Background: Ice-binding proteins improve the cold tolerance of cells by inhibiting ice growth and recrystallization. Results: Crystal structure and mutagenesis data of LeIBP suggests the B face as an ice-binding site. Conclusion: LeIBP structure adopts a ␤-helical fold and the aligned Thr/Ser/Ala residues are critical for ice binding. Significance: LeIBP structure can serve as a structural model for a large number of IBPs.

One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, which is considered a potential cause of tumor recurrence. Infiltrated GBM cells are difficult to completely eradicate surgically and with local therapeutic modalities. Although much effort has focused on understanding the various mechanisms controlling GBM invasiveness, its nature remains poorly understood. In this study, we established highly serial intracranial transplantation. U87R4 cells were highly invasive and displayed stem cell-like properties, as compared to noninvasive but proliferative U87L4 cells. Microarray analysis during serial transplantation revealed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated whereas several cancer stem cell-relevant genes [Frizzled 4 (FZD4) and CD44] were upregulated in more invasive cells. U87R4 cells were resistant to anticancer drug-induced cell death, partly due to downregulation of caspase3 and PDCD4, and they retained activated Wnt/b-catenin signaling due to upregulation of Frizzled 4, which was sufficient to control neurosphere formation. We also found that FZD4 promoted expression of the epithelial to mesenchymal transition regulator SNAI1, along with acquisition of a mesenchymal phenotype. Taken together, our results argue that Frizzled 4 is a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and that it may be a major cause of GBM recurrence and poor prognosis. Cancer Res; 71(8); 3066-75. Ó2011 AACR.

c-Myc dysregulation is one of the most common abnormalities found in human cancer. MicroRNAs (miRNAs) are functionally intertwined with the c-Myc network as multiple miRNAs are regulated by c-Myc, while others directly suppress c-Myc expression. In this work, we identified miR-33b as a primate-specific negative regulator of c-Myc. The human miR-33b gene is located at 17p11.2, a genomic locus frequently lost in medulloblastomas, of which a subset displays c-Myc overproduction. Through a small-scale screening with drugs approved by the US Food and Drug Administration (FDA), we found that lovastatin upregulated miR-33b expression, reduced cell proliferation and impaired c-Myc expression and function in miR-33b-positive medulloblastoma cells. In addition, a low dose of lovastatin treatment at a level comparable to approved human oral use reduced tumour growth in mice orthotopically xenografted with cells carrying miR-33b, but not with cells lacking miR-33b. This work presents a highly promising therapeutic option, using drug repurposing and a miRNA as a biomarker, against cancers that overexpress c-Myc.

Rapid temperature changes within a single day may be critical for populations vulnerable to thermal stress who have difficulty adjusting themselves behaviorally and physiologically. We hypothesized that diurnal temperature range (DTR) is associated with mortality, and that this association is modified by season and socioeconomic status (SES). We evaluated meteorological and mortality data from six metropolitan areas in Korea from 1992 to 2007. We applied generalized linear models (GLM) for quantifying the estimated effects of DTR on mortality after adjusting for mean temperature, dew point temperature, day of the week, and seasonal and long-term trends. Most areas showed a linear DTR-mortality relationship, with evidence of increasing mortality with increasing DTR. Deaths among the elderly (75 years or older), females, the less educated, and the non-hospital population were associated more strongly with DTR than with the corresponding categories. DTR was the greatest threat to vulnerable study populations, with greater influence in the fall season. DTR was found to be a predictor of mortality, and this relationship was modified by season and SES.

IntroductionInflammation has been implicated in cancer aggressiveness. As transglutaminase 2 (TG2), which has been associated with inflammatory signaling, has been suggested to play a role in tumor behavior, we propose that TG2 may be an important linker inducing interleukin (IL)-6-mediated cancer-cell aggressiveness, including distant hematogenous metastasis.MethodsTo investigate the role for TG2 and IL-6, TG2-knocked-down and IL-6-knocked-down cancer cells were generated by using shRNA. Human breast cancer cell xenograft model in highly immunocompromised mice and human advanced breast cancer primary tumor tissue microarrays were used in this study.ResultsIL-6 production in human breast cancer cells was dependent on their TG2 expression level. In vitro tumor-sphere formation was dependent on TG2 and downstream IL-6 production from cancer cells. Primary tumor growth in the mammary fat pads and distant hematogenous metastasis into the lung was also dependent on TG2 and downstream IL-6 expression levels. The effect of TG2 expression on human breast cancer distant metastasis was investigated by analyzing a tissue microarray of primary tumors from 412 patients with their clinical data after 7 years. TG2 expression in primary tumor tissue was inversely correlated with recurrence-free survival (P = 0.019) and distant metastasis-free survival (DMFS) (P = 0.006) in patients with advanced breast cancer. Furthermore, by using public datasets that included a total of 684 breast cancer patients, we found that the combined high expression of TG2 and IL-6 was associated with shorter DMFS, compared with the high expression of IL-6 only (P = 0.013).ConclusionsWe provide evidence that TG2 is an important link in IL-6-mediated tumor aggressiveness, and that TG2 could be an important mediator of distant metastasis, both in a xenograft animal model and in patients with advanced breast cancer.

This study suggests that common genetic variants in the OR10J3 and FCER1A be strongly associated with breast cancer risk among Korean women.

We aimed to identify the factors affecting the successful tumor engraftment in breast cancer patient-derived xenograft (PDX) models. Further, we investigated the prognostic significance and the functional importance of the PDX engraftment-related genes in triple-negative breast cancers (TNBC). The clinico-pathologic features of 81 breast cancer patients whose tissues were used for PDX transplantation were analyzed to identify the factors affecting the PDX engraftment. A gene signature associated with the PDX engraftment was discovered and its clinical importance was tested in a publicly available dataset and in vitro assays. Nineteen out of 81 (23.4 %) transplanted tumors were successfully engrafted into the PDX models. The engraftment rate was highest in TNBC when compared to other subtypes (p = 0.001) and in recurrent or chemotherapy-resistant tumors compared to newly diagnosed primary tumors (p = 0.024). PDX tumors originated from the TNBC cases showed more rapid tumor growth in mice. Gene expression profiling showed that down-regulation of genes involved in the tumor-immune interaction was significantly associated with the successful PDX engraftment. The engraftment gene signature was associated with worse survival outcome when tested in publicly available mRNA datasets of TNBC cases. Among the engraftment-related genes, PHLDA2, TKT, and P4HA2 showed high expression in triple-negative breast cancer cell lines, and siRNA-based gene silencing resulted in reduced cell invasion and proliferation in vitro. Our results show that the PDX engraftment may reflect the aggressive phenotype in breast cancer. Genes associated with the PDX engraftment may provide a novel prognostic biomarker and therapeutic targets in TNBC.

These subtype-specific alterations have promising potentials of new prognostic biomarkers and therapeutic targets combined with surrogate markers of glioblastoma subtypes. However, considering the small number of events, the results of copy number alterations and mutations require further validations.