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.
Highlights
hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide
Since the presence of Fbxw7 reduces the ability of cell colony formation, we investigated whether the ablation of Fbxw7 mRNA affects cell proliferation and expression of cell cycle regulators as c-Myc and Cyclin E, both degradation targets of Fbxw7
We first demonstrated that Fbxw7 is a key tumor suppressor that regulated cell proliferation in different HCC cell lines, given that Fbxw7 mRNA expression correlated negatively with colony formation ability
Summary
HCC is one of the most common malignancies worldwide. It is a common cancer and occurring with increasing frequency in China [1]. Fbxw is a member of the F-box protein family, which determines the substrate specificity of the SCF-type E3 complex, and is able to target various oncogenic proteins for ubiquitination such as Cyclin E, c-Myc, c-Jun, Notch, Presenilin, Mcl-1, Sterol regulatory element-binding proteins (SREBP), mTOR, Krüppel-like factors (KLFs), c-Myb and Aurora A [4,5,6] Because all these characterized substrates are well known oncogenic proteins that are frequently overexpressed in a variety of human cancers, Fbxw is believed to be a tumor suppressor that contributes to the negative regulation of these oncogenic proteins [6]. The role and mechanisms involved in Fbxw are still unclear in HCC
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