| The incidence of ovarian cancer ranks third among gynecological malignant tumors.As two-thirds of ovarian cancer patients are diagnosed in the middle and late stages,the mortality rate remains high.At present,the main clinical treatment about ovarian cancer is surgery combined with chemotherapy,with cisplatin combined with paclitaxel as main chemotherapy regimen.However,the recurrence rate within 2 years is 75%,and the 5-year survival rate is only about 30% after treatment.Therefore,more effective therapies need to be found urgently.Tumor recurrence is a complex multi-step process involving a series of gene regulation,including multiple links such as cell proliferation,adhesion,matrix degradation,cell migration and tumor angiogenesis.But surviving or dying tumor cells are able to proliferate again after treatment.We call this phenomenon of tumor cells emerging from death the "phoenix rising" phenomenon.The mechanism of "phoenix rising" is unclear.In recent years,many studies have shown that the occurrence and development of tumors are closely related to tumor cells and their microenvironment.Tumor and inflammatory cells secrete a series of complex chemical and protein signaling molecules that affect tumor growth and metastasis in autocrine and paracrine ways.Inflammatory cells and mediators are known to play a key role in the formation and development of cancer.As an apoptotic executive protein caspase-3,its activation can activate calcium independent phospholipaseA2(iPLA2),further stimulate the generation of arachidonic acid(AA),activate the AA metabolic pathway,synthesize prostaglandin E2(PGE2)and other factors,change the tumor microenvironment,This could be one of the phoenix rising pathways.Although it has been reported that it can promote the recurrence and metastasis of malignant tumors,its specific causes of tumor recurrence and its downstream mechanism are still unclear.Research has shown that FAK(focal adhesion kinase)plays a key role in a variety of cell movement,cell adhesion,proliferation and survival,and there are a large number of studies show that PGE2 can activate FAK through direct and indirect effects.But whether FAK is related to the phoenix nirvana pathway has not been reported.In this study,we explored the important role of Caspase-3 /iPLA2/AA/PGE2 signaling pathway in the recurrence of ovarian cancer after chemotherapy through cell experiments.Clinical trials were conducted to verify whether the Caspase-3 /iPLA2/AA/PGE2 signaling pathway was activated and the expression of FAK in ovarian cancer tissues after chemotherapy.Methods and results:1.The apoptosis and repopulation cell model of ovarian cancer was constructed by etoposide(VP-16)treatment on SKOV-3.AA and PGE2 contents in cell culture supernatant were detected by ELISA,It was found that the number of cells decreased with time,while the content of PGE2 increased in a time-dependent manner.The protein expressions of Caspase 3,iPLA2 were detected by Western blot.The expression of Caspase 3 and iPLA2 was significantly higher than that of the control group.2.To determine whether PGE2 directly induces ovarian cancer cell proliferation through FAK,SKOV-3 cells were first treated with PGE2 plasmid,the overexpressing cells showed higher proliferating ratio and p-FAK expression.FAK inhibitor PF562271 was added in VP-16 treated repopulation model.The results show that the inhibition of FAK could inhibit the proliferation and repopulation of ovarian cancer cells in VP-16 treatment group,and FAK inhibitor can inhibit the phosphorylation of FAK activation,but does not affect the expression of Caspase 3 and iPLA2.3.By collecting clinical samples,the univariate correlation analysis of ovarian cancer recurrence was first performed.The correlationship between age,type,birth history,smoke,drink,family history,hypertension,diabetes,CA125,CEA and ovarian repopulation was conducted in ovarian cancer individuals.The analysis results showed that type and CA125 were significantly correlated with ovarian repopulation.AA and PGE2 contents in sera of ovarian cancer individuals before or after chemotherapy were detected by ELISA,It was found that the content of PGE2 in serum of the patients after chemotherapy was significantly higher than that of the control group.And the p-FAK protein expression in tissues of ovarian cancer individuals were detected by immunohistochemical stainingAnd p-FAK expression was significantly increased compared to non-chemotherapy(control)group.Conclusion:1.Vp-16 treated skov-3 cells activate the Caspase 3/ iPLA2/AA/PGE2 signaling pathway and release PGE2,which is associated with skov-3 cell proliferation..2.FAK is one of the major factors that downstream of the caspase-3 /iPLA2/AA/PGE2 signaling pathway stimulates skov-3 cell proliferation in ovarian cancer cells.3.Serum PGE2 significantly increased in patients with clinical ovarian cancer after chemotherapy,and p-fak significantly increased in cancer tissues after chemotherapy,further confirming the activation of Caspase 3/ iPLA2/AA/PGE2 signaling pathway.Therefore,FAK may play an important regulatory role in the recurrence of ovarian cancer patients after chemotherapy through the "phoenix nirvana" effect.Data from basic research confirmed that the Caspase 3/ iPLA2/AA/PGE2 pathway was activated when ovarian cancer recurred.FAK was further activated in ovarian cancer cells that were not treated with chemotherapy,Thus plays an important regulatory role in the reproliferation and recurrence of ovarian cancer cells.Clinical data confirmed the activation of PGE2 and FAK after chemotherapy,which may play an important regulatory role in the recurrence of ovarian cancer after chemotherapy. |
PDF Full Text Request