Promoter methylation status of VEGF receptor genes A possible epigenetic biomarker to anticipate the efficacy of intracellular-acting VEGF-targeted drugs in cancer cells

作者：Kim Jeeyeon; Hwang Junha; Jeong Hyeseon; Song Hee Jung; Shin Jieun; Hur Gangmin; Park Young Woo; Lee Suk Hoon; Kim Jei

来源：Epigenetics, 2012, 7(2): 191-200.

DOI：10.4161/epi.7.2.18973

• vascular endothelial growth factor (VEGF)
• VEGF receptor (VEGFR)
• Flt1
• KDR
• promoter hypermethylation
• epigenetic change
• VEGF-targeted drug
• VEGF-specific tyrosine kinase inhibitor
• VEGF-specific antibody
• VEGFR2-specific antibody

We evaluated whether the inhibitory effects of vascular endothelial growth factor (VEGF)-targeted drugs on the proliferation of cancer cells differed according to VEGF receptor (VEGFR) genes, Flt1 and KDR, promoter methylation status. Five hyper-VEGFR-methylation and six no-VEGFR-methylation cancer cells were used for the present study, together with human umbilical endothelial cells (HUVECs) as a control. No-VEGFR-methylation cancer cells showed higher expression of Flt1 and KDR than hyper-VEGFR-methylation cancer cells. Hyper-VEGFR-methylation cancer cells only showed increased expression and protein levels of Flt1 and KDR after treatment with the demethylase 5-aza-2%26apos;-deoxycytidine. Two drugs (a VEGF-specific-antibody, bevacizumab and a KDR-specific-antibody) targeting extracellular VEGF-VEGFR signaling and two VEGF-specific-tyrosine kinase inhibitors (PTK/ZK and sunitinib) targeting intracellular VEGFR signaling were used in the cell proliferation assay. HUVECs showed dose-and time-dependent proliferation decrease with all tested drugs over a 72 h incubation period. No-or hyper-VEGFR-methylation cancer cells showed no significant proliferation differences after treatment with VEGF-specific-antibody or VEGFR2-specific-antibody. After PTK/ZK or sunitinib treatment, no-VEGFR-methylation cancer cells showed dose-or time-dependent decreases in proliferation. Hyper-VEGFR-methylation cancer cells also showed proliferation inhibition by VEGF-specific-tyrosine kinase inhibitors after demethylation of Flt1 and KDR. Proliferation inhibition synergistically increased after combination of demethylation with PTK/ZK in hyper-VEGF-methylation cancer cells. We observed that intracellular targeting of VEGF-VEGFR signaling could be more effective than extracellular targeting of the pathway in the suppression of proliferation of some cancer cells. In particular, the efficacy of intracellular targeting of VEGF-specific-tyrosine kinase inhibitors might be influenced by the epigenetic alteration of VEGFRs.

• 出版日期2012-2