Adenovirus-mediated transfer of shRNA against Elovl6 reduces the progression of hepatocellular carcinoma

Shiau, A. L.; Su, Y. C.; Feng, Y. H.; Huang, Y. S.; Wu, P.; Wu, C. L.

Abstract

The elongation of long-chain fatty acids family member 6(Elovl6), a key enzyme in lipogenesis, catalyzes the elongation of saturated and monounsaturated fatty acids. Insulin resistance is associated with upregulation of Elovl6, which has been linkedto obesity-related malignancies, including hepatocellular carcinoma (HCC). However, the role of Elovl6 in HCC progression remains unclear. In this study, we analyzed the expression ofElovl6 in 61 clinical HCC specimens. Patients with Elovl6 high-expressing tumors were associated with shorter disease-free survival and overall survival compared with those with Elovl6low-expressing tumors. Adenovirus-mediated knockdown ofElovl6 reduced cell proliferation and Akt phosphorylation, leading to cell cycle arrest, as well as increased lipid accumu-lation in HCC cells. Intratumoral treatment with 108 PFU ofadenoviral vectors encoding shRNA against Elovl6 (Ad.shElovl6) at days 10 and 16 significantly suppressed tumorgrowth and prolonged the survival of BALB/c mice bearingsyngeneic HCC, as compared to treatment with the controlvectors. Taken together, our results indicate that Elovl6 en-hances oncogenic activity of HCC and is associated with poorprognosis in patients with HCC. Thus, targeting Elovl6 may be anovel therapeutic strategy for HCC.P065Laminin receptor dependent gold nanoparticlesfor mitochondrial targeted delivery in cancerO Oladimeji1M Singh11: University of KwaZulu-NatalNanocarriers with their array of tunable physicochemical properties have continually shown potential for efficient gene and drug delivery. The exciting potential of the mitochondria asan invariable target present in all tumours has made it a focus ofcancer research in recent times. We studied the efficient delivery of Betulinic acid (BA) to the mitochondria of cancer cells by the biocompatible Epigallocatechin gallate reduced gold nano-particles (Eg-AuNPs). Pertinent to our objective is the high affinity of EGCg for the 67 kDa laminin receptor over expressed in certain tumours. Synthesised AuNPs were either coated with Poly(Ethylene Glycol) (PEG) (p-Eg-AuNP) or Poly(L-Lysine)-graft-Poly(Ethylene Glycol] copolymers (PLL-g-PEG) (Pp-Eg-AuNP) for biocompatibility, then with triphenyl phosphoniumcation (TPP+), for mitochondrial targeting. Following characterization with TEM, NTA zetasiser, FTIR and UV spectros-copy, we determined the cytotoxic and mitochondrial targeting properties of drug-NP conjugates in 67LR negative and positive cancer cell lines, Hep G2 and Caco-2 respectively. Furthermore, a mechanistic study that included cell cycle analysis, apoptosis, and caspase activation assays were conducted to ascertain the possible mechanism of action. Enhanced cellular uptake, with significant localization to the mitochondria were recorded for targeted nanoparticles compared to the non-targeted NPs, with uptake levels markedly higher in the 67LR positive cell line. Consistent with these results were the significant apoptotic effects of targeted T-Pp-BA-Eg-AuNP and T-p-BA-Eg-AuNP compared to the untargeted constructs. These findings emphasize the innate targeting property of Eg-AuNP, their capacity to modulate drug pharmacodynamics and efficiently deliver therapeutics to cancer mitochondria.

Citation

Shiau, A. . L., Su, Y. . C., Feng, Y. . H., Huang, Y. . S., Wu, P., & Wu, C. . L. (2018, October). Adenovirus-mediated transfer of shRNA against Elovl6 reduces the progression of hepatocellular carcinoma. Poster presented at Changing the Face of Modern Medicine: Stem Cell and Gene Therapy Organized Jointly by the European Society of Gene & Cell Therapy (ESGCT), International Society for Stem Cell Research (ISSCR) and the French Society of Gene and Cell Therapy (SFTCG), Lausanne, Switzerland

• Presentation Conference Type: Poster
• Conference Name: Changing the Face of Modern Medicine: Stem Cell and Gene Therapy Organized Jointly by the European Society of Gene & Cell Therapy (ESGCT), International Society for Stem Cell Research (ISSCR) and the French Society of Gene and Cell Therapy (SFTCG)
• Conference Location: Lausanne, Switzerland
• Start Date: Oct 16, 2018
• End Date: Oct 19, 2018
• Deposit Date: Jun 20, 2023