RNA-binding protein insulin-like growth factor II mRNA-binding protein 3 expression promotes tumor invasion and predicts early recurrence and poor prognosis in hepatocellular carcinoma
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Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an RNA-binding protein expressed in embryonic tissues and multiple cancers. To investigate the role of IMP3 in hepatocellular carcinoma (HCC), its protein expression in the surgically resected unifocal tumors of 377 HCC patients (296 men and 81 women) with ages ranging from 7 to 88 years (mean, 55.49 years) was analyzed by immunohistochemistry. IMP3 was expressed in 255 (67.6%) of 377 resected unifocal primary HCCs. IMP3 protein was predominantly expressed in tumor border and invasive front, and it was more abundant in the satellite nodules and tumor thrombi than in the main tumors. The expression correlated with high α-fetoprotein (>200 ng/mL, P < 1 × 10−7), larger tumor size (>5 cm, P = 0.006), high tumor grade (P < 1 × 10−7), and high tumor stage with vascular invasion and various degrees of intrahepatic metastasis (P < 1 × 10−7). IMP3 expression predicted early tumor recurrence (P < 1 × 10−7) and was a strong indicator of poor prognosis (P < 0.0001). Depletion of IMP3 with RNA interference in HCC cell line HA22T caused a decrease in cell motility, invasion, and transendothelial migration. Microarray analysis revealed that IMP3 depletion was associated with downregulation of multiple genes involved in tumor invasion. Conclusion: Our results indicate that IMP3 plays an important role in tumor invasion and metastasis and is a strong prognostic factor for patients with HCC. (HEPATOLOGY 2008.)Keywords:
Tumor progression
Tissue microarray
SUMMARY RNA interference (RNAi) is a powerful research tool that has enabled molecular insights into gene activity, pathway analysis, partial loss-of-function phenotypes, and large-scale genomic discovery of gene function. While RNAi works extremely well in the non-parasitic nematode C. elegans , it is also especially useful in organisms that lack facile genetic analysis. Extensive genetic analysis of the mechanisms, delivery and regulation of RNAi in C. elegans has provided mechanistic and phenomenological insights into why RNAi is so effective in this species. These insights are useful for the testing and development of RNAi in other nematodes, including parasitic nematodes where more effective RNAi would be extremely useful. Here, we review the current advances in C. elegans for RNA delivery methods, regulation of cell autonomous and systemic RNAi phenomena, and implications of enhanced RNAi mutants. These discussions, with a focus on mechanism and cross-species application, provide new perspectives for optimizing RNAi in other species.
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Reverse Genetics
RNA Silencing
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RNA interference (RNAi) is a cellular process by which an mRNA is targeted for degradation by a small interfering RNA that contains a strand complementary to a fragment of the target mRNA, resulting in sequence specific inhibition of gene expression. The discovery of RNAi enabled the use of loss-of-function analyses in many non-model insects other than Drosophila to elucidate the roles of specific genes. The RNAi approach has been widely used on insects in several fields, including embryogenesis, pattern formation, reproduction, biosynthesis and behavior. The increasing availability of insect genomes has made the RNAi technique an indispensable technique for characterizing gene functions in insects. Here we review the current status of RNAi-based experiments in insects and the applications of RNAi for species-specific insecticides, focusing on non-drosophilid insects. We also identify future applications for RNAi-based studies in Entomology.
RNA Silencing
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RNA Silencing
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RNA Silencing
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Abstract High specificity for silencing target genes and single‐copy target genes that yield clear phenotypes are two important factors for the success of RNA interference (RNAi). The lethal giant larvae ( Lgl ) gene appears to be an ideal gene for RNAi because RNAi can effectively suppress its expression and results in molting defects and mortality in Tribolium castaneum . To investigate the suitability of this gene for RNAi in other insects, we identified and characterized DvLgl from the western corn rootworm, Diabrotica virgifera virgifera , a species exhibiting high RNAi efficiency. DvLgl was expressed in all developmental stages and tissues investigated. The deduced DvLgl protein showed high amino‐acid sequence identities and similar domain architecture to Lgls from other insect species. Despite many similarities among insect Lgls, RNAi‐mediated suppression of DvLgl failed to produce a phenotype in D. v. virgifera adults. The difference in developing phenotypes could be attributed greatly to the level of gene suppression and the insect developmental stages for RNAi. These results highlight the variability in RNAi response among insects and showcase the importance of screening multiple target genes when conducting RNAi studies. Our findings are expected to help the design of future RNAi studies and future investigations of Lgl in insects.
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Significance The RNA interference (RNAi) discovered in nematodes has contributed to major advances in basic and applied sciences. RNAi-based methods are being developed for controlling pests and disease vectors. RNAi is highly efficient and systemic in coleopteran insects, but not in other insects. The lower efficiency of RNAi in economically important insects and concerns about resistance development are hindering the widespread use of this technology. To address these problems, a RNAi-sensitive Colorado potato beetle, Leptinotarsa decemlineata , and a cell line derived from this insect were used to identify a dsRNA-binding protein, StaufenC , as a major contributor to RNAi and its resistance. Interestingly, StaufenC homologs are present in only coleopteran insects and are essential for efficient RNAi response and its resistance in these insects.
RNA Silencing
Leptinotarsa
Colorado potato beetle
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RNAi is a new technology for inhibiting gene expression in diverse organisms in recent years.The RNAi effect could spread from cells to cells in some insects,which induce the targeted gene specifically silenced in other tissues by introducing dsRNA into embryos,cavity or partial tissues.As a result,several methods of RNAi in insects have been reported,such as embryo RNAi,larval RNAi,adult RNAi,parental RNAi,feeding RNAi and heritable RNAi based on transgenic technique.These techniques have become widely used tools to knock down gene expression and analyze gene function,especially in non-model insects which the systematic recovery of mutants is not feasible.This paper focused on the systemic gene silencing of RNAi,RNAi technology and its applications in Entomology.
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Functional Genomics
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RNA interference is a powerful tool for investigating gene function which has been used extensively in model organisms such as Caenorhabditis elegans and has been adapted as a high-throughput screening method to identify genes. However, recent research indicates that the application of RNAi to animal parasitic nematodes has some problems. For example, the variability of RNAi to different parasitic nematodes or the same nematode in different stages is great. Reasons to explain why RNAi does not work well in animal parasitic nematodes include: (1) the efficacy of RNAi delivery methods in different nematodes is extremely variable; (2) RNAi mechanism has been applied to related nematodes and most of them are gene functional defect; (3) different lifestyles of nematodes may influence on the efficacy of RNAi. If we can find out the methods which can solve these questions, there are still application prospects for using RNAi in parasitic nematodes with improved RNAi effect.
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The aim of this study was to determine the characteristics of hepatocellular carcinoma at a major health center in southern Turkey. Computed tomography was compared to the combination of ultrasonography and serum alpha-fetoprotein determination in the diagnosis of hepatocellular carcinoma.Of 226 patients with liver cirrhosis, 35 were diagnosed with hepatocellular carcinoma on first admission or during follow-up in the period between 1999 and 2002. The features investigated were, age at time of hepatocellular carcinoma diagnosis, etiology of cirrhosis, severity of cirrhosis at presentation, tumor pattern, stage of hepatocellular carcinoma, serum alpha-fetoprotein level, and dynamic computed tomography findings. Results were compared to previous findings in Turkey and elsewhere.In the hepatocellular carcinoma patients, the male:female ratio was 4:1 and the mean age at presentation was 61 years. Chronic hepatitis B virus infection (65.7%) and chronic hepatitis C virus infection (28.6%) were the most frequently identified risk factors for hepatocellular carcinoma. Forty percent of the patients had Child-Pugh A cirrhosis when they were diagnosed with hepatocellular carcinoma. Sixty-seven percent of patients had fewer than three hepatocellular carcinoma nodules in the liver at the time of diagnosis. Only three of the hepatocellular carcinoma cases were Okuda stage I. The combination of ultrasonography and serum alpha-fetoprotein >20 ng/ml identified hepatocellular carcinoma in 32 of the 35 total cases.The results indicate that hepatitis B virus infection in patients with cirrhosis is still the leading risk factor for the development of hepatocellular carcinoma. Also, early-stage hepatocellular carcinoma is rarely diagnosed in cirrhosis patients from this region of Turkey. Surveillance with computed tomography for early diagnosis of hepatocellular carcinoma seems not to be mandatory.
Hepatitis B
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