Project description:Cartilage Oligomeric Matrix Protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Publicly available mRNA expression array data indicated that COMP is overexpressed in breast cancer tissue. Tissue microarrays derived from two cohorts of patients with breast cancer (n = 122 and n = 498) were immunostained, which revealed varying amounts of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and faster recurrence (metastases). Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdcscid/Rj) mice. Tumors expressing COMP grew to significantly larger volumes and had increased metastasis as compared to control, mock transfected, tumors. In vitro experiments confirmed that COMP expressing cells were more invasive, which was in part related to an upregulation of metalloprotease-9. Further, microarray analyses of gene expression in tumors formed in vivo showed that expression of COMP was protective against endoplasmatic reticulum stress. This observation was confirmed in vitro since COMP expressing cells showed better survival than mock when treated with brefeldin, which leads to accumulation of proteins in endoplasmatic reticulum. The mRNA pathway analyses also implicated a metabolic switch leading to a more severe Warbug effect, which was confirmed in vitro by measurement of cell respiration and lactate production. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by several novel molecular mechanisms.
Project description:Activation of YAP is frequently observed in cancer and is associated with poor outcomes, making it an attractive target for therapeutic intervention. Previous studies have mainly focused on blocking the interaction of YAP with TEAD transcription factors. Here we took a different approach by interfering with the binding of YAP to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. We found that expression of MY-COMP inhibited the binding of B-MYB to YAP, resulting in growth defects, nuclear abnormalities and polyploidization in HeLa cells. Additionally, MY-COMP interfered with normal cell cycle progression of YAP-dependent uveal melanoma cells, but its effects were much weaker in YAP-independent cutaneous melanoma cell lines. MY-COMP antagonized the YAP-dependent expression of MMB-regulated cell cycle genes, providing an explanation for the observed phenotypes. We identified NIMA-related kinase (NEK2) as a candidate target downstream of YAP and B-MYB, contributing to the transformation of YAP-dependent uveal tumor cell lines. Overall, our findings suggest that targeting selected YAP-MMB regulated genes such as NEK2 or inhibiting the WW-domains of YAP to suppress YAP-regulated cell cycle genes could provide a novel mechanism to antagonize the pro-tumorigenic functions of YAP.
Project description:D-galactose orally intake ameliorate DNCB-induced atopic dermatitis by modulating microbiota composition and quorum sensing. The increased abundance of bacteroidetes and decreased abundance of firmicutes was confirmed. By D-galactose treatment, Bacteroides population was increased and prevotella, ruminococcus was decreased which is related to atopic dermatitis.
