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Low-level shRNA cytotoxicity can contribute to MYC-induced hepatocellular carcinoma in adult mice.

ABSTRACT: Short hairpin RNAs (shRNAs) have emerged as a novel therapeutic modality, but there is increasing concern over nonspecific effects in vivo. Here, we used viral vectors to express shRNAs against endogenous p53 in livers of conditional MYC-transgenic mice. As expected, the shRNAs silenced hepatic p53 and accelerated liver tumorigenesis when MYC was concurrently expressed. Surprisingly, various irrelevant control shRNAs similarly induced a rapid onset of tumorigenesis, comparable to carbon tetrachloride (CCl4), a potent carcinogen. We found that even marginal shRNA doses can already trigger histologically detectable hepatoxicity and increased hepatocyte apoptosis. Moreover, we noted that shRNA expression globally dysregulated hepatic microRNA (miRNA) expression, and that shRNA levels and activity further increased in the presence of MYC. In MYC-expressing transgenic mice, the marginal shRNA-induced liver injury sufficed to further stimulate hepatocellular division that was in turn associated with markedly increased expression of the mitotic cyclin B1. Hence, even at low doses, shRNAs can cause low-level hepatoxicity that can facilitate the ability of the MYC oncogene to induce liver tumorigenesis. Our data warrant caution regarding the possible carcinogenic potential of shRNAs when used as clinical agent, particularly in circumstances where tissues are genetically predisposed to cellular transformation and proliferation.

SUBMITTER: Beer S

PROVIDER: S-EPMC2839214 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Low-level shRNA cytotoxicity can contribute to MYC-induced hepatocellular carcinoma in adult mice.

Beer Shelly S Bellovin David I DI Lee Joyce S JS Komatsubara Kimberly K Wang Lora S LS Koh Huishan H Börner Kathleen K Storm Theresa A TA Davis Corrine R CR Kay Mark A MA Felsher Dean W DW Grimm Dirk D

Molecular therapy : the journal of the American Society of Gene Therapy 20091020 1

Short hairpin RNAs (shRNAs) have emerged as a novel therapeutic modality, but there is increasing concern over nonspecific effects in vivo. Here, we used viral vectors to express shRNAs against endogenous p53 in livers of conditional MYC-transgenic mice. As expected, the shRNAs silenced hepatic p53 and accelerated liver tumorigenesis when MYC was concurrently expressed. Surprisingly, various irrelevant control shRNAs similarly induced a rapid onset of tumorigenesis, comparable to carbon tetrachl ...[more]

PMID: 19844192

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Project description:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and liver resection is the only potential curative treatment option for those patients. Postoperative complications specific to elderly surgical patients such as delirium will be increasingly relevant in the coming decades. Herein, we aimed to investigate the risk factors for postoperative delirium in patients who have received hepatectomy for HCC.This is a single medical center observational study and the study subjects comprised 401 individuals who underwent liver resection for hepatocellular carcinoma during January 2009 to October 2013. Multivariate analysis was used to examine whether preoperative, intra-operative, or postoperative variables were associated with the development of delirium.Of the 401 patients who underwent hepatectomy, 34 developed postoperative delirium (8.4%). In the majority of those patients, symptoms and signs of the syndrome occurred on postoperative day 2 and the mean duration of symptoms was 3.61 ± 3.71 days. Multivariate analysis revealed that advanced age (>71 years) [odds ratio (OR) = 1.133, 95% confidence interval (CI): 1.071-1.200, p<0.001], prolonged operative time (>190 minutes) (OR = 1.009, 95% CI: 1.000-1.017, p = 0.038), a decreased postoperative hemoglobin level (< 10.16 g/dL) (OR = 0.777, 95% CI: 0.613-0.983, p = 0.036), and history of hypnotic drug use (OR = 3.074, 95% CI: 1.045-9.039, p = 0.041) were independent risk factors for the development of postoperative delirium after hepatectomy.Although the mechanism of postoperative delirium is not well understood, numbers of studies have shown that patients with postoperative delirium tend to have prolonged hospital stay, worse postoperative outcome and an increased risk of short- and long-term mortality. In this study, we found that advanced age, prolonged operative time, postoperative low hemoglobin level and history of hypnotic drug use are independent risk factors for postoperative delirium.

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Low-level shRNA cytotoxicity can contribute to MYC-induced hepatocellular carcinoma in adult mice.

Publications

Low-level shRNA cytotoxicity can contribute to MYC-induced hepatocellular carcinoma in adult mice.

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