Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression.
Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression.
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DOI：
10.1097/jto.0000000000000007
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Theodorescu D
中科院分区：
文献类型：
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作者：
Guin S;Ru Y;Wynes MW;Mishra R;Lu X;Owens C;Barn AE;Vasu VT;Hirsch FR;Kern JA;Theodorescu D
KRAS突变是非小细胞肺癌（NSCLC）患者预后不良的标志物。RALA和RALB GTP酶位于RAS的下游，并参与RAS介导的肿瘤发生。然而，其在NSCLC中KRAS突变背景下的生物学或预后作用尚不清楚。使用人类肿瘤的表达分析和一组细胞系结合功能性体内和体外实验，我们评估了RAL在NSCLC中的预后和功能重要性及其与KRAS表达和突变的关系。NSCLC患者的免疫组化（N=189）和转录组学（N=337）分析显示RALA和RALB高表达与生存率低相关。在一组14个人NSCLC细胞系中，RALA和RALB在KRAS突变细胞系中具有更高的表达，而RALA而不是RALB活性在KRAS突变细胞系中更高。RAL旁系同源物的耗尽鉴定了依赖RAL表达进行增殖和锚定非依赖性生长的细胞系。总体而言，携带甘氨酸至胱氨酸（G12 C）KRAS突变的NSCLC细胞系的生长对RAL消耗比野生型KRAS细胞系更敏感。使用来自337个人类肿瘤的基因表达和结果数据，RAL-KRAS相互作用分析显示KRAS和RAL parkinsect表达共同影响患者预后。RAL GT3表达对NSCLC患者的KRAS状态具有重要的额外预后信息。同时靶向RAL可能为携带G12 C KRAS突变的NSCLC患者提供一种新的治疗方法。
KRAS mutations are poor prognostic markers for patients with non-small cell lung cancer (NSCLC). RALA and RALB GTPases lie downstream of RAS and are implicated in RAS mediated tumorigenesis. However, their biological or prognostic role in the context of KRAS mutation in NSCLC is unclear. Using expression analysis of human tumors and a panel of cell lines coupled with functional in vivo and in vitro experiments, we evaluated the prognostic and functional importance of RAL in NSCLC and their relationship to KRAS expression and mutation. Immunohistochemical (N=189) and transcriptomic (N=337) analyses of NSCLC patients revealed high RALA and RALB expression was associated with poor survival. In a panel of 14 human NSCLC cell lines, RALA and RALB had higher expression in KRAS mutant cell lines while RALA but not RALB activity was higher in KRAS mutant cell lines. Depletion of RAL paralogs identified cell lines that are dependent on RAL expression for proliferation and anchorage independent growth. Overall, growth of NSCLC cell lines which carry a glycine to cystine (G12C) KRAS mutation were more sensitive to RAL depletion than those with wild-type KRAS. Using gene expression and outcome data from 337 human tumors, RAL-KRAS interaction analysis revealed that KRAS and RAL paralog expression jointly impact patient prognosis. RAL GTPase expression carries important additional prognostic information to KRAS status in NSCLC patients. Simultaneously targeting RAL may provide a novel therapeutic approach in NSCLC patients harboring G12C KRAS mutations.