Methylation of a newly identified region of the INS-IGF2 gene determines IGF2 expression in breast cancer tumors and in breast cancer cells.
Methylation of a newly identified region of the INS-IGF2 gene determines IGF2 expression in breast cancer tumors and in breast cancer cells.
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DOI：
10.18632/oncotarget.27655
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发表时间：
2020-11-03
期刊：
影响因子：
--
通讯作者：
León DD
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文献类型：
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作者：
Radhakrishnan VK;Ravichandran K;Eke C;Ortiz-Vicil A;Tan Q;León M;León DD
IGF2在乳房分化、哺乳、肿瘤生长以及乳腺癌(BC)的发生和发展中起着至关重要的作用。这种生长因子还可以抑制细胞凋亡，促进转移和化疗耐药，从而导致更具侵袭性的肿瘤。我们先前证明，非裔美国女性BC组织中IGF2蛋白水平高于高加索女性。我们还发现，在非裔美国女性的正常乳腺组织中，IGF2蛋白水平很高，而在高加索女性的组织中检测到很少或没有检测到IGF2蛋白。其他研究表明，IGF2基因DNA甲基化减少导致了不同的BC临床特征。因此，我们设计了这项研究，以确定IGF2基因的差异甲基化区域是否对应于配对的(正常/肿瘤)乳腺组织和BC细胞系中IGF2蛋白的表达。甲基化分析采用亚硫酸氢钠分析和甲基化敏感的限制性内切酶消化法。我们的结果显示，在正常乳腺组织中，INS-IGF2区域有一个独特的位点发生高甲基化，而在乳腺癌中则发生了低甲基化。我们将这一地区命名为DVDMR。此外，DVDMR中的甲基化水平与IGF2蛋白水平显著相关。该DMR基因全长257bp，定位于INS-IGF2基因。我们认为DVDMR的甲基化是决定乳腺癌IGF2蛋白表达水平的一种新的表观遗传学生物标志物。由于IGF2促进转移和化疗耐药，我们认为IGF2水平与BC的侵袭性有关。IGF2作为生物标志物的验证将改善BC患者的诊断和治疗。
IGF2 is essential in breast differentiation, lactation, tumor growth, and in breast cancer (BC) development and progression. This growth factor also inhibits apoptosis and promotes metastasis and chemoresistance, contributing to more aggressive tumors. We previously demonstrated that IGF2 protein levels are higher in BC tissues from African American women than in Caucasian women. We also showed that high IGF2 protein levels are expressed in normal breast tissues of African American women while little or no IGF2 was detected in tissues from Caucasian women. Others showed that decreased DNA methylation of the IGF2 gene leads to different BC clinical features. Thus, we designed this study to determine if differentially methylated regions of the IGF2 gene correspond to IGF2 protein expression in paired (Normal/Tumor) breast tissues and in BC cell lines. Methylation analysis was performed using Sodium Bisulphite Analysis and Methylation Sensitive Restriction Enzyme digestion methods. Our results show that a unique site in the INS-IGF2 region is hypermethylated in normal breast and hypomethylated in breast cancer. We designated this region the DVDMR. Furthermore, the methylation levels in the DVDMR significantly correlated with IGF2 protein levels. This novel DMR consists of 257bp localized in the INS-IGF2 gene. We propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer. Since IGF2 promotes metastasis and chemoresistance, we propose that IGF2 levels contribute to BC aggressiveness. Validation of IGF2 as a biomarker will improve diagnosis and treatment of BC patients.