Uncarboxylated osteocalcin promotes proliferation and metastasis of MDA-MB-231 cells through TGF-β/SMAD3 signaling pathway

Abstract

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.

Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

“…Recent reports have provided additional support for IL-8 s role in TNBC progression. These studies implicate IL-8 in the development of bone, brain, and lung metastasis [33][34][35], epithelial mesenchymal transition [36], and expansion of cancer stem cells [37]. Our current findings indicate that only the EDA domain of fibronectin activated NFκB signaling and cytokine release in MDA-MB-468 cells, while both the EDA and III-1c domains elicited the response in MDA-MB-231 cells.…”

Satellite Cell‐Derived Exosomes: A Novel Approach to Alleviate Skeletal Muscle Atrophy and Fibrosis

“…[28,29] Interestingly, the inhibition of Smad3 alone is sufficient to enhance muscle growth. [25,30] During muscle atrophy, muscle cells increase TGF-𝛽1/Smad3 levels and transition to a more fibrotic phenotype. [25] In investigations examining murine models of muscle fibrosis after glycerol-induced injury, researchers administered varying dosages of anti-TGF-𝛽1 antibodies (5 and 12.5 μg); the administration of both dosages resulted in a marked reduction in fibrosis and enhanced muscle regeneration, indicating the potential dual functionality of the anti-TGF-𝛽1 antibody as an anti-fibrotic and myogenic agent.…”

The link between bone-derived factors osteocalcin, fibroblast growth factor 23, sclerostin, lipocalin 2 and tumor bone metastasis

“…In addition, the relationship between OC and tumorigenesis has been noted (33) (36) showed that ucOC facilitated the proliferation and metastasis of breast cancer cells MDA-MB-231 by accelerating the TGF-b/SMAD3 signaling pathway. Furthermore, ucOC also promoted the gene expression of IL-8 and PTHrP, which may act as osteolytic factors in breast cancer cells.…”