Abstract
Calcification is important for the diagnosis of papillary thyroid carcinoma (PTC). Runt-related transcription factor 2 (RUNX2), a master transcription factor associated with osteogenic differentiation, is reportedly related to PTC calcification and invasiveness. However, its regulatory role in this process is somewhat uncharacterized. Here, we attempted to identify genes that regulate RUNX2 and clarify its function in PTC carcinogenesis and calcification. The expression of RUNX2-upstream genes was evaluated by real-time PCR in Nthy-Ori 3-1 normal thyroid cells and TPC1 and BHP10-3 PTC cell lines. Luciferase and chromatin immunoprecipitation assays were performed with candidate genes after cloning the RUNX2 promoter. We found that RUNX2 promoter activity was enhanced by homeobox family A9 (HOXA9). Over-expression of HOXA9 was found to enhance alkaline phosphatase activity, mineralization, and in vitro tumour cell migration and invasion, whereas downregulation had the opposite effects. These results indicate that HOXA9, a positive regulator of RUNX2, can enhance calcification, migration, and invasion in PTC. Our data improve the understanding of the molecular mechanisms of microcalcification in PTC as well as tumorigenesis.
Highlights
Calcification is important for the diagnosis of papillary thyroid carcinoma (PTC)
To discover a novel protein that regulates the expression of RUNX2, we selected seven candidates (catenin beta interacting protein 1 (CTNNBIP1), distal-less homeobox 3 (DLX3), homeobox family A9 (HOXA9), NK2 homeobox 5 (NKX2-5), —> NK3 homeobox 2 (NKX3-2), runt related transcription factor 1 (RUNX1), and SRY-Box 9 (SOX9)) from a transcription factor (TF) search website
We screened the effect of candidates on osteoblastic marker genes including RUNX2, integrin binding sialoprotein (IBSP), and bone gamma-carboxyglutamic acid-containing protein (BGLAP) by measuring mRNA expression levels by real-time PCR
Summary
Calcification is important for the diagnosis of papillary thyroid carcinoma (PTC). Runt-related transcription factor 2 (RUNX2), a master transcription factor associated with osteogenic differentiation, is reportedly related to PTC calcification and invasiveness. Over-expression of HOXA9 was found to enhance alkaline phosphatase activity, mineralization, and in vitro tumour cell migration and invasion, whereas downregulation had the opposite effects These results indicate that HOXA9, a positive regulator of RUNX2, can enhance calcification, migration, and invasion in PTC. Papillary thyroid carcinoma (PTC) is the most common type of malignant thyroid tumour[1,2,3] Calcifications, characteristic of this disease, are important for the diagnosis of PTC4,5. The main function of type I and II RUNX2 is as transcription factors involved in osteoblast differentiation and bone formation[11,12] They are involved in the carcinogenesis of breast and prostate cancers, as well as bone metastasis[13,14]. The regulatory role of RUNX2 in thyroid calcification and carcinogenesis has not been fully elucidated
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