BACKGROUND & AIMS: The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types due to its ability to promote the degradation of numerous oncogenic target proteins. METHODS: Here, we investigated the role of FBXW7 in intrahepatic cholangiocarcinoma (iCCA) using mouse models ad hoc generated, iCCA cell lines, and human iCCA specimens. RESULTS: FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. To identify the molecular mechanisms whereby FBXW7 dysfunction promotes cholangiocarcinogenesis, we generated a mouse model by hydrodynamic tail vein injection of Fbxw7ΔF, a dominant negative form of Fbxw7, either alone or in association with an activated/myristylated form of AKT (myr-AKT). While forced overexpression of Fbxw7ΔF alone did not induce any appreciable abnormality in the mouse liver, co-expression with AKT triggered cholangiocarcinogenesis and mice had to be euthanized by 15 weeks post-injection. At the molecular level, a strong induction of FBXW7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-Myc was consistently confirmed as a FBXW7 target in human CCA cell lines. Most importantly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 only delayed tumorigenesis in the same model. In human iCCA specimens, an inverse correlation between the expression levels of FBXW7 and c-Myc transcriptional activity was observed. CONCLUSIONS: Downregulation of FBXW7 is ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice via c-Myc-dependent mechanisms. Targeting c-Myc might represent an innovative therapy against iCCA exhibiting low FBXW7 expression. LAY SUMMARY: Mounting evidence implies the tumor suppressor role of FBXW7 in many cancer types, including intrahepatic cholangiocarcinoma (iCCA), by its ability to promote the degradation of numerous oncoproteins. Our present findings indicate the ubiquitous low expression of FBXW7, which is inversely correlated with c-MYC activity, in human CCA specimens. In the mouse liver, activation of Fbxw7 together with AKT overexpression induces rapid iCCA formation, which is prevented by c-Myc suppression. Thus, targeting c-MYC might be an effective treatment for human iCCA with low FBXW7 levels.

Loss of Fbxw7 synergizes with activated AKT signaling to promote c-Myc dependent cholangiocarcinogenesis / Wang, Jingxiao; Wang, Haichuan; Peters, Michele; Ding, Ning; Ribback, Silvia; Utpatel, Kirsten; Cigliano, Antonio; Dombrowski, Frank; Xu, Meng; Chen, Xinyan; Song, Xinhua; Che, Li; Evert, Matthias; Cossu, Antonio; Gordan, John; Zeng, Yong; Chen, Xin; Calvisi, Diego F.. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 71:4(2019), pp. 742-752. [10.1016/j.jhep.2019.05.027]

Loss of Fbxw7 synergizes with activated AKT signaling to promote c-Myc dependent cholangiocarcinogenesis

Cigliano, Antonio;Cossu, Antonio;Calvisi, Diego F.
2019-01-01

Abstract

BACKGROUND & AIMS: The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types due to its ability to promote the degradation of numerous oncogenic target proteins. METHODS: Here, we investigated the role of FBXW7 in intrahepatic cholangiocarcinoma (iCCA) using mouse models ad hoc generated, iCCA cell lines, and human iCCA specimens. RESULTS: FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. To identify the molecular mechanisms whereby FBXW7 dysfunction promotes cholangiocarcinogenesis, we generated a mouse model by hydrodynamic tail vein injection of Fbxw7ΔF, a dominant negative form of Fbxw7, either alone or in association with an activated/myristylated form of AKT (myr-AKT). While forced overexpression of Fbxw7ΔF alone did not induce any appreciable abnormality in the mouse liver, co-expression with AKT triggered cholangiocarcinogenesis and mice had to be euthanized by 15 weeks post-injection. At the molecular level, a strong induction of FBXW7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-Myc was consistently confirmed as a FBXW7 target in human CCA cell lines. Most importantly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 only delayed tumorigenesis in the same model. In human iCCA specimens, an inverse correlation between the expression levels of FBXW7 and c-Myc transcriptional activity was observed. CONCLUSIONS: Downregulation of FBXW7 is ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice via c-Myc-dependent mechanisms. Targeting c-Myc might represent an innovative therapy against iCCA exhibiting low FBXW7 expression. LAY SUMMARY: Mounting evidence implies the tumor suppressor role of FBXW7 in many cancer types, including intrahepatic cholangiocarcinoma (iCCA), by its ability to promote the degradation of numerous oncoproteins. Our present findings indicate the ubiquitous low expression of FBXW7, which is inversely correlated with c-MYC activity, in human CCA specimens. In the mouse liver, activation of Fbxw7 together with AKT overexpression induces rapid iCCA formation, which is prevented by c-Myc suppression. Thus, targeting c-MYC might be an effective treatment for human iCCA with low FBXW7 levels.
2019
Loss of Fbxw7 synergizes with activated AKT signaling to promote c-Myc dependent cholangiocarcinogenesis / Wang, Jingxiao; Wang, Haichuan; Peters, Michele; Ding, Ning; Ribback, Silvia; Utpatel, Kirsten; Cigliano, Antonio; Dombrowski, Frank; Xu, Meng; Chen, Xinyan; Song, Xinhua; Che, Li; Evert, Matthias; Cossu, Antonio; Gordan, John; Zeng, Yong; Chen, Xin; Calvisi, Diego F.. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 71:4(2019), pp. 742-752. [10.1016/j.jhep.2019.05.027]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/224825
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