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

Rama Garimella,Peter Rowe,Priyanka Tadikonda,Ossama Tawfik,Sumedha Gunewardena,Peter Van Veldhuizen

doi:10.3390/ijms18030642

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.

Highlights

Osteosarcoma (OS) is the primary malignancy of bone affecting children, adolescents and young adults and accounts for 20%–45% of all bone tumors
The main goal of this study is to evaluate 1α,25(OH)2D3 regulated gene expression in a metastatic human osteosarcoma cell line, 143B, at different stages of their growth by microarray gene expression profiling
Osteosarcoma cell line 143B was obtained from American Type Culture Collection (Manassas, VA, USA)

Summary

Introduction

Osteosarcoma (OS) is the primary malignancy of bone affecting children, adolescents and young adults and accounts for 20%–45% of all bone tumors. Development of lung metastasis is the main cause of death in OS patients [1,2,3]. Despite aggressive chemotherapy and surgical treatments, one third of patients usually relapse with pulmonary metastases [4,5,6]. Several reports indicate that OS patients have decreased bone density, aberrations in vitamin D regulatory system, sub optimal vitamin D levels, oncogenic osteomalacia and increased incidence of pathological fractures which tend to increase lung metastases [7,8,9,10,11,12]. There is an unmet need to identify novel disease and/or therapeutic biomarkers for applications in laboratory medicine and translational oncology to stratify OS patients for response to therapy and enhance their survival

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