Hubaux Roland, Thu Kelsie L, Vucic Emily A, Pikor Larissa A, Kung Sonia H Y, Martinez Victor D, Mosslemi Mitra, Becker-Santos Daiana D, Gazdar Adi F, Lam Stephen, Lam Wan L
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
Hamon Center of Therapeutics, University of Texas South Western, Dallas, TX.
Int J Cancer. 2015 Nov 1;137(9):2072-82. doi: 10.1002/ijc.29577. Epub 2015 May 6.
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.
微管亲和力调节激酶（MARKs）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联，且尚无研究探讨其在肺癌中的作用。在本研究中，我们发现MARK2经常因DNA低甲基化和拷贝数增加而受到破坏，导致在独立的肺癌队列中一致过表达，并且我们证明了MARK2在肺癌生物学中的作用。在肺癌细胞系中对MARK2进行操作表明其参与细胞活力和非锚定依赖性生长。对操作后的细胞系和临床肿瘤标本的分析确定了MARK2在细胞周期激活和DNA修复中的潜在作用。通过荧光素酶测定确定了MARK2与E2F、Myc/Max和NF-κB途径之间的关联，对NF-κB途径的深入评估表明，由于非经典NF-κB信号的激活，MARK2表达与NF-κB之间呈负相关。最后，我们表明高MARK2表达水平与对顺铂（一种用于肺癌的标准一线化疗药物）的耐药性相关。总体而言，我们的工作支持MARK2在促进肺癌恶性表型以及潜在调节对DNA损伤化疗药物顺铂的反应中发挥作用。
