title: Baculovirus-mediated miRNA regulation to suppress hepatocellular carcinoma tumorigenicity and metastasis.
abstract: MicroRNA 122 (miR-122) is a tumor suppressor for hepatocellular carcinoma (HCC) but is lowly expressed in HCC cells. MiR-151 is aberrantly overexpressed in HCC cells and promotes HCC metastasis yet its roles on HCC tumorigenicity are unknown. To combat HCC tumorigenicity/metastasis, we developed Sleeping Beauty (SB)-based hybrid baculovirus (BV) vectors that expressed (i) miR-122 precursors (pre-miR-122), (ii) miR-151 sponges, or (iii) pre-miR-122 and miR-151 sponges. Transduction of aggressive HCC cells (Mahlavu) with the pre-miR-122-expressing BV tremendously enhanced miR-122 levels for >6 weeks, suppressed the levels of downstream effectors (e.g., ADAM10 and Bcl-w), proliferation, anchorage-independent growth, motility and migration/invasion in vitro. Intratumoral injection of the pre-miR-122-expressing BV attenuated the HCC growth/metastasis. The miR-151 sponges-expressing BV diminished the miR-151 levels for 6 weeks, enhanced RhoGDIA expression, suppressed RhoGTPases, as well as motility and migration/invasion of Mahlavu cells. Intratumoral injection of the miR-151 sponge-expressing BV impeded not only HCC metastasis but also cell proliferation, MMP expression and tumor growth in vivo. The BV co-expressing pre-miR-122 and miR-151 sponges also simultaneously enhanced miR-122 expression and inhibited miR-151, and conferred antitumor/anti-metastasis effects albeit lack of synergism. These data implicate the potentials of the SB-based hybrid BV for persistently modulating miRNA and suppressing HCC tumorigenicity/metastasis.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chiu-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jaw-Ching
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Guan-Yu
authors.initials: GY
authors.lastname: Chen
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Pei-Hsiang
authors.initials: PH
authors.lastname: Yuan
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yen-Wen
authors.initials: YW
authors.lastname: Tseng
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Kuei-Chang
authors.initials: KC
authors.lastname: Li
authors.affiliation: Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan.
authors.forename: Shiaw-Min
authors.initials: SM
authors.lastname: Hwang
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Hu
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016367:Baculoviridae / Q000235:genetics*; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015552:Injections, Intralesional; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; C531907:MIRN122 microRNA, human; C548886:MIRN151a microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C485184:enhanced green fluorescent protein; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D049452:Green Fluorescent Proteins; D016392:Proto-Oncogene Proteins pp60(c-src); D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human