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Three genome-wide association studies (GWAS) have been conducted on the genetic susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), two of which consistently identified tagging single nucleotide polymorphisms (SNPs) around HLA-DQ/DR. In contrast, large multi-centre association studies between HBV genotype, mutations and the risk of HCC are relatively rare, and their interactions with host variants are even less. We performed a multi-centre study of 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers as controls to evaluate the effects of HBV genotype, mutations, GWAS-identified HLA-DQ/DR SNPs (rs9272105 and rs9275319) and their interactions on HCC risk. We found HBV genotype C was more frequent in HBV-related HCC. And 11 HBV hotspot mutations were independently and significantly associated with HCC risk. We also detected significant interactions of rs9272105 with both the HBV genotype and mutations. Through stepwise regression analysis, HBV genotype, the 11 mutations, HLA-DQ/DR SNPs, and the interaction of rs9272105 with mutation A1752G were all entered into the HCC prediction model, and the area under the curve for the panel including the HLA-DQ/DR SNPs, HBV genotype and mutations was 0.840. The HBV genotype, the mutations and the HLA-DQ/DR SNPs may serve as biomarkers for the surveillance of HBV persistent carriers.

Skin flaps are frequently performed for diabetic patients in spite of countless detrimental effects of diabetes on flap survival, most of which may result from a defective response of the tissues to low oxygen tension. In this study, the authors explored the feasibility of applying human adipose-derived stem cells (ASCs) to increase the viability of random-patterned skin flaps in streptozotocin-induced diabetic mice. ASCs were isolated from the fresh human lipoaspirates and expanded ex vivo for three passages. After the elevation of caudally based random-patterned skin flaps (3 cm long and 1 cm wide), ASCs suspensions were then injected into the flap (group A). Media containing no ASCs were similarly injected as a control (group B), although nothing was injected into the flap base of mice in control group C. Flap assessments were carried out at post-operative day 7 for evaluation of flap viability. The flap survival rate of group A was significantly higher than those of groups B and C, whereas no difference was observed between groups B and C. Histological examination also demonstrated a statistically significant increase in capillary density in group A over both groups B and C. Furthermore, it was found that ASCs not only augmented the expression of vascular endothelial growth factor and hypoxia-inducible factor-1α (HIF-1α) in flap tissues from dermis of diabetes mice, but also promoted their expression in dermal fibroblasts from diabetic mice. Thus, ASCs could enhance the survival of random-patterned skin flaps in streptozotocin-induced diabetic mice via elevated expression of HIF-1α.

Long noncoding RNAs (lncRNAs) are emerging as key regulators governing fundamental biological processes, and their disorder expression involves in the development of several human cancers. MIR31HG, an lncRNA located in 9p21.3 and 2166 bp in length, has been found to be upregulated in breast cancer and contributes to cell proliferation and invasion. However, the expression pattern and biological function of MIR31HG in gastric cancer are still not well documented. In this study, we found that MIR31HG expression is decreased in gastric cancer tissues and associated with larger tumor size and advanced pathological stage. Patients with lower MIR31HG expression had a relatively poor prognosis. Furthermore, ectopic over-expression of MIR31HG could inhibit gastric cancer (GC) cell proliferation both in vitro and in vivo, while knockdown of MIR31HG by small interfering RNA (siRNA) promoted cell proliferation in GC cells partly via regulating E2F1 and p21 expression. Our findings present that decreased MIR31HG is involved in GC development and could be identified as a poor prognostic biomarker in GC patients.

Estrogen receptor a (ERa or ER) is the only target of breast cancer therapy using antiestrogens. However, about 50% of ER-expressing breast cancer is intrinsically refractory to the antihormone therapy and strategies to improve the therapeutic response are urgently needed. Dynamic ER phosphorylation and dephosphorylation play an important role in ER activity and antihormone response. Although more than 10 kinases participate in phosphorylating ER protein, phosphatases involved remain mostly unidentified. Here, we tested the hypothesis that the protein-tyrosine phosphatase H1 (PTPH1) may regulate ER tyrosine phosphorylation and thereby impact breast cancer antihormone sensitivity. Our results showed that PTPH1 dephosphorylates ER at Tyr537 in vitro and in breast cancer cells. Moreover, PTPH1 stimulates ER nuclear accumulation and increases breast cancer sensitivity to tamoxifen (TAM) and/or fulvestrant in cell culture and in a xenograft model. Further analysis revealed that PTPH1 depends on its catalytic activity to stimulate ER nuclear accumulation and to enhance breast cancer antihormone sensitivity. These studies thus identified PTPH1 as a novel ER phosphatase and further demonstrate a therapeutic potential of enhancing breast cancer sensitivity to antiestrogens through dephosphorylating ER by PTPH1. Mol Cancer Ther; 13(1); 230-8. Ó2013 AACR.

ReviewThe human genome is abundant with interspersed repetitive sequences originated from retrotransposons. Until now, three categories of retrotransposons have remained unequivocally active: LINE-1(L1), Alu, and SVA elements. The first one is autonomous-capable of self-propagation through RNA intermediates-and the latter two are nonautonomous and thus rely on L1 for mobilization. There are approximately 500,000 L1 copies in the human genome, composing 17% of human DNA.

Hepatocellular carcinoma (HCC) is a disease with a high incidence and mortality rate worldwide. However, the mechanisms underlying its pathogenesis are still elusive. In recent years, studies on functions of Krüppel-like factors (KLFs) in HCC have shed new light on this field. To date, five members (KLF4, KLF6, KLF8, KLF9, and KLF17) in the KLF family have been reported to function in the pathogenesis of HCC in multiple ways, which hold the potential of deepening and widening our understanding in the initiation and progression of HCC. In this review, we focus on the functions, roles, and regulatory networks of these five KLFs in HCC, summarize key pathways, and propose areas for further investigation, with the hope that this review will provide a reliable and concise reference for readers interested in this area.