B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it is also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo. We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF-1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Further, B7-H3 promoted ROS-dependent stabilization of HIF-1α by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression.
Control subjects were recruited over the same period as the men presenting with hip fracture to avoid seasonal variation in vitamin D concentrations. We attempted to recruit the same numbers of inpatient and outpatient control subjects as men presenting with hip fracture.
Homeobox A11 (HOXA11) is one of the hypermethylated genes in breast cancer and its function in breast tumorigenesis remains elusive. In this study, we analyzed the methylation status of HOXA11 in 264 paired breast cancer and normal tissue as well as in matched serum samples by MethyLight assay. Further, the function of HOXA11 in breast tumorigenesis was analyzed by cell proliferation and migration assays. We found that HOXA11 was hypermethylated in cancer tissues (45.08%), especially in invasive ductal carcinomas (P<0.001), patients with a family history of cancer (P=0.033), cases with metastatic lymph nodes (P=0.004) and P53 positive group (P=0.017). Kaplan-Meier survival analysis and Cox regression analysis revealed that HOXA11 hypermethylation is an independent predictor of poor outcomes. The over expression of HOXA11 suppressed cell growth in MDA-MB-231, MCF7, SKBR3 and BT474 cells. In conclusion, the hypermethylation of HOXA11 is an independent prognostic biomarker in breast cancer. Additionally, HOXA11 can be a potential tumor suppressor.
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