CRISPR-Cas9 Technology as a Fledgling Avenue in the Therapeutics of Hepatocellular Carcinoma

Abstract

Background and Aim: Since its inception in 2012, the prokaryotic immune-like clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas)9 (CRISPR-Cas9) system has revolutionised the realm of genome editing with visionary implementations in synthetic biology, functional genomic screening, transcriptional modulation and gene therapy. Hepatocellular carcinoma (HCC) with a globally heterogeneous genetic and epigenetic landscape, is a fatal human malignancy, and therefore forms the perfect platform for therapeutic interventions with CRISPR-Cas9. Here we embellish the state-of-the-art on the novel genome engineering utilizations of CRISPR-Cas9 in HCC with plausible future perspectives. Methods: PubMed, Medline, Embase and Cochrane databases were scrutinised for relevant publications in English with keywords “CRISPR-Cas9 and cancer”, “CRISPR-Cas9 and hepatocellular carcinoma,” “applications of CRISPR-Cas9 and hepatocellular carcinoma,” and “genome editing with CRISPR-Cas9 and hepatocellular carcinoma,” unsheathed till April 2017. Manuscripts relating to applications of CRISPR-Cas9 other than in cancers were excluded. Results: Recently, HBV-specific CRISPR-Cas9 systems have effectively mediated pro-oncogenic HBV cccDNA disruption thereby scripting a therapeutic promise in HBV-induced HCC. Evidence illustrate that inhibition of FGF19/FGFR4 by CRISPR-Cas9 signalling significantly overcomes sorafenib resistance in HCC. Data display a CRISPR-Cas9 regulated knockout of a component of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex called ARID2 from human HCC cell lines, to correlate tightly with the disruption of DNA repair, resulting in carcinogen susceptibility and potential hypermutation. Mouse models of CRISPR/Cas9-induced HCC elucidate multiplexed CRISPR/Cas9 mediated functional genomic analyses of hepatobiliary cancers. Additionally, a genome-wide CRISPR screen has identified regulators of mitogen-activated protein kinase as suppressors of mice liver tumours. Conclusion: Despite pitfalls such as Cas9 activity, target site selection and short guide RNA design, delivery methods, off-target effects and the incidence of homology-directed repair affecting the efficiency and specificity of CRISPR-Cas9, this novel technology has ushered in a new era of cellular manipulation with newer vistas in the therapeutic management of HCC. The authors have none to declare.