Identification of novel imprinted tumor suppressor gene on 14q for human renal mil carcinoma

人肾细胞癌(RCC)染色体臂14q32的常见缺失促使我们探索该区域的肿瘤抑制基因(TSG)。我们报道了脂肪细胞分化调控基因14q32上的印迹DLK1是肾细胞癌中的候选TSG。DLK1在早期和晚期肾细胞癌中的表达均减弱，而正常肾组织中DLKI的表达明显减弱。将DLKI重新导入DLK1缺失的肾癌细胞系，显著增加了锚定非依赖性细胞死亡、失巢凋亡，并抑制了裸鼠的肿瘤生长。此外，我们还表明，DLK1的互换印记基因GTL2上游甲基化的获得是RCCS中DLK1失活的关键表观遗传学改变。位于14q32的印记DLKI/GTL2结构域与位于11p15.5的IGF2/H19结构域在结构和表观遗传学上具有相似性。未翻译的H19上游的甲基化导致肾母细胞瘤中IGF2的病理性双等位基因表达。相反，目前的数据表明，未翻译的GTL2上游甲基化的获得导致RCC中DLK1的病理性下调。

A common deletion at chromosomal arm 14q32 in human renal cell carcinoma (RCC) prompted us to explore a tumor suppressor gene (TSG) in this region. We report that imprinted DLK1 at 14q32, a regulator of adipocyte differentiation, is a candidate TSG in RCCs. Expression of DLK1 were diminished in both early and advanced stages of RCCs while normal kidney tissues expressed DLKI. Reintroduction of DLKI into DLK1-null RCC cell lines markedly increased anchorage-independent cell death, anoikis, and suppressed tumor growth in nude mice. Furthermore, we show that gain of methylation upstream of GTL2, a reciprocal imprinted gene for DLK1, is a critical epigenetic alteration for the inactivation of DLK1 in RCCs. The imprinted DLKI/GTL2 domain at 14q32 shares structural and epigenetic similarities with the IGF2/H19 domain at 11p15.5. Gain of methylation upstream of the untranslated H19 leads to pathological biallelic expression of IGF2 in Wilms tumors. In contrast, the present data have shown that gain of methylation upstream of the untranslated GTL2 leads to pathological down regulation of DLK1 in RCCs.