisms, as well as the related risk factors.