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. 2015 Dec 29;6(42):44794-805.
doi: 10.18632/oncotarget.6328.

Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas

Antoine M Snijders  1 , Yueyong Liu  1   2 , Li Su  1 , Yurong Huang  1 , Jian-Hua Mao  1
Affiliations

Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas

Antoine M Snijders et al. Oncotarget. .

Abstract

The tumor suppressor gene FBXW7 is deleted and mutated in many different types of human cancers. FBXW7 primarily exerts its tumor suppressor activity by ubiquitinating different oncoproteins including mTOR. Here we used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that radiation-induced thymic lymphomas from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. Finally, we demonstrated that the Fbxw7 gene signatures identified in mouse tumors significantly overlap with FBXW7 co-expressed genes in human cancers. Importantly these common FBXW7 gene signatures between mouse and human are predictive for disease-free survival in human colon, breast and lung adenocarcinoma cancer patients. These results provide novel insights into the role of FBXW7 in tumor development and have identified a number of potential targets for therapeutic intervention.

Keywords: FBXW7; mTOR; radiation; rapamycin; thymic lymphoma.

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Conflict of interest statement

COMPETING INTEREST

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. Significant transcriptional deregulation in Fbxw7 heterozygous thymic lymphomas
A. Gene transcript levels in thymic lymphomas from vehicle and rapamycin treated Fbxw7+/−p53+/− mice were compared to these in thymic lymphomas from p53+/− mice. B. Unsupervised hierarchical clustering of 259 genes differentially expressed in tumors isolated from vehicle and rapamycin treated Fbxw7+/−p53+/− mice compared to p53+/− mice (increased expression indicated in yellow; decreased expression indicated in blue). C. Gene interaction network of 259 overlapping genes. D. Pathways significantly associated with 259 overlapping genes. E. Normalized expression of Fbxw7, Srebf2 and Hmgcs1 in radiation induced thymic lymphomas of vehicle or rapamycin treated p53+/−,and vehicle or rapamycin treated Fbxw7+/−p53+/− mice.
Figure 2
Figure 2. Enrichment of cell cycle related genes in Fbxw7 heterozygous thymic lymphomas
A. Unsupervised hierarchical clustering of 956 genes differentially expressed in thymic lymphomas of vehicle treated Fbxw7+/−p53+/− mice compared to thymic lymphomas of p53+/− mice (increased expression indicated in yellow; decreased expression indicated in blue). B. Gene interaction network of 956 genes enriched with cell cycle related genes. C. Pathways significantly associated with 956 gene set. D. Normalized expression of Ccnb1 and Bub1b in radiation induced thymic lymphomas of p53+/− and vehicle or rapamycin treated Fbxw7+/−p53+/− mice.
Figure 3
Figure 3. ATF4 stress response genes upregulated in Fbxw7 heterozygous thymic lymphoma after rapamycin treatment
A. Unsupervised hierarchical clustering of 976 genes differentially expressed in thymic lymphomas of rapamcyin treated Fbxw7+/−p53+/− mice compared to thymic lymphomas of p53+/− mice (increased expression indicated in yellow; decreased expression indicated in blue). B. Upstream transcriptional regulator analyses of 976 genes differentially expressed in rapamycin treated mice revealed a significant association with ATF4. C. Pathways significantly associated with 976 gene set. D. Normalized expression of Atf4, Atf5 and in radiation induced thymic lymphomas of p53+/− and vehicle or rapamycin treated Fbxw7+/−p53+/− mice.
Figure 4
Figure 4. Fbxw7 correlated gene expression signature associated with disease free survival in human cancer patients
A. Significant overlap between genes deregulated in thymic lymphomas of Fbxw7+/−p53+/− mice compared to p53+/− mice and genes positively correlated with FBXW7 (Pearson correlation > 0.5) in human colorectal adenocarcinoma (p-value of enrichment 3.3E-13). B. Increased expression of overlapping gene signature is associated with increased disease free survival in human colon cancer patients (GSE40967; p = 0.02). C. Significant overlap between genes deregulated in thymic lymphomas of Fbxw7+/−p53+/− mice compared to p53+/− mice and genes positively correlated with FBXW7 (Pearson correlation > 0.2) in human breast cancer patients (p-value of enrichment 1.0E-05). D. Increased expression of overlapping gene signature is associated with increased disease free survival in human breast cancer patients (GSE1456; p = 0.03 and GSE6352; p = 0.04). E. Significant overlap between genes deregulated in thymic lymphomas of Fbxw7+/−p53+/− mice compared to p53+/− mice and genes positively correlated with FBXW7 (Pearson correlation > 0.2) in human lung cancer patients (p-value of enrichment 9.5E-05). F. Increased expression of overlapping gene signature is associated with increased disease free survival in human lung cancer patients (GSE31210; p = 0.03).
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