Background Triple-negative breast cancer (TNBC) is the most severe type of breast cancer owing to its high heterogeneity, aggressiveness and lack of treatment. Studies have reported that uncarboxylated osteocalcin (GluOC) promotes the development of prostate and other cancers. Studies have also found elevated levels of serum osteocalcin in breast cancer patients with bone metastasis, and serum osteocalcin can be a marker of bone metastasis. However, whether GluOC promotes the development of TNBC and the related mechanisms need to be further clarified. Results Our results revealed that GluOC is associated with the proliferation and metastasis of MDA-MB-231 cells. GluOC increased the viability and proliferation of MDA-MB-231 cells. In addition, GluOC enhanced the metastatic ability of MDA-MB-231 cells by promoting the expression of matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-13 (MMP13), and vascular endothelial growth factor (VEGF) and inducing epithelial-mesenchymal transition (EMT). We also found that GluOC upregulated the expression of interleukin-8 (IL-8) and parathyroid hormone-related protein (PTHrP) genes in MDA-MB-231 breast cancer cells. Moreover, the promoting effect of GluOC was reversed in MDA-MB-231 breast cancer cells treated with specific inhibitor of SMAD3 (SIS3), a SMAD3 phosphorylation inhibitor. Conclusion Our research proved for the first time that GluOC facilitates the proliferation and metastasis of MDA-MB-231 cells by accelerating the transforming growth factor-β (TGF-β)/SMAD3 signaling pathway. Moreover, GluOC also promotes the gene expression of IL-8 and PTHrP. Both IL-8 and PTHrP can act as osteolytic factors in breast cancer cells. This study indicates that GluOC may be a useful target for preventing TNBC bone metastasis.

No abstract

Uncarboxylated osteocalcin (GluOC), a small-molecule protein specifically synthesized and secreted by osteoblasts, is important in the regulation of energy metabolism. In our previous study, GluOC was shown to be effective in ameliorating dyslipidemia and hepatic steatosis in KKAy mice. However, the underlying mechanism of GluOC action on hepatocytes has not been well validated. In this study, oleic acid/palmitic acid (OA/PA)-induced HepG2 and NCTC 1469 cells were used as non-alcoholic fatty liver disease (NAFLD) cell models, and triacylglycerol (TG) levels were measured by oil red O staining, Nile Red staining, and ELISA. The fatty acid synthesis-related protein expression was detected by real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. The results show that GluOC reduced triglyceride levels, and decreased the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and stearyl-coenzyme A desaturase 1 (SCD1). si-SCD1 mimicked the lipid accumulation-reducing effect of GluOC, while overexpression of SCD1 attenuated the effect of GluOC. In addition, GluOC activated AMP-activated protein kinase (AMPK) phosphorylation to affect lipid metabolism in hepatocytes. Overall, the results of this study suggest that GluOC decreases SCD1 by activating AMPK to alleviate hepatocyte lipid accumulation, which provides a new target for improving NAFLD in further research.

Purpose: Phyllodes tumors (PTs) are rare neoplasms with a certain risk of recurrence and/or metastasis. In clinical practice, there is a lack of high-quality clinical studies and unified guidelines to guide the treatment. Materials and Methods:All malignant and recurrence/metastasis PTs were retrospectively collected, which were diagnosed from 2008 to 2022.Results: A total of 82 patients were enrolled, including 69 malignant and 13 borderline tumors. 96.3% (79/82) received surgical treatment. During a median follow-up of 55.5 months, 20 patients (20/82, 24.4%) had distant metastasis (DM), while 32 (32/82, 39.0%) had local recurrence (LR). Univariate analysis showed the survival of PTs was associated with surgical methods (p < 0.001), tumor size (p = 0.026), and biological behavior (p = 0.017), but not age at diagnosis. In relapsed borderline PTs, we did not find deaths due to disease progression. Patients with DM were all malignant PTs, with disease-progression occurring within 3 years in more than 80% of patients. Among salvage treatments, the combination of antiangiogenic drugs improved the prognosis to some extent, with a significant increase in mPFS (2.77 vs. 1.53 months), but no significant statistical results were obtained (p = 0.168). Lactate dehydrogenase (LDH) was an independent predictor of the prognosis for malignant PTs (p = 0.001, HR = 1.203, 95%CI, 1.082-1.336). Conclusion: Borderline PTs rarely metastasize, and even if LR occurs, surgical resection can lead to long-term survival. In metastatic phyllodes tumors (MPT), systemic therapy is not effective, but antiangiogenic drugs may prolong survival.LDH is an independent prognostic factor for malignant PTs to identify high-risk tumors.