NUMB as a Therapeutic Target for Melanoma.
NUMB as a Therapeutic Target for Melanoma.
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NUMB作为黑色素瘤的治疗靶点。
DOI：
10.1016/j.jid.2021.11.027
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发表时间：
2022-07
影响因子：
6.5
通讯作者：
Herlyn, Meenhard
中科院分区：
文献类型：
--
作者：
Hristova, Denitsa M.;Fukumoto, Takeshi;Takemori, Chihiro;Gao, Le;Hua, Xia;Wang, Joshua X.;Li, Ling;Beqiri, Marilda;Watters, Andrea;Vultur, Adina;Gimie, Yusra;Rebecca, Vito;Samarkina, Anastasia;Jimbo, Haruki;Nishigori, Chikako;Zhang, Jie;Cheng, Chaoran;Wei, Zhi;Somasundaram, Rajasekharan;Fukunaga-Kalabis, Mizuho;Herlyn, Meenhard
衔接蛋白NUMB的上调触发多能皮肤干细胞的黑素细胞分化，其与侵袭性黑色素瘤细胞共享许多特性。尽管NUMB在各种人类癌症类型中充当肿瘤抑制因子，但人们对其在黑色素瘤中的作用知之甚少。在这项研究中，我们研究了NUMB在黑色素瘤进展中的作用及其调控机制。癌症基因组图谱黑色素瘤数据集的分析显示，黑色素瘤组织中的高NUMB表达与改善的患者生存相关。此外，NUMB表达在转移性黑素瘤细胞中下调。NUMB敲低显著增加了体外三维胶原基质和体内小鼠模型肺中黑色素瘤细胞的侵袭潜力;它还显著上调了NOTCH靶基因CCNE的表达。以前的研究表明，Wnt信号增加NUMB的表达。通过抑制糖原合成酶激酶-3模拟Wnt刺激，我们增加了NUMB在黑色素瘤细胞中的表达。此外，糖原合成酶激酶-3抑制剂以NUMB依赖性方式减少黑色素瘤细胞的侵袭。总之，我们的结果表明NUMB可能通过其对NOTCH-CCNE轴的调节来抑制黑素瘤的侵袭和转移，并且上调NUMB的抑制剂可以在黑素瘤中发挥治疗作用。
The upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although NUMB acts as a tumor suppressor in various human cancer types, little is known about its role in melanoma. In this study, we investigated the role of NUMB in melanoma progression and its regulatory mechanism. Analysis of The Cancer Genome Atlas melanoma datasets revealed that high NUMB expression in melanoma tissues correlates with improved patient survival. Moreover, NUMB expression is downregulated in metastatic melanoma cells. NUMB knockdown significantly increased the invasion potential of melanoma cells in a three-dimensional collagen matrix in vitro and in the lungs of a mouse model in vivo; it also significantly upregulated the expression of the NOTCH target gene CCNE. Previous studies suggested that Wnt signaling increases NUMB expression. By mimicking Wnt stimulation through glycogen synthase kinase-3 inhibition, we increased NUMB expression in melanoma cells. Furthermore, a glycogen synthase kinase-3 inhibitor reduced the invasion of melanoma cells in a NUMB- dependent manner. Together, our results suggest that NUMB suppresses invasion and metastasis in mela- noma, potentially through its regulation of the NOTCH–CCNE axis and that the inhibitors that upregulate NUMB can exert therapeutic effects in melanoma.
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