MALT1 promotes melanoma progression through JNK/c-Jun signaling.
MALT1 promotes melanoma progression through JNK/c-Jun signaling.
复制标题
DOI：
10.1038/oncsis.2017.68
复制
发表时间：
2017-07-31
期刊：
影响因子：
6.2
通讯作者：
Zhang JY
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang G;Jin J;Degan S;Tameze Y;Zhang JY
黏膜相关淋巴瘤抗原1（MALT1）是一种淋巴瘤致癌基因，作为类半胱天冬酶和衔接蛋白调节信号转导。然而，MALT1在其他实体癌（如黑色素瘤）中的作用尚未得到充分了解。在此，我们证明MALT1在恶性黑色素瘤细胞中过度表达，并预示着无病生存期较差。通过shRNA介导的基因沉默或使用MI - 2化合物进行药理学抑制MALT1，在体外显著降低了A2058和A375黑色素瘤细胞系的细胞生长和迁移。皮下肿瘤生长分析显示，MALT1基因沉默显著降低了肿瘤生长和向肺部的转移。一致地，MALT1缺失的皮下肿瘤细胞凋亡增加，增殖减少。此外，这些肿瘤显示出间充质 - 上皮转化的迹象，表现为E - 钙黏蛋白上调，N - 钙黏蛋白和β1 - 整合素下调。进一步的分子分析表明，肿瘤坏死因子 - α激活c - Jun和核因子 - κB（NF - κB）需要MALT1。强制表达c - Jun上游激活因子MKK7可逆转由MALT1缺失导致的细胞生长和迁移缺陷。相反，通过表达p65ER（一种包含NF - κB p65和他莫昔芬响应突变型雌激素受体的融合蛋白）激活NF - κB，对细胞增殖的影响极小，但减少了由MALT1缺失和TRAIL治疗诱导的细胞死亡。总之，这些发现表明MALT1通过JNK/c - Jun促进黑色素瘤细胞增殖和运动，并通过NF - κB增强黑色素瘤细胞存活，强调MALT1是恶性黑色素瘤的一个潜在治疗靶点和生物标志物。
Mucosa-associated lymphoma antigen 1 (MALT1) is a lymphoma oncogene that regulates signal transduction as a paracaspase and an adaptor protein. Yet, the role of MALT1 in other solid cancers such as melanoma is not well-understood. Here, we demonstrate that MALT1 is overexpressed in malignant melanoma cells, and predicts a poor disease-free survival. MALT1 inhibition via shRNA-mediated gene silencing or pharmacologically with MI-2 compound markedly reduced cell growth and migration of A2058 and A375 melanoma cell lines in vitro. Subcutaneous tumor growth analysis revealed that MALT1 gene silencing significantly reduced tumor growth and metastasis to the lung. Consistently, the subcutaneous tumors with MALT1 loss had increased cell apoptosis and decreased proliferation. In addition, these tumors showed signs of mesenchymal–epithelial transition as indicated by the upregulation of E-cadherin and downregulation of N-cadherin and β1-intergrin. Further molecular analysis revealed that MALT1 is required for c-Jun and nuclear factor-κB (NF-κB) activation by tumor necrosis factor-α. Forced expression of the c-Jun upstream activator MKK7 reversed the cell growth and migration defects caused by MALT1 loss. In contrast, NF-κB activation via expression of p65ER, a fusion protein containing NF-κB p65 and the tamoxifen-responsive mutant estrogen receptor, induced minimal effects on cell proliferation, but diminished cell death induced by MALT1 loss and TRAIL treatment. Together, these findings demonstrate that MALT1 promotes melanoma cell proliferation and motility through JNK/c-Jun, and enhances melanoma cell survival through NF-κB, underscoring MALT1 as a potential therapeutic target and biomarker for malignant melanoma.
登录
查看更多内容
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
10.1
作者：
Dierlamm, Judith;Penas, Eva M. Murga;Siebert, Reiner
通讯作者：
Siebert, Reiner
影响因子：
30.5
作者：
Coornaert, Beatrice;Baens, Mathijs;Beyaert, Rudi
通讯作者：
Beyaert, Rudi
影响因子：
51.1
作者：
Ascierto, Paolo A.;Schadendorf, Dirk;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
影响因子：
8.8
作者：
Fedorenko, I. V.;Gibney, G. T.;Sondak, V. K.;Smalley, K. S. M.
通讯作者：
Smalley, K. S. M.