Complete eradication of hepatomas using an oncolytic adenovirus containing AFP promoter controlling E1A and an E1B deletion to drive IL-24 expression

Abstract

Interleukin (IL)-24, a promising therapeutic gene, has been widely used for Cancer Targeting Gene-Viro-Therapy (CTGVT). In this study, IL-24 was inserted into an oncolytic adenovirus in which the E1A gene is driven by an enhanced, short a-fetoprotein (AFP) promoter and the E1B gene is completely deleted to form Ad.enAFP-E1A-DE1B-IL-24. This construct has a potent antitumor effect on liver cancer cell lines in vitro, but little or no effect on normal cell lines, such as L-02 and QSG-7701. In vivo, the complete elimination of Huh-7 liver cancer in nude mice with Ad.enAFP-E1A-DE1B-IL-24 intratumor injection was observed. The design of Ad.enAFP-E1A-DE1B-IL-24 and its potent antitumor effect on liver cancer have not been published previously. The mechanism of the potent antitumor effect of Ad.enAFP-E1A-DE1B-IL-24 is due to the upregulation of GADD34 and intrinsic and extrinsic apoptotic signaling.

Antitumor activity and inhibitory effects on cancer stem cell-like properties of Adeno-associated virus (AAV) -mediated Bmi-1 interference driven by Bmi-1 promoter for gastric cancer

“…The core promoter sequence primer was synthesized by Invitrogen. The promoter activity of this sequence has been described previously [17]. Bmi-1 shRNA was designed and cloned in the adenoviral vector obtained from Shanghai Shengbo Biotechnology Company.…”

“…Bmi-1 shRNA was designed and cloned in the adenoviral vector obtained from Shanghai Shengbo Biotechnology Company. The sequence of Bmi-1 shRNA was as follows: Bmi-1 shRNA GACCAGACCACUACUGAAU [17]. In order to prove that Bmi-1 shRNA could efficiently transcribed by Bmi-1 promoter, we designed a prober targeting Bmi-1 shRNA sequence, and deteceted the expression of Bmi-1 shRNA in control and Ad-Bmi-1i infected AGS cells detected by QRT-PCR (Figure 1B).…”

“…The sequence of Bmi-1 promoter was synthesized by Invitrogen, The promoter activity of this Bmi-1 promoter has been verified in an earlier study [17]. Bmi-1 shRNAs were as follows: Bmi-1 shRNA GACCAGACCACUACUGAA, which has been verified previously [32].…”

Advances in the mechanisms of action of cancer-targeting oncolytic viruses (Review)

“…The approach to achieving tumor-selective viral replication has been to alter the function of the control of genetic transcription, which is essential in viral replication, to a tissue-or tumor-specific promoter. These promoters include human telomerase reverse transcription (hTERT) (19), hypoxia-inducible factor-1 (20), prostate-specific antigen (21) and α-fetoprotein (22), among others. hTERT has been identified as a major protein that functions to maintain telomere length in tumors; however, it demonstrates little or no expression in normal cells, allowing cancer cells to subvert the Hayflick limit (23).…”

Homologous recombination-based adenovirus vector system for tumor cell-specific gene delivery

“…[1][2][3] To improve the transduction efficiency, specificity, and safety of Ad vectors, multiple strategies for targeting Ad5 to tumor tissues have been explored. One method is to regulate the expression of E1A and/or E1B using the tumor specific promoters, such as α-fetoprotein promoter for hepatocellular carcinoma, 4 tyrosinase enhancer/promoter for melanoma, 5 and prostate-specific antigen promoter for prostate cancer. 6 However, this approach is usually restricted by cancer types and cancer cell heterogeneity.…”