Significance of MTDH expression in the developing process of hepatocellular carcinoma--《Hainan Medical Journal》2015年22期
Significance of MTDH expression in the developing process of hepatocellular carcinoma
LUO Yi-LIU Yong-TAN ZXIONG Huo-SHI Zhen-YANG Li-DANG Yi-Department of Pathology,the First Affiliated Hospital of Guangxi Medical UDepartmetn of Medical Oncology,the First Affiliated Hospital of Guangxi Medical U
Objective To investigate the relationship between the expression of metadherin(MTDH) and the carcinogenesis of hepatocellular carcinoma(HCC) and its related significance. Methods Immunohistochemistry was adopted to detect the expression levels of MTDH, CD34, vascular endothelial growth factor(VEGF), nm23, p53, p21 and Ki-67 in a cohort of 89 pairs of HCC tissues and their matched adjacent hepatic tissues, 37 cases of hepatocirrhosis tissues and 25 cases of normal hepatic tissues. Meanwhile, we analyzed the correlation between MTDH and several clinicopathological parameters as well as some immunohistochemical indexes. Results The positive rate of MTDH expression in HCC tissues(57.3%) was significantly higher than that in either hepatocirrhosis tissues(29.7%) or normal hepatic tissue(24.0%, P0.05). The MTDH expression was closely related to T category, distant metastasis, HBV infection, microvessel density and the expression of nm23 and Ki-67(P0.05). For the 61 cases of HCC which were followed up, the overall average recurrence time was(57.841±3.025) months, and no statistical significance was found between MTDH-positive group [(47.791 ± 4.226) months] and MTDH-negative group [(59.418 ± 3.507) months], P0.05. Conclusion MTDH might be implicated as a crucial part in invasion, metastasis and angiogenesis in HCC,which has the potential to be a novel biomarker for the assessment of the development and prognosis of HCC.
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, April 2015, Pages 220–228
Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7, , , , , , , , , , , , , , , , , a Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USAb Neuroscience Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USAc Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USASpinal muscular atrophy (SMA) is a neuromuscular disease caused by disruption of the survival motor neuron 1 (SMN1) gene, partly compensated for by the paralogous gene SMN2. Exon 7 inclusion is critical for full-length SMN protein production and occurs at a much lower frequency for SMN2 than for SMN1. Antisense oligonucleotide (ASO)-mediated blockade of an intron 7 splicing silencer was previously shown to promote inclusion of SMN2 exon 7 in SMA mouse models and mediate phenotypic rescue. However, downstream molecular consequences of this ASO therapy have not been defined. Here we characterize the gene-expression changes that occur in an induced model of SMA and show substantial rescue of those changes in central nervous system tissue upon intracerebroventricular administration of an ASO that promotes inclusion of exon 7, with earlier administration promoting greater rescue. This study offers a robust reference set of preclinical pharmacodynamic gene expression effects for comparison of other investigational therapies for SMA.AbbreviationsASO, antisense oligonucleotide; Cdkn1A, cyclin-dependent kinase inhibitor 1A; cDNA, complementary DNA; FDR, false discovery rate; FUS, fused in sarcoma; Hist1H1C, histone cluster 1, H1C; ICV, intracerebroventricular; ISS, intronic splicing silencer; P, post-natal day; Partek GS, Partek& Genomics Suite&; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; qPCR, quantitative polymerase chain reaction; RT, reverse transcription; SMA, spinal muscular atrophy; SMN, survival motor neuron; snRNP, small nuclear ribonucleoproteinKeywordsSpinal muscular atrophy; Gene expression; Mouse model; SMN2; Antisense; Oligonucleotide1. IntroductionSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder in which progressive α-motor neuron degeneration leads to weakness and atrophy of primarily proximal skeletal muscles . The underlying genetic defect is the loss of function, usually deletion, of survival motor neuron 1 (SMN1)
, which encodes the protein SMN involved in the assembly of small nuclear ribonucleoprotein complexes . A neighboring gene centromeric to SMN1 at chromosome 5q13, SMN2, arose from duplication and subsequent mutation of SMN1 and is unique to humans
. The handful of nucleotide differences between SMN1 and SMN2 include a C&T transition in SMN2 at position 6 of exon 7. Together with an intronic splicing silencer (ISS) in intron 7, termed ISS-N1
, this nucleotide difference suppresses inclusion of exon 7, thereby encoding a truncated protein product, SMNΔ7, which is essentially non-functional and rapidly degraded. However, at some frequency, SMN2 does generate transcripts that include exon 7 and encode a full-length SMN protein identical to that encoded by SMN1.SMN2 is itself subject to gene duplication, and its copy number is the major genetic modifier of SMA phenotype from type I (severe with infantile onset) to type IV (mild with adult onset). This pattern is recapitulated in murine models of SMA in which knockout of the single murine Smn gene, which results in embryonic lethality
, can be rescued by a variable copy number of the human SMN2 transgene. Smn knockout mice with two copies of SMN2 (Smn&/&; SMN2+/0) model a severe form of SMA, with mice surviving ~ 1 week
 and . A strain with an additional human SMN2 complementary DNA (cDNA) transgene lacking exon 7 (Smn&/&; SMN2+/0; SMNΔ7) lives to ~ 15 days . Mice with four copies of the SMN2 transgene (Smn&/&; SMN2+/+) model a very mild form of SMA and have a normal lifespan, but develop ear and tail necrosis likely secondary to vascular deficits .The partly compensatory activity of SMN2 has made it an attractive target for molecules that promote inclusion of exon 7 and therefore increase the level of functional SMN protein in the setting of SMN1 deficiency. Indeed, a 2&-O-(2-methoxyethyl)-modified antisense oligonucleotide (ASO), designated ASO 10-27, targets a site within intron 7 that overlaps with ISS-N1 and promotes efficient inclusion of SMN2 exon 7. ASO 10-27, which mediates partial phenotypic rescue of both severe and mild models of SMA
 and , also is known as ISIS-SMNRx, a drug currently undergoing investigation in children and infants with SMA.In evaluating the pharmacodynamic profile and therapeutic efficacy of candidate compounds, a model with an intermediate phenotype is of particular value. Therefore, an induced model of SMA was developed by administering adult mice with mild SMA an ASO, designated ASO 20-37, that targets a purine-rich exon splicing enhancer region in the middle of exon 7 and promotes skipping of SMN2 exon 7 beyond background levels of exon 7 exclusion
 and . We recently described the phenotypic and histopathologic effects of induced SMN depletion and repletion with ASO 20-37 (skip) and ASO 10-27 (therapeutic), respectively, delivered by intracerebroventricular (ICV) injection in neonatal
mice with SMA. The consequences of SMN2 mis-splicing were progressive and dose dependent. For instance, in 2-month-old mice administered the skip ASO 20-37, effects on body weight and locomotor activity were apparent by day 30 after injection of the 100-μg dose, but not until after day 60 at the 25-μg dose. SMA-like pathology appeared in parallel and included reduced α-motor neuron density, neuromuscular junction defects, decreased muscle fiber sizes and reduced numbers of central synapses onto motor neurons. Early ICV, but not intraperitoneal, administration of the therapeutic ASO 10-27 at 5 or 22 days after ICV delivery of the skip ASO 20-37 significantly prolonged survival and reversed the subset of abnormal phenotypes analyzed.
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