PTCSC3 Is Involved in Papillary Thyroid Carcinoma Development by Modulating<i>S100A4</i>Gene Expression

Jendrzejewski, Jarosław; Thomas, Andrew; Liyanarachchi, Sandya; Eiterman, Andrew; Tomšič, Jerneja; He, Hao; Radomska, Hanna S.; Li, Wei; Nagy, Rebecca; Sworczak, Krzysztof; Chapelle, Albert de la

doi:10.1210/jc.2015-2247

Cited by 66 publications

(53 citation statements)

References 31 publications

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“…The rs920778 C>T polymorphism leads to increased HOTAIR RNA expression, which might be the underlying mechanism in conferring PTC susceptibility. These data support the hypothesis that functional SNPs influencing lncRNA regulation may explain a part of PTC genetic basis171819.…”

Section: Discussionsupporting

confidence: 86%

Onco-lncRNA HOTAIR and its functional genetic variants in papillary thyroid carcinoma

Zhu

et al. 2016

Sci Rep

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The role of long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) and its functional single nucleotide polymorphisms (SNPs) in papillary thyroid carcinoma (PTC) is still largely unclear. Therefore, we investigated the involvement of lncRNA HOTAIR and its three haplotype-tagging SNPs (htSNPs) in PTC. There was higher expression of HOTAIR in PTC tissues compared to normal tissues. A series of gain-loss assays demonstrated that HOTAIR acts as a PTC oncogene via promoting tumorigenic properties of PTC cells. Additionally, the functional HOTAIR rs920778 genetic variant was a PTC susceptibility SNP. Subjects with the HOTAIR rs920778 TT genotype had an odds ratio (OR) of 1.88, 1.25 and 1.61 (P = 6.0 × 10−6, P = 0.028 and P = 3.2 × 10−5) for developing PTC in Shandong, Jiangsu and Jilin case-control sets compared with subjects with the CC genotype. This statistically significant associations were only found between the rs920778 genetic polymorphism and PTC risk in females but not in males. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was confirmed both in vitro and in vivo. Our results demonstrate that functional SNPs influencing lncRNA regulation may explain a part of PTC genetic basis.

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Section: Discussionsupporting

confidence: 86%

Onco-lncRNA HOTAIR and its functional genetic variants in papillary thyroid carcinoma

Zhu

et al. 2016

Sci Rep

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“…Located in the promoter of a long non-coding RNA (lncRNA) gene named Papillary Thyroid Carcinoma Susceptibility Candidate 3 (PTCSC3), the risk allele of rs944289 impacts the expression of PTCSC3 by altering the binding affinity for the transcription factors C/EBPa and C/EBPb (10). PTCSC3 was shown to possess tumor suppressor properties by inhibiting the motility and invasion potential of PTC cells through the suppression of S100A4 transcription (11). The variant rs965513 at 9q22 is located in close vicinity of the Forkhead Box E1 (FOXE1) gene.…”

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confidence: 99%

Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

Jendrzejewski

Liyanarachchi

Nagy

et al. 2016

Thyroid

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Background: Papillary thyroid cancer (PTC) is reported to be highly heritable in epidemiological studies. Genome-wide association studies (GWAS) have uncovered several variants associated with PTC predisposition. It remains unknown whether these variants might contribute to better clinical stratification of PTC patients. Methods: In order to assess the usefulness of germline genetic analyses in the management of PTC patients, the genotypes of five variants (rs965513, rs944289, rs116909374, rs2439302, and rs966423) were determined in 1216 PTC patients and 1416 controls. Additionally, the expression of seven genes located close to GWAS variants (PTCSC3, MBIP, NKX2-1, FOXE1, DIRC3, PTCSC2, and NRG1) were measured in 73 PTC paired tumor/normal tissues, respectively. Next, the association was analyzed between the genotypes of the germline variants and the levels of gene expression with clinical/pathological features such as age, sex, TNM staging, multifocality status, extrathyroidal expansion, and MACIS score. Results: The risk allele of rs965513 was associated with larger tumor size ( p = 0.025) and extrathyroidal expansion (odd ratio [OR] = 1.29, p = 0.045). The variant rs2439302 showed association with lymph node metastasis (OR = 1.24, p = 0.016), and multifocality status of the tumor (OR = 1.24, p = 0.012). The expression of MBIP was associated with T stage ( p = 0.010). MBIP and PTCSC3 displayed lower expression in PTC tissue in males than in females ( p = 0.025 and p = 0.036, respectively). NKX2-1 displayed lower expression in patients with N1 stage ( p = 0.040). Conclusions: The studied germline risk alleles predisposing to PTC were associated with a more aggressive course of the disease reflected by larger tumor diameter, higher multifocality rate, and more advanced N stage at the time of diagnosis. These results show that germline variants not only predispose to PTC but also might impact its clinical course. However, these associations were only moderate, and further large multi-ethnic studies are required to evaluate the usefulness of these germline variants in the clinical stratification of PTC patients.

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“…S100A4 is not only a metastatic protein but also an oncoprotein that plays a critical role in the development of tumors. Depletion of S100A4 resulted in impaired proliferation and invasive capacity, including thyroid cancer [17,21,42], suggesting the importance of S100A4 in progressive phenotypes of cancers. Our in vitro study showed that targeting S100A4 in 8505C and Cal-62 cells decreases cell proliferation, invasion and migration and increases cell apoptosis.…”

Section: Potent Inhibitors Of Braf V600ementioning

confidence: 99%

S100A4 Knockout Sensitizes Anaplastic Thyroid Carcinoma Cells Harboring BRAFV600E/Mt to Vemurafenib

Jiao

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Anaplastic thyroid cancer (ATC), with 25% BRAF^V600E mutation, is one of the most lethal human malignancies that currently has no effective therapy. Vemurafenib, a BRAFV600E inhibitor, has shown promise in clinical trials, including ATC patients, but is being hampered by the acquisition of drug resistance. Therefore, combination therapy that includes BRAF^V600E inhibition and avoids resistance is a clinical need. Methods: ATC cell lines 8505C ^{(BRAFV600E/mt)}, SW1736 ^{(BRAFV600E/mt)}, KAT18 ^{(BRAFV600E/wt)} and Cal-62^{(BRAFV600E/wt)} cells were used in the study. The ability of S100A knockout or /and in combination with the BRAF inhibitor vemurafenib on growth, apoptosis, invasion and apoptosis in ATC cells in vitro was demonstrated by MTT and BrdUrd incorporation assay, Annexin-V-FITC staining analyzed by flow cytometry, Transwell migration and Matrigel invasion assay. S100A4,pERK1/2, pAKT and pROCK1/2 protein was detected by western blot assay; Small molecule inhibitors of Y27632, U0126, MK-2206 and constitutively active forms of pCDNA-Myc-pERK, pCMV6-HA-Akt, pCMV-RhoA were employed, and the mechanistic studies were performed. We assessed the efficiency of in vivo combination treatment with S100A4 knockout and Vemurafenib on tumors. Results: S100A4 knockout induced apoptosis and reduced proliferation by inactivation of pAKT and pERK signals, and inhibited invasion and migration by inactivation of pAKT and RhoA/ROCK1/2 signals in 8505C or Cal-62 cells in vitro, and vice versa in SW1736 and KAT18 cells. Vemurafenib did not affect apoptosis of both 8505C and SW1736 cells, but reduced proliferation via arresting cell cycle, and promoted cell migration and invasion in vitro. Combination treatment with S100A4 knockdown and vemurafenib reduced cell proliferation, migration and invasion in vitro compared to the S100A4 knockdown or Vemurafenib alone. Vemurafenib treatment resulted in a transient inhibition of pERK expression and gradually activation of pAKT expression, but quickly recovery from ERK1/2 activation inhibition by vemurafenib treatment in 4 h for SW1736 and 8505C cells. Combined treatment completely inhibited ERK1/2 and AKT activation during 48 h. In an in vivo mouse model of SW1736 and 8505C, vemurafenib treatment alone did not significantly inhibit tumor growth in both of the tumors, but inhibited tumor growth in combined groups. Conclusion: Our results show S100A4 knockout alone inhibits ATC cells (rich endogenous S100A4) survival and invasion, regardless of the BRAF^V600E status, and potentiates the effect of vemurafenib on tumor regression in vitro and in vivo. In addition, S100A4 knockout potently inhibits the recovery from ERK1/2 activation inhibition and the AKT activation following vemurafenib treatment and reversed the vemurafenib resistance. This therapeutic combination may be of benefit in patients with ATC.

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PTCSC3 Is Involved in Papillary Thyroid Carcinoma Development by ModulatingS100A4Gene Expression

Abstract: 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.

Cited by 66 publications

References 31 publications

Onco-lncRNA HOTAIR and its functional genetic variants in papillary thyroid carcinoma

Onco-lncRNA HOTAIR and its functional genetic variants in papillary thyroid carcinoma

Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

S100A4 Knockout Sensitizes Anaplastic Thyroid Carcinoma Cells Harboring BRAFV600E/Mt to Vemurafenib

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