Mixed lineage kinase ZAK promotes epithelial-mesenchymal transition in cancer progression.
Mixed lineage kinase ZAK promotes epithelial-mesenchymal transition in cancer progression.
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混合谱系激酶 ZAK 促进癌症进展中的上皮间质转化。
DOI：
10.1038/s41419-017-0161-x
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发表时间：
2018-02-02
影响因子：
9
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Li L;Su N;Zhou T;Zheng D;Wang Z;Chen H;Yuan S;Li W
ZAK是一种混合的谱系激酶，通常被描述为细胞生长的正或负调节因子。我们确定它是在我们的Kinome cDNA筛查中发现的上皮间充质转化(EMT)有效调节因子中最热门的基因之一。异位表达Zak可促进多种上皮细胞系的EMT表型和抗凋亡能力，但对不同细胞系的细胞生长有不同的影响。相反，侵袭性间充质癌细胞中ZAK的缺失逆转了EMT表型，增加了对常规细胞毒药物的敏感性，并减弱了骨转移潜能，对原发肿瘤生长几乎没有影响。从机制上讲，ZAK介导的EMT与ZEB1的激活和上皮剪接调节蛋白(ESRPs)的抑制有关，从而导致CD44的表达从上皮CD44v8-9亚型转变为间充质CD44s亚型。值得注意的是，转录分析表明，在许多人类癌症类型中，ZAK的过度表达与低存活率显著相关。对乳腺浸润性癌的组织芯片分析进一步支持ZAK过度表达是影响乳腺癌总生存率的一个独立的不良预后因素。通过与ZAK联合使用，乳腺癌其他常见临床病理标志物的预后准确率提高了21%。综上所述，这些结果表明促进EMT是ZAK在癌症进展中的主要作用。他们还强调了它作为识别高危患者的生物标记物的潜力，并表明它有望成为抑制转移和克服耐药性的治疗靶点。
ZAK, a mixed lineage kinase, is often described as a positive or negative regulator of cell growth. We identified it as one of the top hits in our kinome cDNA screen for potent regulators of epithelial mesenchymal transition (EMT). Ectopic expression of ZAK promoted EMT phenotypes and apoptosis resistance in multiple epithelial cell lines, while having different impacts on cell growth in different cell lines. Conversely, depletion of ZAK in aggressive mesenchymal cancer cells reversed EMT phenotypes, increased sensitivity to conventional cytotoxic drugs, and attenuated bone metastasis potential, with little impact on primary tumor growth. Mechanistically, ZAK-mediated EMT is associated with activation of ZEB1 and suppression of epithelial splicing regulatory proteins (ESRPs), which results in a switch in CD44 expression from the epithelial CD44v8–9 isoform to the mesenchymal CD44s isoform. Of note, transcriptomic analysis showed that ZAK overexpression is significantly associated with poor survival in a number of human cancer types. Tissue microarray analysis on breast invasive carcinoma further supported that ZAK overexpression is an independent poor prognostic factor for overall survival in breast cancer. Through combination with ZAK, prognostic accuracy of other common clinicopathological markers in breast cancer is improved by up to 21%. Taken together, these results suggest that promoting EMT is the primary role for ZAK in cancer progression. They also highlight its potential as a biomarker to identify high-risk patients, and suggest its promise as a therapeutic target for inhibiting metastasis and overcoming drug resistance.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8
作者：
Horiguchi, K.;Sakamoto, K.;Koinuma, D.;Semba, K.;Inoue, A.;Inoue, S.;Fujii, H.;Yamaguchi, A.;Miyazawa, K.;Miyazono, K.;Saitoh, M.
通讯作者：
Saitoh, M.
影响因子：
16.6
作者：
Liu, Jinfeng;McCleland, Mark;Stawiski, Eric W.;Gnad, Florian;Mayba, Oleg;Haverty, Peter M.;Durinck, Steffen;Chen, Ying-Jiun;Klijn, Christiaan;Jhunjhunwala, Suchit;Lawrence, Michael;Liu, Hanbin;Wan, Yinan;Chopra, Vivek;Yaylaoglu, Murat B.;Yuan, Wenlin;Ha, Connie;Gilbert, Houston N.;Reeder, Jens;Pau, Gregoire;Stinson, Jeremy;Stern, Howard M.;Manning, Gerard;Wu, Thomas D.;Neve, Richard M.;de Sauvage, Frederic J.;Modrusan, Zora;Seshagiri, Somasekar;Firestein, Ron;Zhang, Zemin
通讯作者：
Zhang, Zemin
EMT，癌症干细胞和耐药性：癌症战争中新兴的邪恶轴。
影响因子：
8
作者：
Singh, A.;Settleman, J.
通讯作者：
Settleman, J.