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Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma.
Mol Cancer. 2014 May 17; 13:110.MC

Abstract

BACKGROUND

The E3 ubiquitin ligase Fbxw7 functions as a general tumor suppressor by targeting several well-known oncoproteins for ubiquitination and proteasomal degradation. However, the clinical significance of Fbxw7 and the mechanisms involved in the anti-cancer effect of Fbxw7 in HCC are not clear.

METHOD

The Fbxw7 and YAP expression in 60 samples of surgical resected HCC and matched normal tumor-adjacent tissues were assessed using IHC or immunoblotting. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay and MTT assay were used to detect proliferation and apoptosis of HCC cells. The regulatory effect of Fbxw7 on YAP in HCC cells was confirmed by qRT-PCR, immunoblotting and immunofluorescence. Co-immunoprecipitation was used to analyze interaction between YAP and Fbxw7. Nude mice subcutaneous injection, Ki-67 staining and TUNEL assay were used to evaluate tumor growth and apoptosis in vivo.

RESULTS

In this study, we found that Fbxw7 expression was impaired in HCC tissues and loss of Fbxw7 expression was correlated with poor clinicopathological features including large tumor size, venous infiltration, high pathological grading and advanced TNM stage. Additionally, we demonstrated that patients with positive Fbxw7 expression had a better 5-year survival and Fbxw7 was an independent factor for predicting the prognosis of HCC patients. We confirmed that Fbxw7 inhibited HCC by inducing both apoptosis and growth arrest. Elevated YAP expression was observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated that Fbxw7 was inversely associated with YAP protein expression in HCC tissues. We also found that Fbxw7 regulated YAP protein abundance by targeting YAP for ubiquitination and proteasomal degradation in HCC. Furthermore, restoring YAP expression partially abrogated Fbxw7 induced HCC cell apoptosis and growth arrest in vitro and in vivo.

CONCLUSION

These results indicate that Fbxw7 may serve as a prognostic marker and that YAP may be a potential target of Fbxw7 in HCC.

Authors+Show Affiliations

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableDepartment of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. liuqingguang@vip.sina.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24884509

Citation

Tu, Kangsheng, et al. "Fbxw7 Is an Independent Prognostic Marker and Induces Apoptosis and Growth Arrest By Regulating YAP Abundance in Hepatocellular Carcinoma." Molecular Cancer, vol. 13, 2014, p. 110.
Tu K, Yang W, Li C, et al. Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma. Mol Cancer. 2014;13:110.
Tu, K., Yang, W., Li, C., Zheng, X., Lu, Z., Guo, C., Yao, Y., & Liu, Q. (2014). Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma. Molecular Cancer, 13, 110. https://doi.org/10.1186/1476-4598-13-110
Tu K, et al. Fbxw7 Is an Independent Prognostic Marker and Induces Apoptosis and Growth Arrest By Regulating YAP Abundance in Hepatocellular Carcinoma. Mol Cancer. 2014 May 17;13:110. PubMed PMID: 24884509.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma. AU - Tu,Kangsheng, AU - Yang,Wei, AU - Li,Chao, AU - Zheng,Xin, AU - Lu,Zhongtang, AU - Guo,Cheng, AU - Yao,Yingmin, AU - Liu,Qingguang, Y1 - 2014/05/17/ PY - 2014/02/11/received PY - 2014/05/15/accepted PY - 2014/6/3/entrez PY - 2014/6/3/pubmed PY - 2015/1/13/medline SP - 110 EP - 110 JF - Molecular cancer JO - Mol. Cancer VL - 13 N2 - BACKGROUND: The E3 ubiquitin ligase Fbxw7 functions as a general tumor suppressor by targeting several well-known oncoproteins for ubiquitination and proteasomal degradation. However, the clinical significance of Fbxw7 and the mechanisms involved in the anti-cancer effect of Fbxw7 in HCC are not clear. METHOD: The Fbxw7 and YAP expression in 60 samples of surgical resected HCC and matched normal tumor-adjacent tissues were assessed using IHC or immunoblotting. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay and MTT assay were used to detect proliferation and apoptosis of HCC cells. The regulatory effect of Fbxw7 on YAP in HCC cells was confirmed by qRT-PCR, immunoblotting and immunofluorescence. Co-immunoprecipitation was used to analyze interaction between YAP and Fbxw7. Nude mice subcutaneous injection, Ki-67 staining and TUNEL assay were used to evaluate tumor growth and apoptosis in vivo. RESULTS: In this study, we found that Fbxw7 expression was impaired in HCC tissues and loss of Fbxw7 expression was correlated with poor clinicopathological features including large tumor size, venous infiltration, high pathological grading and advanced TNM stage. Additionally, we demonstrated that patients with positive Fbxw7 expression had a better 5-year survival and Fbxw7 was an independent factor for predicting the prognosis of HCC patients. We confirmed that Fbxw7 inhibited HCC by inducing both apoptosis and growth arrest. Elevated YAP expression was observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated that Fbxw7 was inversely associated with YAP protein expression in HCC tissues. We also found that Fbxw7 regulated YAP protein abundance by targeting YAP for ubiquitination and proteasomal degradation in HCC. Furthermore, restoring YAP expression partially abrogated Fbxw7 induced HCC cell apoptosis and growth arrest in vitro and in vivo. CONCLUSION: These results indicate that Fbxw7 may serve as a prognostic marker and that YAP may be a potential target of Fbxw7 in HCC. SN - 1476-4598 UR - https://www.unboundmedicine.com/medline/citation/24884509/Fbxw7_is_an_independent_prognostic_marker_and_induces_apoptosis_and_growth_arrest_by_regulating_YAP_abundance_in_hepatocellular_carcinoma_ L2 - https://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-13-110 DB - PRIME DP - Unbound Medicine ER -