Abstract
Highly selective therapy for hepatocellular carcinoma (HCC) remains an unmet medical need. In present study, we found that the tumor suppressor microRNA, let-7 was significantly downregulated in a proportion of primary HCC tissues (12 of 33, 36.4%) and HCC cell lines. In line with this finding, we have engineered a chimeric Ad5/11 fiber oncolytic adenovirus, SG7011let7T, by introducing eight copies of let-7 target sites (let7T) into the 3′ untranslated region of E1A, a key gene associated with adenoviral replication. The results showed that the E1A expression (both RNA and protein levels) of the SG7011let7T was tightly regulated according to the endogenous expression level of the let-7. As contrasted with the wild-type adenovirus and the control virus, the replication of SG7011let7T was distinctly inhibited in normal liver cells lines (i.e. L-02 and WRL-68) expressing high level of let-7 (>300 folds), whereas was almost not impaired in HCC cells (i.e. Hep3B and PLC/PRF/5) with low level of let-7. Consequently, the cytotoxicity of SG7011let7T to normal liver cells was successfully decreased while was almost not attenuated in HCC cells in vitro. The antitumor ability of SG7011let7T in vivo was maintained in mice with Hep3B xenograft tumor, whereas was greatly decreased against the SMMC-7721 xenograft tumor expressing a high level of let-7 similar with L-02 when compared to the wild-type adenovirus. These results suggested that SG7011let7T may be a promising anticancer agent or vector to mediate the expression of therapeutic gene, broadly applicable in the treatment for HCC and other cancers where the let-7 gene is downregulated.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of death from cancer, resulting in more than 600,000 deaths each year [1]
The antitumor ability of SG7011let7T in vivo was maintained in mice with Hep3B xenograft tumor, whereas was greatly decreased against the SMMC-7721 xenograft tumor expressing a high level of let-7 similar with L-02 when compared to the wild-type adenovirus
The results showed that let-7a was significantly downregulated in HepG2 (0.066), Hep3B (0.021), and PLC/PRF/5 (0.010) cell lines as compared with normal liver cell line, L-02 (1.000) and WRL-68 (0.703), while it was slightly down-regulated in Huh7 (0.834) and SMMC-7721 (0.941) cell lines (Fig. 1)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of death from cancer, resulting in more than 600,000 deaths each year [1]. The antitumor efficacy of SG7011let7T as a monotherapy was evaluated in two kinds of s.c. xenograft HCC tumor model (i.e. Hep3B and SMMC-7721). In Hep3B xenografts model, a tumor model with low level of let-7, significant antitumor efficacy was observed. By day 28, the placebo treated tumors had increased 10fold in volume whereas the SG7011let7T treated tumors as a concentration of WAd5 pfu per dose grown a little in size (1.6 fold of the day 1 volume) (Fig. 6A) These results indicated that the antitumor effect of SG7011let7T was closed to that of WAd5 in. In the SMMC-7721 xenografts models, a tumor model containing let-7 at a level corresponding to normal hepatocytes, almost no antitumor effect was displayed in the SG7011let7T treatment. The curve of tumor growth in the SG7011let7T-treated group was similar with that of placebo control while significantly different from the WAd5-
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