Jingxiao Wang1, Haichuan Wang2, Michele Peters3, Ning Ding4, Silvia Ribback3, Kirsten Utpatel5, Antonio Cigliano6, Frank Dombrowski3, Meng Xu7, Xinyan Chen8, Xinhua Song9, Li Che9, Matthias Evert5, Antonio Cossu10, John Gordan11, Yong Zeng12, Xin Chen13, Diego F Calvisi14. 1. School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, United States. 2. Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, United States; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China. 3. Institute of Pathology, University of Greifswald, Greifswald, Germany. 4. Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. 5. Institute of Pathology, University of Regensburg, Regensburg, Germany. 6. Institute of Pathology, University of Greifswald, Greifswald, Germany; Institute of Pathology, University of Regensburg, Regensburg, Germany. 7. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, United States; Department of General Surgery, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China. 8. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, United States; Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China. 9. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, United States. 10. Unit of Pathology, Azienda Ospedaliero Universitaria Sassari, Sassari, Italy. 11. Department of Medicine, University of California, San Francisco, CA, United States. 12. Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China. Electronic address: zengyong@medmail.com.cn. 13. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, United States. Electronic address: xin.chen@ucsf.edu. 14. Institute of Pathology, University of Greifswald, Greifswald, Germany; Institute of Pathology, University of Regensburg, Regensburg, Germany. Electronic address: diego.calvisi@klinik.uni-regensburg.de.
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. Herein, we aimed to elucidate its role in intrahepatic cholangiocarcinoma (iCCA). METHODS: Herein, we first confirmed that FBXW7 gene expression was reduced in human iCCA specimens. To identify the molecular mechanisms by which 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). We then confirmed the role of c-MYC in human iCCA cell lines and its relationship to FBXW7 expression in human iCCA specimens. RESULTS: FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. 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: There is mounting evidence that FBXW7 functions as a tumor suppressor in many cancer types, including intrahepatic cholangiocarcinoma, through its ability to promote the degradation of numerous oncoproteins. Herein, we have shown that the low expression of FBXW7 is ubiquitous in human cholangiocarcinoma specimens. This low expression is correlated with increased c-MYC activity, leading to tumorigenesis. Our findings suggest that targeting c-MYC might be an effective treatment for intrahepatic cholangiocarcinoma.
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. Herein, we aimed to elucidate its role in intrahepatic cholangiocarcinoma (iCCA). METHODS: Herein, we first confirmed that FBXW7 gene expression was reduced in human iCCA specimens. To identify the molecular mechanisms by which 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). We then confirmed the role of c-MYC in human iCCA cell lines and its relationship to FBXW7 expression in human iCCA specimens. RESULTS:FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. 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: There is mounting evidence that FBXW7 functions as a tumor suppressor in many cancer types, including intrahepatic cholangiocarcinoma, through its ability to promote the degradation of numerous oncoproteins. Herein, we have shown that the low expression of FBXW7 is ubiquitous in humancholangiocarcinoma specimens. This low expression is correlated with increased c-MYC activity, leading to tumorigenesis. Our findings suggest that targeting c-MYC might be an effective treatment for intrahepatic cholangiocarcinoma.
Authors: J W Lee; Y H Soung; H J Kim; W S Park; S W Nam; S H Kim; J Y Lee; N J Yoo; S H Lee Journal: Eur J Cancer Date: 2006-07-05 Impact factor: 9.162
Authors: K J Schmitz; H Lang; J Wohlschlaeger; G C Sotiropoulos; H Reis; K W Schmid; H A Baba Journal: World J Gastroenterol Date: 2007-12-28 Impact factor: 5.742
Authors: B Xin; M Yamamoto; K Fujii; T Ooshio; X Chen; Y Okada; K Watanabe; N Miyokawa; H Furukawa; Y Nishikawa Journal: Oncogene Date: 2017-05-08 Impact factor: 9.867
Authors: Antonio Cigliano; Shanshan Zhang; Silvia Ribback; Sara Steinmann; Marcella Sini; Cindy E Ament; Kirsten Utpatel; Xinhua Song; Jingxiao Wang; Maria G Pilo; Fabian Berger; Haichuan Wang; Junyan Tao; Xiaolei Li; Giovanni M Pes; Serena Mancarella; Gianluigi Giannelli; Frank Dombrowski; Matthias Evert; Diego F Calvisi; Xin Chen; Katja Evert Journal: J Exp Clin Cancer Res Date: 2022-06-03
Authors: Haichuan Wang; Xinhua Song; Haotian Liao; Pan Wang; Yi Zhang; Li Che; Jie Zhang; Yi Zhou; Antonio Cigliano; Cindy Ament; Daphne Superville; Silvia Ribback; Melissa Reeves; Giovanni M Pes; Binyong Liang; Hong Wu; Matthias Evert; Diego F Calvisi; Yong Zeng; Xin Chen Journal: Hepatology Date: 2021-06-15 Impact factor: 17.298
Authors: Kyungjoo Cho; Simon Weonsang Ro; Sang Hyun Seo; Youjin Jeon; Hyuk Moon; Do Young Kim; Seung Up Kim Journal: Cancers (Basel) Date: 2019-12-19 Impact factor: 6.639