MicroRNAs (miRNAs) can bind to the 3 0 -untranslated regions (UTRs) of messenger RNAs, where they interfere with translation and thereby regulate cell differentiation, apoptosis and tumorigenesis. Genetic polymorphisms in the 3 0 -UTRs targeted by miRNAs alter the strength of miRNA binding in a manner that affects the behavior of individual miRNAs. The histone methyltransferase SET8 has been reported to methylate TP53 and regulate genomic stability. We analyzed a single-nucleotide polymorphism (rs16917496) within the miR-502 miRNA seed region for the 3 0 -UTR of SET8 in Chinese patients with hepatocellular carcinoma (HCC). The SET8 CC genotype was independently associated with longer postoperative survival in patients with HCC by multivariate analysis (relative risk, 0.175; 95% CI 5 0.053-0.577; p 5 0.004). The SET8 CC genotype was associated with reduced SET8 protein levels based on the immunostaining of 51 HCC tissue samples. We also found that the low SET8 levels were associated with longer HCC survival. Our data suggest that SET8 modifies HCC outcome by altering its expression, which depends, at least in part, on its binding affinity with miR-502. The analysis of genetic polymorphisms in miRNA binding sites can help to identify patient subgroups that are at high risk for poor disease outcomes.Hepatocellular carcinoma (HCC) is the fifth most common cancer and is responsible for more than half a million deaths each year, which makes it the third leading cause of cancer deaths worldwide. 1 The severity of HCC and the lack of effective treatment strategies make the disease a major challenge faced by the cancer researchers. This disease is strongly associated with several risk factors, including chronic hepatitis B virus (HBV), chronic hepatitis C virus (HCV) and alcohol abuse.2 The incidence of HCC has increased steeply in Asia and Africa, where HBV and HCV are more prevalent than in other continents. HBV infection is a challenging health issue in China, where $93 million people are HBV carriers and 30 million have chronic hepatitis B.2,3 Alcohol abuse is also increasing in China, where $6.6% of males and 0.1% of females in the population have been diagnosed with alcohol dependence. 4 Many of these people develop liver disease, such as alcoholic hepatitis and cirrhosis, which make them susceptible to HCC. Despite improved clinical detection methods and therapies, the prognosis of the patients with postoperative HCC is still poor because of a high recurrence rate. Although the molecular mechanism of HCC carcinogenesis is still not fully understood, there are many prognostic factors and predictors of recurrence associated with the disease, including tumor size, tumor quantity, cell differentiation, venous invasion and degree of inflammation. [5][6][7][8] MicroRNAs (miRNAs) are RNA molecules with lengths of $22 nucleotides that act as post-transcriptional regulators of mRNA expression by base pairing to the 3 0 untranslated region (UTR) or mRNAs and repressing translation.9,10 A growing body of evidence suggests th...

Summary Among numerous finite element techniques, few models can perfectly (without any numerical problems) break through MacNeal's theorem: any 4‐node, 8‐DOF membrane element will either lock in in‐plane bending or fail to pass a C0 patch test when the element's shape is an isosceles trapezoid. In this paper, a 4‐node plane quadrilateral membrane element is developed following the unsymmetric formulation concept, which means two different sets of interpolation functions for displacement fields are simultaneously used. The first set employs the shape functions of the traditional 4‐node bilinear isoparametric element, while the second set adopts a novel composite coordinate interpolation scheme with analytical trail function method, in which the Cartesian coordinates (x,y) and the second form of quadrilateral area coordinates (QACM‐II) (S,T) are applied together. The resulting element US‐ATFQ4 exhibits amazing performance in rigorous numerical tests. It is insensitive to various serious mesh distortions, free of trapezoidal locking, and can satisfy both the classical first‐order patch test and the second‐order patch test for pure bending. Furthermore, because of usage of the second form of quadrilateral area coordinates (QACM‐II), the new element provides the invariance for the coordinate rotation. It seems that the behaviors of the present model are beyond the well‐known contradiction defined by MacNeal's theorem. Copyright © 2015 John Wiley & Sons, Ltd.

Summary A recent unsymmetric 4‐node, 8‐DOF plane element US‐ATFQ4, which exhibits excellent precision and distortion‐resistance for linear elastic problems, is extended to geometric nonlinear analysis. Since the original linear element US‐ATFQ4 contains the analytical solutions for plane pure bending, how to modify such formulae into incremental forms for nonlinear applications and design an appropriate updated algorithm become the key of the whole job. First, the analytical trial functions should be updated at each iterative step in the framework of updated Lagrangian formulation that takes the configuration at the beginning of an incremental step as the reference configuration during that step. Second, an appropriate stress update algorithm in which the Cauchy stresses are updated by the Hughes‐Winget method is adopted to estimate current stress fields. Numerical examples show that the new nonlinear element US‐ATFQ4 also possesses amazing performance for geometric nonlinear analysis, no matter whether regular or distorted meshes are used. It again demonstrates the advantages of the unsymmetric finite element method with analytical trial functions.

Small nucleolar RNA host gene 3 (SNHG3), a long noncoding RNA (lncRNA), acts as an oncogene in hepatocellular carcinoma (HCC), whereas microRNA (miR)-326 plays an inhibitory role in some types of human cancers, including melanoma, osteosarcoma, and gastric cancer. In the present study, by analyzing 47 tissue specimens of human HCC, we found that the relative expression levels of SNHG3 were significantly higher in HCC tissues than those in the adjacent noncancerous tissues, whereas the relative expression levels of miR-326 were significantly lower in HCC tissues. Furthermore, the relative mRNA levels of Sma and Mad Related Family 3 (SMAD3) and zinc finger E-box binding homeobox 1 (ZEB1) were significantly higher in HCC tissues compared with the adjacent noncancerous tissues. In human HCC cell lines, SNHG3 overexpression promoted the proliferation, migration, and epithelial-mesenchymal transition and inhibited apoptosis, whereas knockdown of SNHG3 expression exerted the opposite effects. Importantly, miR-326 or miR-326 inhibitor restored the aforementioned effects of SNHG3 overexpression or SNHG3 knockdown. We thus found that the miR-326-response element is present in SNHG3 and the 3'-untranslated region of SMAD3 mRNA. In fact, SNHG3 overexpression increased the expression levels of SMAD3 and ZEB1, while miR-326 decreased the expression levels of SMAD3. These results suggest that SNHG3 may function as a competing endogenous RNA (ceRNA) for miR-326, which in turn enhances SMAD3 and ZEB1 expression. In conclusion, we propose that SNHG3 promotes HCC progression via the miR-326/SMAD3/ZEB1 signaling pathway. The findings may provide novel targets for the diagnosis and treatment of HCC.

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BackgroudAccumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) has been described for different types of cancers and might be associated with cancer risk and disease outcome. We used a population-based series of esophageal squamous cell carcinoma (ESCC) patients for investigating the prediction power of SNPs in mitochondrial D-loop.MethodsThe D-loop region of mtDNA was sequenced for 60 ESCC patients recorded in the Fourth Hospital of Hebei Medical University between 2003 and 2004. The 5 year survival curve were calculated with the Kaplan-Meier method and compared by the log-rank test at each SNP site, a multivariate survival analysis was also performed with the Cox proportional hazards method.ResultsThe SNP sites of nucleotides 16274G/A, 16278C/T and 16399A/G were identified for prediction of post-operational survival by the log-rank test. In an overall multivariate analysis, the 16278 and 16399 alleles were identified as independent predictors of ESCC outcome. The length of survival of patients with the minor allele 16278T genotype was significantly shorter than that of patients with 16278C at the 16278 site (relative risk, 3.001; 95% CI, 1.029 - 8.756; p = 0.044). The length of survival of patients with the minor allele 16399G genotype was significantly shorter than that of patients with the more frequent allele 16399A at the 16399 site in ESCC patients (relative risk, 3.483; 95% CI, 1.068 - 11.359; p = 0.039).ConclusionGenetic polymorphisms in the D-loop are independent prognostic markers for patients with ESCC. Accordingly, the analysis of genetic polymorphisms in the mitochondrial D-loop can help identify patient subgroups at high risk of a poor disease outcome.

It has been implicated that reactive oxygen species (ROS) play important roles in modulating tumor progression. However, the mechanisms by which redox-regulated tumor progression are largely unknown. We previously demonstrated that reduced intracellular redox conditions could be achieved in stably transfected small cell lung cancer cells with gamma-glutamylcysteine synthetase (gamma-GCSh) cDNA which encodes a rate-limiting enzyme in the biosynthesis of glutathione (GSH), a major physiological redox regulator. In the present study, using DNA microarray analyses, we compared the expression profiles between the gamma-GCSh-transfected cells and their nontransfected counterpart. We observed downregulation of several matrix metalloproteinases (MMPs), i.e., MMPI and MMP3, and MMP10 in the transfected cells. Dot blot and Northern blot hybridizations confirmed that, among the 18 MMP gene family members and four tissue inhibitors of matrix metalloprotein family (TIMP) analyzed, the expression levels of these three MMPs were consistently reduced. Transiently increased gamma-GCSh expression using tetracycline-inducible gamma-GCSh adenoviral expression system also showed down-regulation of MMP3 and MMP10, but not MMP1. Our results demonstrated that redox regulation of MMP1, MMP3 and MMP10 expression depend upon different modes of redox manipulation. These results bear implication that antioxidant modulation of antitumor progression may be contributed at least in part by the downregulation of a subset of metrix metalloproteins.

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