In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes.
In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes.
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DOI：
10.1158/2159-8290.cd-14-1347
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发表时间：
2015-07
期刊：
影响因子：
28.2
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
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作者：
Li Chew C;Lunardi A;Gulluni F;Ruan DT;Chen M;Salmena L;Nishino M;Papa A;Ng C;Fung J;Clohessy JG;Sasaki J;Sasaki T;Bronson RT;Hirsch E;Pandolfi PP
磷酸酶PTEN和INPP4B被认为是通过拮抗PI3K/AKT信号而起到肿瘤抑制作用的，并且在人类癌症中经常失调。虽然PTEN已被广泛研究，但对于INPP4B发挥其肿瘤抑制功能及其在体内肿瘤发生中的作用的潜在机制知之甚少。在这里，我们发现Inpp4b的部分或完全缺失使Pten杂合小鼠的良性甲状腺腺瘤病变转变为致死性和转移性滤泡样甲状腺癌（FTC）。重要的是，对人甲状腺癌细胞系和标本的分析显示，FTC中INPP4B下调。在机制上，我们发现INPP4B，而不是PTEN，在甲状腺癌细胞的早期内体中富集，在那里它选择性地抑制AKT2的激活，进而抑制肿瘤的增殖和不依赖锚定的生长。因此，我们通过内体中PI3K/AKT通路的局部调控，发现INPP4B在FTC肿瘤发生和转移中是一种新的肿瘤抑制因子。
The phosphatases PTEN and INPP4B have been proposed to act as tumor suppressors by antagonizing PI3K/AKT signaling, and are frequently dysregulated in human cancer. While PTEN has been extensively studied, little is known about the underlying mechanisms by which INPP4B exerts its tumor suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or complete loss of Inpp4b morphs benign thyroid adenoma lesions in Pten heterozygous mice into lethal and metastatic follicular-like thyroid cancer (FTC). Importantly, analyses of human thyroid cancer cell lines and specimens reveal INPP4B downregulation in FTC. Mechanistically, we find that INPP4B, but not PTEN, is enriched in the early endosomes of thyroid cancer cells, where it selectively inhibits AKT2 activation and in turn tumor proliferation and anchorage-independent growth. We therefore identify INPP4B as a novel tumor suppressor in FTC oncogenesis and metastasis through localized regulation of PI3K/AKT pathway at the endosomes.