Recombinant human adenovirus-p53 injection induced apoptosis in hepatocellular carcinoma cell lines mediated by p53-Fbxw7 pathway, which controls c-Myc and cyclin E
Authors: Xin Zheng
Jing Zhang
Qingguang Liu
Chao Li
Jie Gao
Zhenyu Zhou
Yingmin Yao
Kangsheng Tu
Journal: PloS one (2013)
Discipline: Multidisciplinary
Keywords: F-box; WD repeat domain-containing 7; tumor suppressor; ubiquitination; oncoproteins
Affiliations: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Abstract:  F-box and WD repeat domain-containing 7 (Fbxw7/hAgo/hCdc4/Fbw7) is a p53-dependent tumor suppressor and leads to ubiquitination-mediated suppression of several oncoproteins including c-Myc, cyclin E, Notch, c-Jun and others. Our previous study has indicated that low expression of Fbxw7 was negatively correlated with c-Myc, cyclin E and mutant-p53 in hepatocellular carcinoma (HCC) tissues. But the role and mechanisms of Fbxw7 in HCC are still unknown. Here, we investigated the function of Fbxw7 in HCC cell lines and the anti-tumor activity of recombinant human adenovirus-p53 injection (rAd-p53, Gendicine) administration in vitro and in vivo. Fbxw7-specific siRNA enhanced expression of c-Myc and cyclin E proteins and increased proliferation in cell culture. rAd-p53 inhibited tumor cell growth with Fbxw7 upregulation and c-Myc and cyclin E downregulation in vitro and a murine HCC model. This effect could be partially reverted using Fbxw7-specific siRNA. Here, we suggest that the activation of Fbxw7 by adenoviral delivery of p53 leads to increased proteasomal degradation of c-Myc and cyclin E enabling growth arrest and apoptosis. Addressing this pathway, we identified that rAd-p53 could be a potential therapeutic agent for HCC. 

Retracted: Yes

PubPeer comments:
 This post is part of a series highlighting ethically challenged xenografts in nude mice. In the previous posting, the three mice shown all suffered necroses, implying that this was a general problem for that particular cancer when xenografted https: pubpeer.com publications 0FBFCA16FC9A1B27D3969C782A45E4 At least according to these UK-based guidelines, tumours should not exceed 1.5 cm diameter and mice with necrotic xenografts should be terminated within two days https: www.ncbi.nlm.nih.gov pmc articles PMC2883160 In Fig. 5 of this PLOS ONE paper, the control xenografts are much too big. A ruler is helpfully provided, as are the plotted volumes which reach ~6 cm3. Tumours should not be allowed to develop to the point where they impair locomotion. But is that the case for the mouse second from right? ![image] , 
 I thank PLOS One for conducting an investigation and then retracting this paper for unethical animal husbandry. Although I first posted this in early 2018 at PubPeer, I did not contact the journal with my concerns until later in 2019. I became motivated to do so when it had become clear that they had put in place sufficient resources to review past papers for ethics and fraud allegations. ![image] , 
 2020 retraction norice. https: journals.plos.org plosone article?id=10.1371 journal.pone.0231287 After this article [1] was published, concerns were raised about the mouse tumor sizes reported in Figure 5. The underlying data for Figure 5, which were provided in post-publication discussions, confirmed that tumors up to 8.6 cm3 were observed in these experiments. The authors also confirmed that in some cases tumors exceeded 20 mm in diameter. They provided general information about health monitoring and endpoint guidance at their institution, and noted that animal health was monitored every three days with increased monitoring of clinical signs and symptoms for animals bearing tumors 1.5 cm in diameter. In response to queries about the experimental endpoints, the authors clarified that they planned the experiments aiming to assess differences in tumor growth and survival, but at five weeks post-implantation they terminated the experiment because they observed three cases in which tumors impaired locomotion. The authors did not provide further study-specific information as to humane endpoint criteria or specific animal welfare considerations. A member of PLOS ONEu2019s Animal Research Advisory Group assessed the article and the authorsu2019 comments and confirmed that the tumor sizes reported in this article far exceed community standards for humane endpoint limits in mouse tumor studies. The advisor noted that the tumor results present a significant animal welfare and ethical concern. In light of the above concerns, the PLOS ONE Editors retract this article. The editors regret that these concerns were not addressed at the time of the original review process. KT notified the journal that all authors disagree with retraction. XZ, ZZ, CL, JZ, JG, YY, QL either could not be reached or did not respond directly. Reference 1.Tu K, Zheng X, Zhou Z, Li C, Zhang J, Gao J, et al. (2013) Recombinant Human Adenovirus-p53 Injection Induced Apoptosis in Hepatocellular Carcinoma Cell Lines Mediated by p53-Fbxw7 Pathway, Which Controls c-Myc and Cyclin E. PLoS ONE 8(7): e68574. https: doi.org 10.1371 journal.pone.0068574 ,