INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas.
INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas.
复制标题
在黑色素瘤的子集中，INPP4B 上调并通过 SGK3 发挥致癌驱动作用。
DOI：
10.18632/oncotarget.5359
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发表时间：
2015-11-24
期刊：
影响因子：
--
通讯作者：
Zhang XD
中科院分区：
文献类型：
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作者：
Chi MN;Guo ST;Wilmott JS;Guo XY;Yan XG;Wang CY;Liu XY;Jin L;Tseng HY;Liu T;Croft A;Hondermarck H;Scolyer RA;Jiang CC;Zhang XD
肌醇多磷酸4-磷酸酶II型（INPP4B）负调节PI3K/Akt信号传导，并在某些类型的癌症中具有肿瘤抑制作用。然而，我们发现它在黑色素瘤的一个子集中上调。在这里，我们报告说，INPP4B可以通过激活血清和糖皮质激素调节激酶3（SGK3）在黑色素瘤作为致癌驱动程序。虽然INPP4B敲低抑制黑素瘤细胞增殖并延缓黑素瘤异种移植物生长，但INPP4B的过表达增强黑素瘤细胞和黑素细胞增殖并触发黑素细胞的锚定非依赖性生长。值得注意的是，INPP4B介导的黑色素瘤细胞增殖与Akt的激活无关，但由SGK3介导。黑素瘤细胞中INPP4B的上调与由于基因拷贝数减少导致的miRNA（miR）-494和/或miR-599的丢失相关。事实上，miR-494或miR-599的过表达下调了INPP4B，降低了SGK3活化，并抑制了黑素瘤细胞增殖，而抗miR-494或抗miR-599的引入上调了INPP4B，增强了SGK3活化，并促进了黑素瘤细胞增殖。总的来说，这些结果将INPP4B的上调确定为通过在黑色素瘤亚组中激活SGK3的致癌机制，这意味着靶向INPP4B并恢复miR-494和miR-599作为治疗具有高INPP4B表达的黑色素瘤的新方法。
Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates PI3K/Akt signalling and has a tumour suppressive role in some types of cancers. However, we have found that it is upregulated in a subset of melanomas. Here we report that INPP4B can function as an oncogenic driver through activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) in melanoma. While INPP4B knockdown inhibited melanoma cell proliferation and retarded melanoma xenograft growth, overexpression of INPP4B enhanced melanoma cell and melanocyte proliferation and triggered anchorage-independent growth of melanocytes. Noticeably, INPP4B-mediated melanoma cell proliferation was not related to activation of Akt, but was mediated by SGK3. Upregulation of INPP4B in melanoma cells was associated with loss of miRNA (miR)-494 and/or miR-599 due to gene copy number reduction. Indeed, overexpression of miR-494 or miR-599 downregulated INPP4B, reduced SGK3 activation, and inhibited melanoma cell proliferation, whereas introduction of anti-miR-494 or anti-miR-599 upregulated INPP4B, enhanced SGK3 activation, and promoted melanoma cell proliferation. Collectively, these results identify upregulation of INPP4B as an oncogenic mechanism through activation of SGK3 in a subset of melanomas, with implications for targeting INPP4B and restoring miR-494 and miR-599 as novel approaches in the treatment of melanomas with high INPP4B expression.