title: Construction of an oncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells.
abstract: Selective replication in tumor cells is a highly desirable feature for oncolytic viruses. Recent studies have shown that microRNAs (miRNAs) play important roles in controlling gene expression, and that certain tissue-specific miRNAs are frequently downregulated in malignant cells. miR-122 is a liver-specific microRNA. It is abundantly expressed in normal hepatocytes but is absent in many hepatocellular carcinoma (HCC) cells. We hypothesized that expression of an essential viral gene by a liver-specific promoter would initially restrict virus replication to cells of hepatic origin and that adding miR-122 complementary sequences to the viral gene would make the transcripts degradable by miR-122 in normal hepatocytes, thus further confining its replication to HCC. We have constructed such an oncolytic herpes simplex virus by linking the essential viral glycoprotein H gene with the liver-specific apolipoprotein E (apoE)-AAT promoter and by adding the miR-122a complimentary sequence to the 3' untranslated region (3'UTR). To further increase the safety of this virus, complementary sequences from miR-124a and let-7 were also engineered into the same 3'UTR. Designated liver-cancer specific oncolytic virus (LCSOV), it was highly selective in killing HCC cells and in shrinking HCC xenografts. We conclude that LCSOV is a highly specific oncolytic virus that can precisely target HCC.
authors.affiliation: Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas 77204, USA.
authors.forename: Xinping
authors.initials: X
authors.lastname: Fu
authors.forename: Armando
authors.initials: A
authors.lastname: Rivera
authors.forename: Lihua
authors.initials: L
authors.lastname: Tao
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
authors.forename: Xiaoliu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000628:therapy*; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000235:genetics* / Q000502:physiology; D056189:Viral Tropism; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001057:Apolipoproteins E; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human