Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

Abstract

Abnormal high activation of survivin is involved in carcinogenesis of various types of cancer. Survivin has been shown to promote cell proliferation in human hepatocellular carcinoma (HCC). Survivin-targeting approaches have become a promising strategy for treating HCC. Here, we used a reporter system to screen effective survivin siRNA sequences. The effect of vector-based survivin short hairpin RNA (shRNA) on the malignant phenotype of HCC cells in vitro and in vivo was determined, and an adenovirusmediated shRNA expression vector was developed to decrease survivin expression of the established HCC tumor in nude mice. In vitro study showed that stable survivin knockdown inhibited cancer cell proliferation, enhanced apoptotic susceptibility, arrested cell cycle in the G1 phase and resulted in apparent mitotic catastrophe. Moreover, cells stably expressing survivin shRNA showed decreased tumorigenicity in nude mice. An additional in vivo study showed that intratumoral injection of adenovirus-delivered survivin shRNA suppressed tumor growth by spontaneous apoptosis of cancer cells and significantly prolonged animal survival. In conclusion, we proved the therapeutic potential of survivin shRNA for the treatment of HCC. And our results indicated that adenovirus-delivered shRNA may serve as a novel therapeutic for HCC.

Optimization and apoptosis induction by RNAi with UTMD technology in vitro

“…Experimental data indicated that degradation of survivin was the main trigger for apoptosis induction. After the expression of survivin was downregulated, a marked block in the G 0 /G 1 phase of the cell cycle was observed and cell apoptosis induction was examined, which was similar to other reports that did not use this technique (32). These data have laid a foundation for further investigation into cervical carcinoma therapeutics.…”

Expression of ankyrin repeat and SOCS box containing 4 (ASB4) confers migration and invasion properties of hepatocellular carcinoma cells

“…Adding value to the clinical usefulness of oncofetal molecules, some of them have also been examined for their therapeutic potentials. Representative candidates include cadherin-17 and survivin, for which suppression of their levels is known as a way to counteract liver tumorigenesis in both in vitro and in vivo experimental settings (17,38). In this study, an alleviation of migration and invasion in HCC cells was clearly shown upon ASB4 suppression, providing a solid evidence for the involvement of ASB4 in the presentation of these tumor phenotypes.…”

RNA Interference-Mediated Validation of Survivin and Apollon/BRUCE as New Therapeutic Targets for Cancer Therapy

“…Moreover, survivin knockdown caused radio-sensitization, which was paralleled by an increased activity of caspases, in wild type-p53 but not in mutant-p53 sarcoma cells [68], and in non-small cell lung cancer cell lines [69]. Recently, Zang et al [70] demonstrated that survivin knockdown, through the use of an adenovirus-mediated shRNA expression vector, inhibited the growth of human hepatocellular carcinoma cell lines, induced an apoptotic response and blocked the cell cycle in G 1 phase resulting in an apparent mitotic catastrophe. Furthermore, intratumoral injection of adenovirus-delivered survivin shRNA suppressed tumor growth inducing spontaneous apoptosis of cancer cells and significantly prolonging animal survival [70].…”

“…Recently, Zang et al [70] demonstrated that survivin knockdown, through the use of an adenovirus-mediated shRNA expression vector, inhibited the growth of human hepatocellular carcinoma cell lines, induced an apoptotic response and blocked the cell cycle in G 1 phase resulting in an apparent mitotic catastrophe. Furthermore, intratumoral injection of adenovirus-delivered survivin shRNA suppressed tumor growth inducing spontaneous apoptosis of cancer cells and significantly prolonging animal survival [70]. Finally, transfection of endothelial cells with survivin-specific siRNAs induced a marked increase in the rate of apoptosis, a dose-dependent inhibition of their migration on vitronectin, and a decrease in capillary formation [71].…”