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Articles by B Hu
Total Records ( 6 ) for B Hu
  Y Gao , Y He , J Ding , K Wu , B Hu , Y Liu , Y Wu , B Guo , Y Shen , D Landi , S Landi , Y Zhou and H. Liu
 

Hepatocellular carcinoma (HCC) is the fifth most common malignancy caused by environmental and genetic factors. MicroRNAs (miRNAs) are a class of short non-coding RNAs with posttranscriptional regulatory functions. They participate in diverse biological pathways and function as gene regulators. Genetic polymorphisms in 3' untranslated regions (3' UTRs) targeted by miRNAs alter the strength of miRNA binding, with consequences on regulation of target genes thereby affecting the individual's cancer risk. We have previously predicted polymorphisms falling in miRNA-binding regions of cancer genes. We selected an insertion/deletion (Indel) polymorphism (rs3783553) in the 3' UTR of interleukin (IL)-1 (IL1A) for a case–control study in a Chinese population. With samples from 403 HCC patients and 434 healthy control individuals, strong evidence of association was observed for the variant homozygote. This association was validated in a second independent case–control study with 1074 HCC patients and 1239 healthy control individuals (odds ratio = 0.62; 95% confidence interval = 0.49–0.78). We further show that the ‘TTCA’ insertion allele for rs3783553 disrupts a binding site for miR-122 and miR-378, thereby increasing transcription of IL-1 in vitro and in vivo. These findings suggest that functional polymorphism rs3783553 in IL1A could contribute to HCC susceptibility. Considering IL-1 affects not only various phases of the malignant process, such as carcinogenesis, tumor growth and invasiveness, but also patterns of interactions between malignant cells and the host's immune system, our results indicated that IL-1 may be a promising target for immunotherapy, early diagnosis and intervention of HCC.

  C. V Camacho , B Mukherjee , B McEllin , L. H Ding , B Hu , A. A Habib , X. J Xie , C. S Nirodi , D Saha , M. D Story , A. S Balajee , R. M Bachoo , D. A Boothman and S. Burma
 

DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by ionizing radiation. Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells. We previously demonstrated that complex DSBs induced by high-linear energy transfer (LET) Fe ions are repaired slowly and incompletely, whereas those induced by low-LET gamma rays are repaired efficiently by mammalian cells. To determine whether Fe-induced DSBs are more potently tumorigenic than gamma ray-induced breaks, we irradiated ‘sensitized’ murine astrocytes that were deficient in Ink4a and Arf tumor suppressors and injected the surviving cells subcutaneously into nude mice. Using this model system, we find that Fe ions are potently tumorigenic, generating tumors with significantly higher frequency and shorter latency compared with tumors generated by gamma rays. Tumor formation by Fe-irradiated cells is accompanied by rampant genomic instability and multiple genomic changes, the most interesting of which is loss of the p15/Ink4b tumor suppressor due to deletion of a chromosomal region harboring the CDKN2A and CDKN2B loci. The additional loss of p15/Ink4b in tumors derived from cells that are already deficient in p16/Ink4a bolsters the hypothesis that p15 plays an important role in tumor suppression, especially in the absence of p16. Indeed, we find that reexpression of p15 in tumor-derived cells significantly attenuates the tumorigenic potential of these cells, indicating that p15 loss may be a critical event in tumorigenesis triggered by complex DSBs.

  B Hu , K Lefort , W Qiu , B. C Nguyen , R. D Rajaram , E Castillo , F He , Y Chen , P Angel , C Brisken and G. P. Dotto
 

Epithelial–mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that maintenance of the hair follicle keratinocyte cell fate is defective in mice with mesenchymal deletion of the CSL/RBP-J gene, the effector of "canonical" Notch signaling. Hair follicle reconstitution assays demonstrate that this can be attributed to an intrinsic defect of dermal papilla cells. Similar consequences on hair follicle differentiation result from deletion of Wnt5a, a specific dermal papilla signature gene that we found to be under direct Notch/CSL control in these cells. Functional rescue experiments establish Wnt5a as an essential downstream mediator of Notch–CSL signaling, impinging on expression in the keratinocyte compartment of FoxN1, a gene with a key hair follicle regulatory function. Thus, Notch/CSL signaling plays a unique function in control of hair follicle differentiation by the underlying mesenchyme, with Wnt5a signaling and FoxN1 as mediators.

  J. X Liu , B Hu , Y Wang , J. F Gui and W. Xiao
 

Studies have attributed several functions to the Eaf family, including tumor suppression and eye development. Given the potential association between cancer and development, we set forth to explore Eaf1 and Eaf2/U19 activity in vertebrate embryogenesis, using zebrafish. In situ hybridization revealed similar eaf1 and eaf2/u19 expression patterns. Morpholino-mediated knockdown of either eaf1 or eaf2/u19 expression produced similar morphological changes that could be reversed by ectopic expression of target or reciprocal-target mRNA. However, combination of Eaf1 and Eaf2/U19 (Eafs)-morpholinos increased the severity of defects, suggesting that Eaf1 and Eaf2/U19 only share some functional redundancy. The Eafs knockdown phenotype resembled that of embryos with defects in convergence and extension movements. Indeed, knockdown caused expression pattern changes for convergence and extension movement markers, whereas cell tracing experiments using kaeda mRNA showed a correlation between Eafs knockdown and cell migration defects. Cardiac and pancreatic differentiation markers revealed that Eafs knockdown also disrupted midline convergence of heart and pancreatic organ precursors. Noncanonical Wnt signaling plays a key role in both convergence and extension movements and midline convergence of organ precursors. We found that Eaf1 and Eaf2/U19 maintained expression levels of wnt11 and wnt5. Moreover, wnt11 or wnt5 mRNA partially rescued the convergence and extension movement defects occurring in eafs morphants. Wnt11 and Wnt5 converge on rhoA, so not surprisingly, rhoA mRNA more effectively rescued defects than either wnt11 or wnt5 mRNA alone. However, the ectopic expression of wnt11 and wnt5 did not affect eaf1 and eaf2/u19 expression. These data indicate that eaf1 and eaf2/u19 act upstream of noncanonical Wnt signaling to mediate convergence and extension movements.

  M. B Greenblatt , A Aliprantis , B Hu and L. H. Glimcher
 

Patients taking immunosuppressive drugs, like cyclosporine A (CsA), that inhibit calcineurin are highly susceptible to disseminated fungal infections, although it is unclear how these drugs suppress resistance to these opportunistic pathogens. We show that in a mouse model of disseminated Candida albicans infection, CsA-induced susceptibility to fungal infection maps to the innate immune system. To further define the cell types targeted by CsA, we generated mice with a conditional deletion of calcineurin B (CnB) in neutrophils. These mice displayed markedly decreased resistance to infection with C. albicans, and both CnB-deficient and CsA-treated neutrophils showed a defect in the ex vivo killing of C. albicans. In response to the fungal-derived pathogen-associated molecular pattern zymosan, neutrophils lacking CnB displayed impaired up-regulation of genes (IL-10, Cox2, Egr1, and Egr2) regulated by nuclear factor of activated T cells, the best characterized CnB substrate. This activity was Myd88 independent and was reproduced by stimulation with the β(1,3) glucan curdlan, indicating that dectin-1, rather than toll-like receptors, is the upstream activator of calcineurin. Our results suggest that disseminated fungal infections seen in CsA-treated patients are not just a general consequence of systemic suppression of adaptive immunity but are, rather, a result of the specific blockade of evolutionarily conserved innate pathways for fungal resistance.

 
 
 
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