Function Analysis Of Mutant P53 And TGF-β Signal During Lung Cancer Tumorigenesis And Metastasis

Specific p53 mutations abrogate the tumor suppressive functions by gaining new abilities to promote tumorigenesis. Inactivation of p53 is known to distort the TGF-β signaling, which paradoxically displays both tumor-suppressive and pro-oncogenic function. The molecular mechanisms how mutant p53 simultaneously antagonizes tumor-suppressive and synergizes tumor-promoting function of TGF-β pathway remain elusive. Here we demonstrate that mutant p53 differentially regulates subsets of TGF-β target genes, by an enhanced binding to the MH2 domain in Smad3 upon the integration of ERK signaling, therefore disrupting the Smad3/Smad4 complex formation. Silencing Smad2, inhibition of ERK or introducing a phosphorylation defective mutation at Ser392 in p53 abrogates the R175H mutant p53 dependent regulation of these TGF-β target genes. Our study provide a mechanism to reconcile the seemingly contradictory observations that mutant p53 can both attenuate and cooperate with the TGF-β pathway to promote cancer cell malignancy in a same cell type.Smad4 is a central mediator of TGF-β signaling, its expression is down-regulated or lost at the malignant stage in several cancer types, and its functions as tumor suppressor are highly context-specific as exemplified by head-and-neck cancer and pancreatic cancer. In order to reveal its role during lung cancer progression, we knock out Smad4 in one of the classical lung cancer mouse model (genotype:KRasG12D/p53-/-). Smad4 deficiency does not initiate the tumorigenesis but acts as a promoter to accelerate or synergize the development and progression of lung cancer which is started by other oncogenic pathway. Further investigation indicates the absence of Smad4 will increase the PAK3 expression, which does not under control of conical TGF-β signal. Experimental data suggests that PAK3 can pass the oncogenic signal to JNK-Jun by phosphorylation the MKK7. A compound from plant named Fisetin can directly block the signal from PAK3 to MKK7, which will lead to the inhibition of lung cancer cells’ metastasis and invasion. Our results uncover the important role of PAK3 during the lung cancer progression, which could be a potential clinical target for the treatment of lung cancer metastasis and invasion at later stage and at the same time, we also suggest a potential inhibitor for PAK3.