Viral Hepatitis

Biography

Biography: Dr. Jian Guan

Abstract

Therapy with let-7 miRNAs is a potential strategy for human  (HCC). A major challenge for the clinical utility of let-7 miRNAs is the lack of an effective, non-toxic carrier. Recently we confirmed the antitumor efficacy and potential off-target effects of cholesterol-conjugated let-7a mimics (Chol-let-7a) in preclinical models. Subcuneous and orthotopic xenograft were treated with Chol-let-7a or negative control miRNA through local injections or systemic delivery. Ultrasonography was used to evaluate tumor growth and metastasis. Histopathology and ultra structural features of the liver and kidney were used to evaluate toxicity after systemic treatment. Chol-let-7a inhibited HCC growth (Inhibitory rate, 56.3%) and tumor invasion when delivered by means of local injection in a subcutaneous xenograft model. Chol-let-7a was shown to effectively carry let-7a to the target tumors and produce satisfactory antitumor effects (Inhibitory rate, 66.5%) in an orthotopic xenograft model when administered systemically. In addition, Chol-let-7a-treated tumor cells showed no significant atypia and mitoses were very rare per unit of measurement in most areas after systemic therapy. Let-7a-treated xenografts revealed a significant up regulation of let-7a miRNA, and down regulation of three ras genes and ras proteins, especially n-ras/N-RAS was most strongly affected at the transcript and post-transcriptional levels. After continuous Chol-let-7a treatment, only some non-specific reaction changes were observed in liver and kidney in nude mice. These results suggested that Chol-let-7a produces inhibitory effects when administered locally and systemically. Chol-let-7a induced mild damage in liver and kidney after long-term treatment. Thus, systemically delivered Chol-let-7a is a promising therapeutic drug candidate for HCC.