Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer.
Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer.
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DOI：
10.1002/ijc.29577
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发表时间：
2015-11-01
影响因子：
6.4
通讯作者：
Lam WL
中科院分区：
文献类型：
--
作者：
Hubaux R;Thu KL;Vucic EA;Pikor LA;Kung SH;Martinez VD;Mosslemi M;Becker-Santos DD;Gazdar AF;Lam S;Lam WL
微管亲和力调节激酶（MARK）参与多种细胞功能，但很少有研究将MARK激酶表达与癌症相关，也没有研究探讨其在肺癌中的作用。在这项研究中，我们发现MARK 2经常被DNA低甲基化和拷贝增加破坏，导致独立的肺肿瘤队列中一致的过度表达，我们证明了MARK 2在肺肿瘤生物学中的作用。肺细胞系中MARK 2的操作揭示了其参与细胞活力和非贴壁依赖性生长。对操作的细胞系和临床肿瘤标本的分析确定了MARK 2在细胞周期激活和DNA修复中的潜在作用。通过荧光素酶试验鉴定了MARK 2与E2 F、Myc/Max和NF-κB通路之间的关联，对NF-κB通路的深入评估表明，由于非经典NF-κB信号传导的激活，MARK 2表达与NF-κB之间存在负相关。最后，我们发现MARK 2高表达水平与顺铂耐药相关，顺铂是肺癌的标准一线化疗药物。总的来说，我们的工作支持MARK 2在促进肺癌恶性表型中的作用，并可能调节对DNA损伤化疗药物顺铂的反应。
Microtubule affinity-regulating kinases (MARKs) are involved in several cellular functions but few studies have correlated MARK kinase expression with cancer, and none have explored their role in lung cancer. In this study, we identified MARK2 as frequently disrupted by DNA hypomethylation and copy gain, resulting in concordant overexpression in independent lung tumor cohorts and we demonstrate a role for MARK2 in lung tumor biology. Manipulation of MARK2 in lung cell lines revealed its involvement in cell viability and anchorage-independent growth. Analyses of both manipulated cell lines and clinical tumor specimens identified a potential role for MARK2 in cell cycle activation and DNA repair. Associations between MARK2 and the E2F, Myc/Max, and NF-κB pathways were identified by luciferase assays and in-depth assessment of the NF-κB pathway suggests a negative association between MARK2 expression and NF-κB due to activation of non-canonical NF-κB signaling. Finally, we show that high MARK2 expression levels correlate with resistance to cisplatin, a standard first line chemotherapy for lung cancer. Collectively, our work supports a role for MARK2 in promoting malignant phenotypes of lung cancer and potentially modulating response to the DNA damaging chemotherapeutic, cisplatin.