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Kim, Jee Yeon,Hwang, Junha,Lee, Seo Hyun,Lee, Hyo Jin,Jelinek, Jaroslav,Jeong, Hyeseon,Lim, Jae Sung,Kim, Jin Man,Song, Kyu Sang,Kim, Byung Hoon,Lee, Sukhoon,Kim, Jei BioMed Central 2015 Clinical epigenetics Vol.7 No.-
<P><B>Background</B></P><P>The vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling pathway is involved in cancer-related biological functions and is a therapeutic target in cancer. However, the influence of epigenetic regulation of VEGF-VEGFR signaling-related genes remains unclear. Here, we evaluated the effects of <I>FLT1</I> and <I>KDR</I> promoter hypermethylation combined with drugs targeting VEGF-VEGFR signaling on cancer-related phenotypes in renal cancer cells (RCCs) and examined changes in <I>FLT1</I> and <I>KDR</I> promoter hypermethylation in tissues from patients with renal cancer.</P><P><B>Results</B></P><P>In vitro experiments were performed to evaluate the effects of beavacizumab (an anti-VEGF antibody), an anti-FLT1 peptide, an anti-KDR antibody, and the VEGFR tyrosine kinase inhibitors (TKIs) sunitinib and axitinib in 13 RCC lines with different levels of <I>FLT1</I> and/or <I>KDR</I> promoter methylation and in 2 FLT1 or KDR in vitro knockdown models. The synergistic effects of sunitinib and axitinib treatment were also evaluated in four RCC lines having different levels of <I>FLT1</I> and/or <I>KDR</I> methylation. In our in vitro experiments, bevacizumab and an anti-KDR antibody did not affect the proliferation of RCCs having <I>FLT1</I> and/or <I>KDR</I> hypermethylation. In contrast, in RCCs with <I>FLT1</I> hypermethylation, proliferation inhibition was counteracted by treatment with an anti-FLT1 peptide and both VEGF-TKIs (sunitinib and axitinib). Demethylation with sunitinib or axitinib synergistically increased proliferation inhibition in the RCCs exhibiting <I>FLT1</I> hypermethylation. Using in vitro <I>FLT1</I> or <I>KDR</I> knockdown models, decreased proliferation inhibition following anti-FLT1 peptide, sunitinib, and axitinib treatment was observed only in <I>FLT1</I>-knockdown cells. In patients with renal cancer who received sunitinib, <I>FLT1</I> promoter methylation was higher in renal cancer tissues from eight nonresponders (stable or progressive disease assessed by the Response Evaluation Criteria in Solid Tumors) than in cancer tissues from five responders (complete response or partial response).</P><P><B>Conclusions</B></P><P>The present data showed that hypermethylated <I>FLT1</I> was important for the efficacy of anti-VEGF/VEGFR drugs targeting FLT1 or intracellular VEGFR signaling. <I>FLT1</I> hypermethylation causing alterations of FLT1 function could serve as a useful biomarker for predicting changes in <I>FLT1</I> status in RCCs.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13148-015-0134-9) contains supplementary material, which is available to authorized users.</P>