Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity.
Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity.
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DOI：
10.1158/0008-5472.can-09-1605
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Yun Z
中科院分区：
文献类型：
--
作者：
Kim Y;Lin Q;Zelterman D;Yun Z
氧合减少或缺氧抑制分化并促进干细胞的维持。缺氧通常发生在实体瘤中，并促进恶性进展。缺氧肿瘤具有侵袭性，表现出干细胞样特征。然而，目前尚不清楚缺氧是否以及如何调节癌细胞分化和维持癌细胞的干细胞性。在这里，我们发现缺氧增加了神经元肿瘤细胞中干细胞基因DLK1或δ样1同源物（果蝇）的表达。抑制DLK1增强自发分化，降低克隆原性，减少体内肿瘤生长。DLK1过表达抑制分化，增强致瘤潜能。我们进一步表明DLK1细胞质结构域，特别是酪氨酸339和丝氨酸355，是维持克隆原性和致瘤性所必需的。由于在许多肿瘤类型中发现DLK1表达升高，我们的观察结果表明，缺氧和DLK1可能构成了调节癌症干细胞样功能和致瘤性的重要干细胞途径。
Reduced oxygenation, or hypoxia, inhibits differentiation and facilitates stem cell maintenance. Hypoxia commonly occurs in solid tumors and promotes malignant progression. Hypoxic tumors are aggressive and exhibit stem cell–like characteristics. It remains unclear, however, whether and how hypoxia regulates cancer cell differentiation and maintains cancer cell stemness. Here, we show that hypoxia increases the expression of the stem cell gene DLK1, or delta-like 1 homologue (Drosophila), in neuronal tumor cells. Inhibition of DLK1 enhances spontaneous differentiation, decreases clonogenicity, and reduces in vivo tumor growth. Overexpression of DLK1 inhibits differentiation and enhances tumorigenic potentials. We further show that the DLK1 cytoplasmic domain, especially Tyrosine339 and Serine355, is required for maintaining both clonogenicity and tumorigenicity. Because elevated DLK1 expression is found in many tumor types, our observations suggest that hypoxia and DLK1 may constitute an important stem cell pathway for the regulation of cancer stem cell–like functionality and tumorigenicity.