Hyperglycemia induces PFKFB3 overexpression and promotes malignant phenotype of breast cancer through RAS/MAPK activation.

BACKGROUND: Breast cancer is the most common tumor in women worldwide. Diabetes mellitus is a global chronic metabolic disease with increasing incidence. Diabetes mellitus has been reported to positively regulate the development of many tumors. However, the specific mechanism of hyperglycemic environment regulating breast cancer remains unclear. PFKFB3 (6-phosphofructose-2-kinase/fructose-2, 6-bisphosphatase 3) is a key regulatory factor of the glycolysis process in diabetes mellitus, as well as a promoter of breast cancer. So, we want to explore the potential link between PFKFB3 and the poor prognosis of breast cancer patients with hyperglycemia in this study. METHODS: Cell culture was utilized to construct different-glucose breast cancer cell lines. Immunohistochemistry was adopted to analyze the protein level of PFKFB3 in benign breast tissues, invasive ductal carcinoma with diabetes and invasive ductal carcinoma without diabetes. The Kaplan-Meier plotter database and GEO database (GSE61304) was adopted to analyze the survival of breast cancer patients with different PFKFB3 expression. Western blot was adopted to analyze the protein level of PFKFB3, epithelial-mesenchymal transition (EMT)-related protein and extracellular regulated protein kinases (ERK) in breast cancer cells. Gene Set Cancer Analysis (GSCA) was utilized to investigate the potential downstream signaling pathways of PFKFB3. TargetScan and OncomiR were utilized to explore the potential mechanism of PFKFB3 overexpression by hyperglycemia. Transfections (including siRNAs and miRNA transfection premiers) was utilized to restrain or mimic the expression of the corresponding RNA. Cell functional assays (including cell counting, MTT, colony formation, wound-healing, and cell migration assays) were utilized to explore the proliferation and migration of breast cancer cells. RESULTS: In this study, we demonstrated that the expression of PFKFB3 in breast cancer complicated with hyperglycemia was higher than that in breast cancer with euglycemia through cell experiment in vitro and histological experiment. PFKFB3 overexpression decreased the survival period of breast cancer patients and was correlated with a number of clinicopathological parameters of breast cancer complicated with diabetes. PFKFB3 promoted the proliferation and migration of breast cancer in a hyperglycemic environment and might be regulated by miR-26. In addition, PFKFB3 stimulated epithelial-mesenchymal transition of breast cancer in a hyperglycemic environment. In terms of downstream mechanism exploration, we predicted and verified the cancer-promoting effect of PFKFB3 in breast cancer complicated with hyperglycemia through RAS/MAPK pathway. CONCLUSIONS: In conclusion, PFKFB3 could be overexpressed by hyperglycemia and might be a potential therapeutic target for breast cancer complicated with diabetes.

Revealing the Effect of Surface Composition on Multiwalled Carbon Nanotubes Supported Pt-Fe Alloy Electrocatalysts for Methanol Oxidation Performance.

The designs of efficient and inexpensive Pt-based catalysts for methanol oxidation reaction (MOR) are essential to boost the commercialization of direct methanol fuel cells. Here, the highly catalytic performance PtFe alloys supported on multiwalled carbon nanotubes (MWCNTs) decorating nitrogen-doped carbon (NC) have been successfully prepared via co-engineering of the surface composition and electronic structure. The Pt1 Fe3 @NC/MWCNTs catalyst with moderate Fe3+ feeding content (0.86 mA/mgPt ) exhibits 2.26-fold enhancement in MOR mass activity compared to pristine Pt/C catalyst (0.38 mA/mgPt ). Furthermore, the CO oxidation initial potential of Pt1 Fe3 @NC/MWCNTs catalyst is lower relative to Pt/C catalyst (0.71 V and 0.80 V). Benefited from the optimal surface compositions, the anti-corrosion ability of MWCNT, strong electron interaction between PtFe alloys and MWCNTs and the N-doped carbon (NC) layer, the Pt1 Fe3 @NC/MWCNTs catalyst presents an improved MOR performance and anti-CO poisoning ability. This study would open up new perspective for designing efficient electrocatalysts for the DMFCs field.

[Clinicopathologic analysis of Langerhans cell histiocytosis in adults].

OBJECTIVE: To explore the clinical features, pathomorphology, immunohistochemical characteristics and prognosis of Langerhans cell histiocytosis (LCH) in adults. METHODS: Twenty-three cases of adult LCH were retrieved from Ningbo Diagnostic Pathology Center during the period from January 2005 to December 2011. And their clinical presentation, pathomorphology and immunohistochemical characteristics were analyzed. RESULTS: The mean age of patients was 37.2 years (range: 20 - 58). The male-to-female ratio was 1.6:1. Of 23 LCH patients, 26 lesions were found including 14 bone tissue lesions (53.8%), followed by 4 lymph node lesions and 4 skin lesions (both 15.4%), as well as 1 soft tissue, liver, parotid and buccal lesion respectively (all 3.8%). Clinically, uni-system and unifocal disease was predominant (19 cases, 82.6%), followed by uni-system and multifocal disease (1 case, 4.3%), multi-system disease (3 cases, 13.0%). Histologically, all cases of LCH revealed diffused distribution of Langerhans cells, accompanied by a variable number of eosinophils, lymphocytes, neutrophils and multinucleated giant cells. Immunohistochemically, the expression of CD1a, Langerin, S-100 protein and CD68 was 100% (23/23), 100% (20/20), 95.6% (22/23) and 90.5% (19/21) respectively. All lesions were treated by surgical therapy. Sixteen patients were available for follow-up examination and 14 patients survived. The 3 and 5-year cumulative survival rates were 92.9% and 79.6% respectively. CONCLUSIONS: LCH of adults occurs predominantly in bone and presents mainly as uni-system or unifocal defects. Surgical excision is generally effective and the prognosis is fair.

Immunosuppressive effect of bladder cancer on function of dendritic cells involving of Jak2/STAT3 pathway.

Function of dendritic cells (DCs) is impaired by some cancer cells. However, the effect of bladder cancer cell (BCC) on phenotype and function of DCs remains unclear. In this study, healthy human peripheral blood mononuclear cells (PBMCs) derived DCs were co-cultured with BCC pumc-91 and adriamycin-resistant pumc-91/ADM. The expression of DC markers and costimulatory molecules decreased after co-culture. Co-cultured DCs rapidly underwent apoptosis, and had a declined capability to produce IL-8 and RANTES. Furthermore, co-cultured DCs showed impaired allogeneic T cell proliferation and T cell-derived cytokine secretion. Finally, AG490, a Jak2/STAT3 inhibitor, restored the expression of DC markers and costimulatory molecules. Of note, compared with control DCs, DCs co-cultured with pumc-91 produced more IP-10; DCs co-cultured with pumc-91/ADM secreted more MIG. Taken together, these results suggest BCC may inhibit maturation and function of DCs involving of Jak2/STAT3 pathway, and there may be different mechanisms by which adriamycin-resistant BCC restrains DC function in antitumor immune response.