Vitamin D Impacts the Expression of Runx2 Target Genes and Modulates Inflammation, Oxidative Stress and Membrane Vesicle Biogenesis Gene Networks in 143B Osteosarcoma Cells

Abstract

Osteosarcoma (OS) is an aggressive malignancy of bone affecting children, adolescents and young adults. Understanding vitamin D metabolism and vitamin D regulated genes in OS is an important aspect of vitamin D/cancer paradigm, and in evaluating vitamin D as adjuvant therapy for human OS. Vitamin D treatment of 143B OS cells induced significant and novel changes in the expression of genes that regulate: (a) inflammation and immunity; (b) formation of reactive oxygen species, metabolism of cyclic nucleotides, sterols, vitamins and mineral (calcium), quantity of gap junctions and skeletogenesis; (c) bone mineral density; and (d) cell viability of skeletal cells, aggregation of bone cancer cells and exocytosis of secretory vesicles. Ingenuity pathway analysis revealed significant reduction in Runx2 target genes such as fibroblast growth factor -1, -12 (FGF1 and FGF12), bone morphogenetic factor-1 (BMP1), SWI/SNF related, matrix associated actin dependent regulator of chromatin subfamily a, member 4 (SMARCA4), Matrix extracellular phosphoglycoprotein (MEPE), Integrin, β4 (ITGBP4), Matrix Metalloproteinase -1, -28 (MMP1 and MMP28), and signal transducer and activator of transcription-4 (STAT4) in vitamin D treated 143B OS cells. These genes interact with the inflammation, oxidative stress and membrane vesicle biogenesis gene networks. Vitamin D not only inhibited the expression of Runx2 target genes MMP1, MMP28 and kallikrein related peptidase-7 (KLK7), but also migration and invasion of 143B OS cells. Vitamin D regulated Runx2 target genes or their products represent potential therapeutic targets and laboratory biomarkers for applications in translational oncology.

Overexpression of BMP1 reflects poor prognosis in clear cell renal cell carcinoma

“…Hence, BMP1 involves in the activation of the TGF-β and BMP signaling pathways [13]. In recent years, BMP1 upregulation may increase cancer invasiveness in gastric cancer [14], lung cancers [15], osteosarcoma [16], and colon cancer [17]. Nevertheless, to the best of our knowledge, the involvement of BMP1 in ccRCC has not understood yet.…”

1,25(OH)2D3regulates the proangiogenic activity of pericyte through VDR‐mediated modulation of VEGF production and signaling of VEGF and PDGF receptors

“…Growth factors, environmental stress, and inflammatory cytokines can activate p38 . Hedges et al demonstrated the involvement of p38 in VSMC migration .…”

“…How 1,25(OH) 2 D 3 causes the increased expression of α 5 β 1 integrin remains elusive, and may be linked to induction of calcification as demonstrated in VSMC through α 5 β 1 /ERK/Runx2 pathway . The interaction between Runx2 and VDR modulates the expression of many genes affecting various cellular functions including adhesion and migration . However, the direct role of VDR and its potential interactions with other coregulatory factors that may affect integrin expression is complex and needs further investigation.…”

Calcitriol exerts an anti‐tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response

“…Previous investigations revealed that vitamin D, including calcitriol, alone or in combination with other agents, exerts antineoplastic effects in osteosarcoma . However, the precise molecular mechanism underlying the anti‐tumor effect of calcitriol in osteosarcoma cells remains unknown.…”

“…(8)(9)(10) Previous investigations revealed that vitamin D, including calcitriol, alone or in combination with other agents, exerts antineoplastic effects in osteosarcoma. (12)(13)(14) However, the precise molecular mechanism underlying the anti-tumor effect of calcitriol in osteosarcoma cells remains unknown. Furthermore, the anti-tumor potential of calcitriol for the treatment of osteosarcoma has not been extensively investigated in animal models.In this study, we examined the effects of calcitriol on osteosarcoma cells in vitro and in vivo using our syngeneic…”