ABSTRACT
Disabled-2 (Dab2) and PAR-3 (partitioning defective 3) are reported to play critical roles in maintaining retinal microvascular endothelial cells biology by regulating VEGF-VEGFR-2 signaling. The role of Dab2 and PAR-3 in glomerular endothelial cell (GEnC) is unclear. In this study, we found that, no matter whether with vascular endothelial growth factor (VEGF) treatment or not, decreased expression of Dab2 could lead to cell apoptosis by preventing activation of VEGF-VEGFR-2 signaling in GEnC, accompanied by reduced membrane VEGFR-2 expression. And silencing of PAR-3 gene expression caused increased apoptosis of GEnC by inhibiting activation of VEGF-VEGFR-2 signaling and membrane VEGFR-2 expression. In our previous research, we found that the silencing of syndecan-1 gene expression inhibited VEGF-VEGFR-2 signaling by modulating internalization of VEGFR-2. And our further research demonstrated that downregulation of syndecan-1 lead to no significant change in the expression of Dab2 and PAR-3 both at messenger RNA and protein levels in GEnC, while phosphorylation of Dab2 was significantly increased in GEnC transfected with Dab2 small interfering RNA (siRNA) compared with control siRNA. Atypical protein kinase C (aPKC) could induce phosphorylation of Dab2, thus negatively regulating VEGF-VEGFR-2 signaling. And we found that decreased expression of syndecan-1 lead to activation of aPKC, and aPKC inhibitor treatment could block phosphorylation of Dab2 in GEnC. Besides, aPKC inhibitor treatment could activate VEGF-VGEFR-2 signaling in GEnC transfected with syndecan-1 siRNA in a dose-dependent manner. In conclusion, we speculated that phosphorylation of Dab2 is involved in preventing activation of VEGF-VEGFR-2 signaling in GEnC transfected with syndecan-1 siRNA. This provides a new target for the therapy of GEnC injury and kidney disease.
Subject(s)
Adaptor Proteins, Vesicular Transport/physiology , Endothelial Cells/metabolism , Kidney Glomerulus/metabolism , Nerve Tissue Proteins/physiology , Animals , Apoptosis , Cells, Cultured , Endothelial Cells/cytology , Kidney Glomerulus/cytology , Protein Kinase C/metabolism , Rats , Syndecan-1/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
OBJECTIVE: To investigate the effect of HR-HPV positive,HR-HPV load and SCC-Ag positive on the recurrence of cervical cancer after radical resection.METHODS: The clinical data of cervical cancer patients who underwent radical resection of cervical cancer in People's Hospital of Zengcheng District from January 2010 to January2019 were retrospectively collected.The patients were followed up regularly,and the preoperative HR-HPV positive,loading,the amount of SCC-Ag expression were determined;the recurrence and metastasis of cervical cancer were analyzed,and the value of HR-HPV positive,HR-HPV loading and SCC-Ag in predicting the recurrence and metastasis of cervical cancer were analyzed.RESULTS: A total of 438 patients with cervical cancer were included.There was no significant difference in pathological type,or postoperative Meigs-Brunschwig pathological staging between the recurrence group(n=42)and the non-recurrence group(n=396)(P>0.05).The difference in the proportion of HRHPV positive(40/42 vs. 144/396),HR-HPV loading and SCC-Ag positive(34/42 vs. 64/396)was statistically significant between non-recurrence group and recurrence group(P0.05).Multivariate logistic regression analysis showed that distant metastasis,FIGO staging of cervical cancer,HR-HPV positive,and SCC-Ag were independent factors affecting cervical cancer recurrence(P<0.05).When predicting by individual indicator,the specificity and positive predictive value of HR-HPV positive for predicting cervical cancer recurrence were 99.18% and 95.23% at the highest,and the negative predictive value of HR-HPV was87.37% at the highest.When SCC-Ag was used to predict cervical cancer recurrence,the sensitivity was up to 33.33%.The sensitivity of combined prediction was 64.51%,the specificity was 99.46%,the positive predictive value was97.41%,and the negative predictive value was 94.44%.CONCLUSION: Distant metastasis,FIGO staging,HR-HPV positive,and SCC-Ag are independent factors affecting cervical cancer recurrence.The combination of HR-HPV positive,HR-HPV loading and SCC-Ag has certain value for predicting recurrence of cervical cancer,and the prediction value is the highest.
