PTCSC3 Is Involved in Papillary Thyroid Carcinoma Development by Modulating S100A4 Gene Expression.
BACKGROUND
We previously showed that a long noncoding RNA gene, PTCSC3, located close to the variant rs944289 that predisposes to papillary thyroid carcinoma (PTC) might target the S100A4 gene.


OBJECTIVE
The aim was to investigate the impact of PTCSC3 on S100A4 expression and its role in cancer development.


METHODS
S100A4 abundance was analyzed by quantitative PCR (qPCR) in unaffected and tumor tissue from n = 73 PTC patients. The expression of PTCSC3 and S100A4 was studied in BCPAP and TPC-1 cell lines with forced expression of PTCSC3 by qPCR. Expression of S100A4 target genes (VEGF and MMP-9) was studied in the BCPAP cell line with forced expression of PTCSC3 by qPCR, reverse transcriptase PCR, and Western blot. The impact of PTCSC3 on BCPAP motility and invasiveness was analyzed by the Transwell and Matrigel assays, respectively.


METHODS
This was a laboratory-based study using cells from clinical samples and thyroid cancer cell lines.


METHODS
We aimed to find evidence for a link between the expression of PTCSC3 and thyroid carcinogenesis.


RESULTS
Expression data from PTC cell lines pinpointed S100A4 as the most significantly downregulated gene in the presence of PTCSC3. S100A4 was upregulated in tumor tissue (P = 9.33 × 10(-7)) while PTCSC3 was strongly downregulated (P = 2.2 × 10(-16)). S100A4 transcription was moderately correlated with PTCSC3 expression in unaffected thyroid tissue (r = 0.429, P = .0001), and strongly in unaffected tissue of patients with the risk allele of rs944289 (r = 0.685, P = 7.88 × 10(-5)). S100A4, VEGF, and MMP-9 were suppressed in the presence of PTCSC3 (P = .0051, P = .0090, and P =.0037, respectively). PTC cells expressing PTCSC3 showed reduction in motility and invasiveness (P = 4.52 × 10(-5) and P = 1.0 × 10(-4), respectively).


CONCLUSIONS
PTCSC3 downregulates S100A4, leading to a reduction in cell motility and invasiveness. We propose that PTCSC3 impacts PTC predisposition and carcinogenesis through the S100A4 pathway.
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Jaroslaw
J
Jendrzejewski
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Andrew
A
Thomas
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Sandya
S
Liyanarachchi
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Andrew
A
Eiterman
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Jerneja
J
Tomsic
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Huiling
H
He
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Hanna S
HS
Radomska
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Wei
W
Li
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Rebecca
R
Nagy
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Krzysztof
K
Sworczak
Human Cancer Genetics Program, Comprehensive Cancer Center (J.J., A.T., S.L., A.E., J.T., H.H., H.S.R., W.L., R.N., A.d.l.C.), The Ohio State University, Columbus, Ohio, 43210; and Department of Endocrinology and Internal Medicine (J.J., K.S.), Medical University of Gdansk, Poland.
Albert
A
de la Chapelle
D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D022661:RNA, Untranslated / Q000235:genetics*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics*; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C000603517:Ptcsc3 untranslated RNA, human; D022661:RNA, Untranslated; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D042461:Vascular Endothelial Growth Factor A; C077591:S100A4 protein, human; D020780:Matrix Metalloproteinase 9