Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas.
Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas.
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DOI：
10.1371/journal.pone.0002125
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发表时间：
2008-05-07
期刊：
影响因子：
3.7
通讯作者：
Felsher DW
中科院分区：
文献类型：
--
作者：
Tran PT;Fan AC;Bendapudi PK;Koh S;Komatsubara K;Chen J;Horng G;Bellovin DI;Giuriato S;Wang CS;Whitsett JA;Felsher DW
有条件的转基因模型已经确定，肿瘤需要持续的癌基因激活来维持肿瘤，表现出被称为“癌基因成瘾”的现象。然而，大多数癌症是由多种遗传事件引起的，这使得难以确定哪些癌基因或癌基因的组合将是其治疗的最有效靶点。为了研究MYC和K-rasG 12 D癌基因如何合作启动和维持肿瘤发生，我们产生了肺腺癌和淋巴瘤的双条件转基因肿瘤模型。MYC和K-rasG 12 D协同肿瘤发生的能力以及这些癌基因失活导致肿瘤消退的能力取决于特定的组织背景。MYC、K-rasG 12 D或MYC/K-rasG 12 D诱导的淋巴瘤在一种或两种癌基因失活后表现出持续消退。然而，与此形成鲜明对比的是，MYC诱导的肺肿瘤在癌基因失活后未能完全消退;而K-rasG 12 D诱导的肺肿瘤完全消退。重要的是，MYC和K-rasG 12 D两者的组合失活更频繁地导致肺肿瘤完全消退。为了解释MYC和K-rasG 12 D在维持肺肿瘤中的不同作用，我们发现K-rasG 12 D信号传导的下游介质Stat 3和Stat 5在条件性K-rasG 12 D而不是MYC失活后去磷酸化。相反，Stat 3在MYC和/或K-rasG 12 D失活后在淋巴瘤细胞中变得去磷酸化。有趣的是，发现MYC诱导的肺肿瘤在MYC失活后未能消退，具有持续的Stat 3和Stat 5磷酸化。总之，我们的研究结果指出了K-Ras和相关下游Stat效应通路在淋巴瘤和肺肿瘤的启动和维持中的重要性。我们认为，联合靶向致癌途径更有可能是有效的治疗肺癌和淋巴瘤。
Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as “oncogene-addiction.” However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment. To examine how the MYC and K-rasG12D oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-rasG12D to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-rasG12D- or MYC/K-rasG12D-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-rasG12D-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-rasG12D resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-rasG12D in maintenance of lung tumors, we found that the down-stream mediators of K-rasG12D signaling, Stat3 and Stat5, are dephosphorylated following conditional K-rasG12D but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-rasG12D. Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation. Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas.
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影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
56.9
作者：
Jain, M;Arvanitis, C;Felsher, DW
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Felsher, DW
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45.3
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Heinrich, MC;Corless, CL;Fletcher, JA
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15.9
作者：
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Bromberg, Jacqueline F.
影响因子：
10.5
作者：
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