Knockdown of S100A4 blocks growth and metastasis of anaplastic thyroid cancer cells in vitro and in vivo

Abstract

Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. It is often incurable because it does not respond to radioiodine, radiotherapy, or chemotherapy. With conventional treatment, the median survival is about 6 months; therefore, new treatment options are needed. S100A4 is a calcium-binding protein related to the metastatic potential of carcinoma. Previous study has found S100A4 was overexpressed in human papillary thyroid carcinomas (PTC) tissues, and overexpression of S100A4 is associated with thyroid tumour invasion and metastasis. In the present study, we first examined S100A4 protein expression in 14 ATC tissues, 20 PTC tissues and 14 normal thyroid tissue by immunohistochemistry analysis. We then knocked down of S100A4 expression by RNA interference (S100A4 siRNA) and investigated its effects on growth and metastasis in two human ATC cell lines 8505C (BRAFV600E) and Cal-62 (BRAFwt) in vitro and in vivo. S100A4 and BRAFV600E protein expression was evaluated by western blot assay and immunohistochemistry analysis. Using immunohistochemistry, we found that high levels of S100A4 were detected in ATC specimens and PTC specimens. No S100A4 staining was observed in normal thyroid tissues. S100A4 siRNA significantly decreased proliferation and increased apoptosis, and inhibited the invasive potential of the two cells in vitro. In addition, S100A4 siRNA could effectively inhibit BRAFV600E expression in the 8505C cells, and treatment with 100 ng/ml human recombinant BRAF V600E in S100A4 siRNA/8505C cells could partly restore its proliferative and invasive ability. Results of implantation in vivo showed S100A4 shRNA could significantly inhibit abdominal cavity metastasis and tumor growth in vivo. Furthermore, knockdown of S100A4 has significant role on invasion, metastasis and growth inhibition in the 8505C cells than that of in the Cal-62 cells. These results support the hypothesis that S100A4 contributes significantly to growth and metastasis, and that down-regulation of S100A4 expression decreases the metastatic potential of ATC cells. Furthermore, down-regulation of S100A4 expression is more marked in BRAFV600E cells than that of in the BRAFwt cells.

FAM107B is regulated by S100A4 and mediates the effect of S100A4 on the proliferation and migration of MGC803 gastric cancer cells

“…S100A4 is a member of the S100 family of Ca 2þ -binding proteins. S100A4 can influence various biological characteristics of several different kinds of cancer cells (Cheng et al, 2016;Qi et al, 2016;Zhang et al, 2016). The increased S100A4 expression was closely correlated with invasion, lymph node metastasis, and poor prognosis of gastric cancer (Li et al, 2013;Natarajan et al, 2014;Niu et al, 2015).…”

“…FAM107B gene is located on chromosome 10p13 and encode FAM107B protein consisting of 131 aa, also known as HITS. S100A4 can influence various biological characteristics of several different kinds of cancer cells (Cheng et al, 2016;Qi et al, 2016;Zhang et al, 2016). By screening a multiple organ tumor and normal tissue microarray, Nakajima et al (2012) found that HITS expression was decreased in tumor tissues of the stomach, breast, thyroid, and other kinds of tissues.…”

Interplay between Trx‐1 and S100P promotes colorectal cancer cell epithelial–mesenchymal transition by up‐regulating S100A4 through AKT activation

“…[51][52][53] Overexpression of S100A4 promotes metastasis in several experimental animal models, in contrast, down-regulation of S100A4 expression reduces the metastatic capacity of cancer cells. 24,51,[54][55][56][57][58] In CRC, S100A4 is overexpressed and its expression is correlated with patient outcome. 59,60 Consistent with that, our results showed that the expression of S100A4 was higher in human CRC tissues compared with their normal counterpart tissues, and higher expression of S100A4 was significantly correlated with lymph node metastasis and poor survival.…”

Long Non-coding RNA PTCSC3 Promotes Apoptosis of Human Papillary Thyroid Carcinomas by Regulating S100A4

“…S100A4 is a Ca 2+ -binding protein that are associated with diverse cellular processes, there aer cell invasion, proliferation and cell-cell interaction (12)(13)(14) . S100A4 was reported to be overexpressed in human PTC tissues and lymph node metastases (15,16) , and knockdown of S100A4 inhibited the growth and metastasis in anaplastic papillary thyroid carcinomas cells (17) . VEGF and MMP-9 are downstream targets of S100A4 and the suppression of S100A4 also results in suppressed expressions about VEGF and MMP-9, which in turn suppresses the invasion of thyroid carcinoma cells (18,19) VEGF is an essential endothelial cell mitogen and is an important factor in angiogenesis (20) .…”