Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway.
Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway.
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DOI：
10.18632/oncotarget.3742
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发表时间：
2015-06-10
期刊：
影响因子：
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通讯作者：
Kato M
中科院分区：
文献类型：
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作者：
Thang ND;Yajima I;Kumasaka MY;Iida M;Suzuki T;Kato M
Deltex-3-like (DTX3L) 是一种 E3 连接酶，是 Deltex (DTX) 家族的成员，也称为 B 淋巴瘤和 BAL 相关蛋白 (BBAP)。此前，我们建立了 RFP/RET 转基因小鼠，其中全身皮肤色素沉着过度、良性黑素细胞肿瘤和黑色素瘤逐步发展。在这里，我们发现 RFP/RET 转基因小鼠和人黑色素瘤细胞系的自发性黑色素瘤中的 Dtx3l/DTX3L 水平分别显着高于良性黑色素细胞和原代培养的正常人上皮黑色素细胞。人体组织的免疫组织化学分析显示，80%以上的黑色素瘤高表达DTX3L。在 Dtx3l/DTX3L 耗尽的鼠和人黑色素瘤细胞中，FAK/PI3K/AKT 信号传导的活性降低，但 MEK/ERK 信号传导的活性并未降低。总之，我们不仅证明了黑色素瘤细胞中 DTX3L 水平的增加，而且还证明了 DTX3L 通过 FAK/PI3K/AKT 而不是 MEK/ERK 信号传导介导的黑色素瘤侵袭和转移调节。我们对人 BRAFV600E 抑制剂耐药性黑色素瘤细胞的分析显示，与 DTX3L 完整细胞相比，DTX3L 耗尽的细胞的侵袭减少了约 80%。因此，DTX3L在临床上是一个潜在的治疗靶点，也是黑色素瘤的潜在生物标志物。
Deltex-3-like (DTX3L), an E3 ligase, is a member of the Deltex (DTX) family and is also called B-lymphoma and BAL-associated protein (BBAP). Previously, we established RFP/RET-transgenic mice, in which systemic hyperpigmented skin, benign melanocytic tumor(s) and melanoma(s) develop stepwise. Here we showed that levels of Dtx3l/DTX3L in spontaneous melanoma in RFP/RET-transgenic mice and human melanoma cell lines were significantly higher than those in benign melanocytic cells and primarily cultured normal human epithelial melanocytes, respectively. Immunohistochemical analysis of human tissues showed that more than 80% of the melanomas highly expressed DTX3L. Activity of FAK/PI3K/AKT signaling, but not that of MEK/ERK signaling, was decreased in Dtx3l/DTX3L-depleted murine and human melanoma cells. In summary, we demonstrated not only increased DTX3L level in melanoma cells but also DTX3L-mediated regulation of invasion and metastasis in melanoma through FAK/PI3K/AKT but not MEK/ERK signaling. Our analysis in human BRAFV600E inhibitor-resistant melanoma cells showed about 80% decreased invasion in the DTX3L-depleted cells compared to that in the DTX3L-intact cells. Thus, DTX3L is clinically a potential therapeutic target as well as a potential biomarker for melanoma.