MAP-ing glioma invasion: Mitogen-activated protein kinase kinase 3 and p38 drive gliorna invasion and progression and predict patient survival
MAP-ing glioma invasion: Mitogen-activated protein kinase kinase 3 and p38 drive gliorna invasion and progression and predict patient survival
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DOI：
10.1158/1535-7163.mct-06-0711
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发表时间：
2007-04-01
影响因子：
5.7
通讯作者：
Berens, Michael E.
中科院分区：
文献类型：
--
作者：
Demuth, Tim;Reavie, Linsey B.;Berens, Michael E.
虽然星形胶质细胞脑肿瘤不会全身转移，但在肿瘤发生过程中，胶质瘤细胞采用了传统疗法靶向性差的侵袭性表型;因此，胶质瘤患者死于局部侵袭性肿瘤人群的复发。我们的工作旨在识别和验证侵袭性人类胶质瘤的新治疗靶点和生物标志物。通过激光捕获显微切割和全人类基因组表达微阵列从三维球体体外侵袭测定中产生侵袭性胶质瘤细胞相对于静止同源物的转录组。定性差异表达的候选侵袭基因证实了定量逆转录-PCR，临床上通过免疫组织化学组织芯片，免疫印迹手术标本，和两个独立的基因表达数据集的神经胶质肿瘤。基于细胞的测定和离体脑切片侵袭研究用于功能验证。我们确定丝裂原活化蛋白激酶（MAPK）激酶3（MKK 3）作为胶质瘤中p38 MAPK的关键激活剂; MKK 3激活与体外和体内p38激活密切相关。我们进一步报道，这些MAPK家族成员是肿瘤侵袭、进展和患者生存率差的强促进剂。任一候选物的抑制导致体外胶质瘤侵袭性显著降低。与合成致死性的概念一致，我们表明，通过干扰这些基因来抑制侵袭，极大地提高了被捕胶质瘤细胞对细胞毒性疗法的敏感性。因此，我们的研究结果表明，通过p38抑制剂加替莫唑胺的新型治疗组合干扰MKK 3信号传导，增加了胶质瘤对化疗的脆弱性。
Although astrocytic brain tumors do not metastasize systemically, during tumorigenesis glioma cells adopt an invasive phenotype that is poorly targeted by conventional therapies; hence, glioma patients die of recurrence from the locally invasive tumor population. Our work is aimed at identifying and validating novel therapeutic targets and biomarkers in invasive human gliomas. Transcriptomes of invasive glioma cells relative to stationary cognates were produced from a three-dimensional spheroid in vitro invasion assay by laser capture microdissection and whole human genome expression microarrays. Qualitative differential expression of candidate invasion genes was confirmed by quantitative reverse transcription-PCR, clinically by immunohistochemistry on tissue microarray, by immunoblotting on surgical specimens, and on two independent gene expression data sets of glial tumors. Cell-based assays and ex vivo brain slice invasion studies were used for functional validation. We identify mitogen-activated protein kinase (MAPK) kinase 3 (MKK3) as a key activator of p38 MAPK in glioma; MKK3 activation is strongly correlated with p38 activation in vitro and in vivo. We further report that these members of the MAPK family are strong promoters of tumor invasion, progression, and poor patient survival. Inhibition of either candidate leads to significantly reduced glioma invasiveness in vitro. Consistent with the concept of synthetic lethality, we show that inhibition of invasion by interference with these genes greatly sensitizes arrested glioma cells to cytotoxic therapies. Our findings therefore argue that interference with MKK3 signaling through a novel treatment combination of p38 inhibitor plus temozolomide heightens the vulnerability of glioma to chemotherapy.