Papillary Thyroid Cancer Invasion Research Articles

FTO/IGF2BP2-mediated N6 methyladenosine modification in invasion and metastasis of thyroid carcinoma via CDH12.

Epigenetic reprogramming plays a critical role in cancer progression of cancer, and N6-methyladenosine (m6A) is the most common RNA modification in eukaryotes. The purpose of this study was to explore the related modification mode of m6A regulator construction and evaluate the invasion and migration of thyroid cancer. Our results showed that m6A levels were significantly increased in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) samples, which may have been induced by the down-regulation of demethylase fat mass and obesity-associated gene (FTO). Moreover, FTO inhibited PTC and ATC invasion and metastasis through the epithelial-to-mesenchymal transition (EMT) pathway in vivo and in vitro. Mechanistically, an m6A-mRNA epitranscriptomic microarray showed that Cadherin 12 (CDH12) is the key target gene mediated by FTO in an m6A-dependent manner. CDH12 promotes invasion and metastasis through the EMT pathway in thyroid cancer, both in vivo and in vitro. Furthermore, we found that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an important m6A reading protein, that regulates the stability of CDH12 mRNA and mediates EMT progression, thereby promoting the invasion and metastasis of PTC and ATC. Thus, FTO, IGF2BP2 and CDH12 may be effective therapeutic targets for PTC and ATC with significant invasion or distant metastasis. Schematic summary of FTO-IGF2BP2 axis in modulation of CDH12 mRNA m6A and upregulation of CDH12 expression in the invasion and metastasis of thyroid carcinoma.

CXCR4 promotes migration, invasion, and epithelial-mesenchymal transition of papillary thyroid carcinoma by activating STAT3 signaling pathway.

Papillary thyroid cancer (PTC) is a serious threat to human health worldwide, while metastasis in the early phase limits therapeutic success and leads to poor survival outcomes. The CXC chemokine receptor type 4 (CXCR4) plays an important role in many cellular movements such as transcriptional modulation, cell skeleton rearrangement, and cell migration, and the change in CXCR4 levels are crucial in various diseases including cancer. In this study, we explored the role of CXCR4 in the migration and invasion of PTC and investigated the potential mechanisms underlying its effects. We analyzed the expression levels of CXCR4 in PTC tissues and cell lines. Would healing migration, Transwell invasion assay in vitro, and tail-vein lung metastasis assay In vivo were performed to evaluated the migration and invasion abilities of PTC cells with stable CXCR4 knockdown or overexpression. Signal transducers and activators of transcription (STAT3) signaling pathway-related protein expressions were examined by Western blotting assays. The results showed that CXCR4 was highly expressed in PTC cell lines and PTC tissues. CXCR4 knockdown in PTC cells dampened the migration, invasion, and epithelial-mesenchymal transition (EMT), whereas CXCR4 overexpression enhanced these properties. In vivo, we also found that CXCR4 promoted the metastasis of PTC. Mechanistic studies showed that CXCR4 played these vital roles through the STAT3 signaling pathway. Furthermore, PTC patients with high CXCR4 or p-STAT3 expression correlated with aggressive clinical characteristics such as extrathyroidal extension (ETE), and lymph node metastasis (LNM). We provided evidence that CXCR4 might activate the STAT3 signaling pathway and further promote PTC development. Thus, CXCR4 might be a novel therapeutic target for PTC.

Network Pharmacological Analysis and Experimental Validation of the Effects of Silybin on Proliferation, Migration, and Immunotherapy of Papillary Thyroid Cancer.

The study aimed to use network pharmacology research and in vitro experiments to investigate the material basis and molecular mechanisms of silybin in the treatment of papillary thyroid carcinoma. Papillary thyroid cancer (PTC) has a decent prognosis; however, recurrence and metastasis are the leading causes of death in patients with PTC. A key research focus in thyroid cancer treatment is the inhibition of PTC proliferation, invasion, and migration. Silybin, the major active element in the traditional Chinese herb silymarin, has been used to treat a range of diseases, including cancer, but no study has been undertaken to determine whether it can help prevent PTC. In this study, we attempted to determine through network pharmacology and in vitro experiments if silybin inhibits the development of papillary thyroid cancer by inhibiting cell cycle and invasive migration. To predict the probable targets and underlying mechanisms of silybin against PTC, a network pharmacology research was performed. In vitro experiments were conducted to further evaluate silybin's anti-cancer properties and priority targets against PTC. The datasets revealed a total of 489 silybin targets acting on PTC, and functional enrichment analysis suggested that the target genes were enriched in functions and pathways related to PTC development, invasion, migration, and immunotherapy. By constructing these target PPI networks, the seven hub genes, fibronectin 1 (FN1), tissue inhibitor of metalloproteinases 1 (TIMP1), N-cadherin (CDH2), collagen type III alpha 1 chain (COL3A1), cyclin D1 (CCND1), AP-1 transcription factor subunit (JUN), and hepatocyte growth factor receptor (MET) were found. These hub genes were determined to be highly linked to a worse clinicopathological form, a higher risk of metastatic recurrence, and a worse prognosis of PTC. The common immunological checkpoint gene expression levels were positively correlated with the expression levels of the hub genes. Silybin decreased the proliferative and metastatic capacity of PTC cells, according to in vitro investigations. When PTC was treated with silybin, the FN1/AKT signaling pathway was blocked, CCND1 expression was reduced, and CDH2, Vimentin, Snail, Slug and PD-L1 expressions were dramatically reduced, while E-cadherin expression was significantly elevated. These findings provide preliminary evidence that silybin inhibits PTC cell proliferation, metastasis, and invasion by altering the FN1/AKT signaling pathway and inhibiting the EMT process. Silybin can reverse immunosuppression in papillary thyroid cancer by affecting immunological checkpoint gene expression levels. These studies provide a theoretical and experimental scientific basis for the potential anticancer effects of silybin on PTC.

Functional analysis of ESM1 by shRNA-mediated knockdown of its expression in papillary thyroid cancer cells.

Endothelial specific molecule-1 (ESM1) is implicated as an oncogene in multiple human cancers. However, the function of ESM1 in papillary thyroid cancer (PTC) is not well understood. The current study aimed to investigate the effect of ESM1 on the growth, migration, and invasion of PTC to provide a novel perspective for PTC treatment. The expression levels of ESM1 in PTC tissues form 53 tumor tissue samples and 59 matching adjacent normal tissue samples were detected by immunohistochemical analysis. Knockdown of ESM1 expression in TPC-1 and SW579 cell lines was established to investigate its role in PTC. Moreover, cell proliferation, apoptosis, wound healing, and transwell assays were conducted in vitro to assess cell proliferation, migration and invasion. The findings revealed that ESM1 expression was significantly higher in PTC tissues than that found in paraneoplastic tissues (P<0.0001). Knockdown of ESM1 expression inhibited the proliferation, migration, and invasion of TPC-1 and SW579 cells in vitro. Compared with the control group, the mRNA and protein levels of ESM1 in PTC cells were significantly reduced following knockdown of its expression (P<0.01). In addition, ESM1-knockdown cells indicated decreased proliferation and decreased migratory and invasive activities (P<0.01, P<0.01, P<0.001, respectively). ESM1 was identified as a major gene in the occurrence and progression of PTC, which could increase the proliferation, migration, and invasion of PTC cells. It may be a promising diagnostic and therapeutic target gene.

Analysis of the Value of Ultrasound Imaging Combined with Serum Indicators in Evaluating the Invasiveness of Papillary Thyroid Carcinoma

Objective: To analyze the value of ultrasound imaging combined with serum indicators in evaluating the invasiveness of papillary thyroid cancer (PTC). Methods: One hundred and fifty patients with papillary thyroid cancer admitted to our hospital from September 2019 to December 2022 were selected. Pathological tissue testing was performed on all patients. According to the size, shape, boundary, internal echo, and characteristics such as microcalcification, the patients were divided into the PTC metastasis group (n = 55) and the PTC group (n = 95). The detection rate of ultrasound imaging combined with serum indicators and the invasiveness of PTC were observed and analyzed. Results: The detection rate of ultrasound imaging combined with serum indicators in both groups was significantly better than that of ultrasound imaging and serum indicators (P &lt; 0.05). The detection rate of ultrasound imaging combined with serum indicators was compared between the groups. The removal rate of the PTC metastasis group was significantly better than that of the PTC group (P &lt; 0.05). The levels of thyroid-stimulating hormone (TSH), thyroglobulin (Tg), thyroglobulin antibodies (TgAb), and thyroid autoantibodies (TPOAb) in the PTC group were lower than those of the PTC metastasis group (P &lt; 0.05). Conclusion: Ultrasound imaging combined with serum indicators like TSH, Tg, TgAb, and TPOAb has important clinical significance in evaluating the invasiveness of PTC.

The association between integrin β4 overexpression and lymphovascular invasion in papillary thyroid cancer.

Lymphovascular invasion is an independent prognostic marker in papillary thyroid carcinomas. In addition, integrin β4 is associated with advanced progression and metastasis in many malignancies. We aimed to investigate the relationship between integrin β4 and lymphovascular invasion in papillary thyroid carcinoma. 73 patients with papillary thyroid cancer (48 patients with lymphovascular invasion and 25 patients without) were included in our study. The immunohistochemical staining score for integrin b4 was evaluated according to the percentage and intensity of staining. The staining intensity was scored as 0 (no staining), 1 (weak staining - light yellow), 2 (medium staining - yellow-brown), and 3 (strong staining - brown). The staining was scored by multiplying the percentage and intensity of staining. The mean percentage of integrin b4 staining was 63.54 ± 22.26% in the group with lymphovascular invasion and 10.2 ± 22.48% in the group without lymphovascular invasion (p < 0.001). When evaluated in terms of staining score, it was found to be 107.08 ± 45.29 in the group with lymphovascular invasion and 16.2 ± 40.03 in the group without lymphovascular invasion (p < 0.001). There was a linear relationship between the percentage of integrin β4 and the staining scores (r² = 0.881; p < 0.001). In the by receiver-operating characteristic (ROC) curve analysis for the cut-off value of the percentage of integrin b4 staining, the area under the curve was found to be 0.916. The cut-off value for the percentage of integrin b4 was found to be 35 (sensitivity 91.7% and specificity 88%) (odds 80.66%). A significant relationship was found between integrin b4 expression and lymphovascular invasion in papillary thyroid carcinomas. Integrin b4 expression level can be used as a marker to predict the presence of lymphovascular invasion in papillary thyroid carcinomas, especially in large tumours where it may not be possible to sample the entire tumour.

Tetraspanin 1 regulates papillary thyroid tumor growth and metastasis through c-Myc-mediated glycolysis.

Papillary thyroid cancer (PTC) is the most common form of thyroid cancer and is characterized by its tendency for lymphatic metastasis, leading to a poor prognosis. Tetraspanin 1 (TSPAN1) is a member of the tetra-transmembrane protein superfamily and has been implicated in tumorigenesis and cancer metastasis in various studies. However, the role of TSPAN1 in PTC tumor development remains unclear. In this study, we aimed to investigate the impact of TSPAN1 on PTC cell behavior. Our results demonstrate that knockdown of TSPAN1 inhibits PTC cell proliferation, migration, and invasion, while overexpression of TSPAN1 has the opposite effect. These findings suggest that TSPAN1 might play a role in the tumorigenesis and invasiveness of PTC. Mechanistically, we found that TSPAN1 activates the ERK pathway by increasing its phosphorylation, subsequently leading to upregulated expression of c-Myc. Additionally, we observed that TSPAN1-ERK-c-Myc axis activation promotes glycolytic activity in PTC cells, as evidenced by the upregulation of glycolytic genes such as LDHA. Taken together, our findings indicate that TSPAN1 acts as an oncogene in PTC by regulating glycolytic metabolism. This discovery highlights the potential of TSPAN1 as a promising therapeutic target for PTC treatment. Further research in this area could provide valuable insights into the development of targeted therapies for PTC patients.

Retracted] MicroRNA‑744 suppresses cell proliferation and invasion of papillary thyroid cancer by directly targeting NOB1.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the cell migration and invasion assay data shown in Fig.5C were strikingly similar to data appearing in different form in other articles by different authors at different research institutes. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 1903‑1910, 2019; DOI: 10.3892/mmr.2019.9826].

Hypoxic papillary thyroid carcinoma cells-secreted exosomes deliver miR-221-3p to normoxic tumor cells to elicit a pro-tumoral effect by regulating the ZFAND5

Papillary thyroid cancer (PTC) has seen a worldwide expansion in incidence in the past three decades. Tumor-derived exosomes have been associated with the metastasis of cancer cells and are present within the local hypoxic tumor microenvironment, where they mediate intercellular communication by transferring molecules including microRNAs (miRNAs) between cells. Although miRNAs have been shown to serve as non-invasive biomarkers for cancer diagnosis, the role of hypoxia-induced tumor-derived exosomes in PTC progression remains unclear. Herein, we investigated the differentially expressed miRNA expression profiles from GEO datasets (GSE191117 and GSE151180) by using the DESeq package in R and identified a novel role for miR-221-3p as an oncogene in PTC development. In vivo and in vitro loss and gain assays were used to clarify the mechanism of hypoxic PTC cells derived exosomal-miR-221-3p in PTC. miR-221-3p was upregulated in human PTC plasma exosomes, tissues and cell lines. We found that hypoxic PTC cells derived exosomal-miR-221-3p promoted normoxic PTC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro, while inhibition of miR-221-3p limited PTC tumor growth in our PTC xenograft model in nude mice. We finally identified ZFAND5, to be a miR-221-3p target. Mechanistically, hypoxic PTC cell lines-derived exosomes carrying miR-221-3p promoted PTC tumorigenesis by regulating ZFAND5. Our findings further the understanding of the underlying mechanisms associated with PTC progression and identify exosomal-miR-221-3p as a potential biomarker for the diagnosis and prognosis of PTC patients. Our study also suggests that miR-221-3p inhibitors could be a potential treatment strategy for PTC.

Perineural Invasion in Papillary Thyroid Cancer: A Rare Indicator of Aggressive Disease.

Perineural invasion (PNI) is associated with aggressive tumor behavior, increased locoregional recurrence, and decreased survival in many carcinomas. However, the significance of PNI in papillary thyroid cancer (PTC) is incompletely characterized. Patients diagnosed with PTC and PNI from 2010-2020 at a single, academic center were identified and matched using a 1:2 scheme to patients without PNI based on gross extrathyroidal extension (ETE), nodal metastasis, positive margins, and tumor size (±4 cm). Mixed and fixed effects models were used to analyze the association of PNI with extranodal extension (ENE)-a surrogate marker of poor prognosis. In total, 78 patients were included (26 with PNI, 52 without PNI). Both groups had similar demographics and ultrasound characteristics preoperatively. Central compartment lymph node dissection was performed in most patients (71%, n = 55), and 31% (n = 24) underwent a lateral neck dissection. Patients with PNI had higher rates of lymphovascular invasion (50.0% vs. 25.0%, p = 0.027), microscopic ETE (80.8% vs. 44.0%, p = 0.002), and a larger burden [median 5 (interquartile range [IQR] 2-13) vs. 2 (1-5), p = 0.010] and size [median 1.2 cm (IQR 0.6-2.6) vs. 0.4 (0.2-1.4), p = 0.008] of nodal metastasis. Among patients with nodal metastasis, those with PNI had an almost fivefold increase in ENE [odds ratio [OR] 4.9 (95% confidence interval [CI] 1.5-16.5), p = 0.008] compared with those without PNI. More than a quarter (26%) of all patients had either persistent or recurrent disease over follow-up (IQR 16-54 months). PNI is a rare, pathologic finding that is associated with ENE in a matched cohort. Additional investigation into PNI as a prognostic feature in PTC is warranted.

KMT2D Regulates the NCOA6/THRB Signal Axis through Epigenetic Modification to Promote the Migration and Invasion of Papillary Thyroid Cancer.

The histone lysine methyltransferase Histone-lysine N-methytransferase 2D (KMT2D) is a common mutated gene in a variety of cancers, including papillary thyroid cancer (PTC). However, the mechanism of KMT2D on the progression of PTC remains unclear. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to evaluate KMT2D expression between human normal cell (Nthy-ori 3-1) and PTC cells (TPC1, IHH-4 and BCPAP). Proliferation, migration and invasion of TPC1, IHH-4 and BCPAP were assessed by Cell Counting Kit-8 (CCK-8), Wound-healing assay and Transwell assay. The mechanism of KMT2D on thyroid papillary cancer was explored with Chromatin immunoprecipitation assay (ChIP), qRT-PCR and Western blotting. The expression of KMT2D in PTC cells was significantly increased. Downregulation of KMT2D significantly decreased the proliferation, migration and invasion of PTC cells, which was correlated with decreased expression levels of H3K4me2, H3K9me2, NCOA6 and THRB. Meanwhile, ChIP assay demonstrated that KMT2D was associated with NCOA6. Study have shown that the downregulation of KMT2D reduces proliferation, migration and invasion of thyroid papillary carcinoma cells through epigenetic modification of NCOA6/THRB signal axis. These results provide a new insight into the role of KMT2D in migration and invasion of PTC.

IncRNA XIST Stimulates Papillary Thyroid Cancer Development through the miR-330-3p/PDE5A Axis

Long non-coding RNAs (lncRNAs) possess both tumor suppressive and oncogenic functions in papillary thyroid cancer (PTC). Among all the thyroid cancers, PTC is the most prevalent form. Herein, we aim to determine the regulatory mechanisms and functions of lncRNA XIST in the multiplication, invasion, and survival of PTC. Quantitative reverse transcription polymerase chain reaction and Western blot experiments were performed to determine the patterns of lncRNA XIST, miR-330-3p, and PDE5A expressions. The subcellular localization of XIST was determined through subcellular fractionation. Bioinformatics analyses were performed to determine miR-330-3p's relationships with XIST and PDE5A, which were further confirmed through luciferase reporter assays. Loss-of-function combined with Transwell, CCK-8, and caspase-3 activity experiments were performed to determine the mechanism of the XIST/miR-330-3p/PDE5A axis in regulating the malignancy of PTC cells. Xenograft tumor experiment was employed to study the influence of XIST on tumor development in vivo. The PTC cell lines and tissues manifested considerably high levels of lncRNA XIST expression. The XIST knockdown inhibited proliferation, blocked migration, and strengthened apoptosis among PTC cells. Moreover, its knockdown suppressed PTC tumor development in vivo. XIST repressed miR-330-3p to stimulate the malignant behaviors of PTC. Through the downregulation of PDE5A, miR-330-3p attenuated the capability of PTC cells to grow, migrate, and survive. lncRNA XIST promotes tumor development in PTC through the regulation of the miR-330-3p/PDE5A axis. The findings from this study provide new insights into the treatment of PTC.

Clinical significance of extrathyroidal extension to major vessels in papillary thyroid carcinoma.

Gross extrathyroidal extension (gETE) into major vessel is considered the most advanced stage of the locally advanced papillary thyroid cancer (PTC). Surgical intervention may not benefit some patients at this disease stage or even result in intraoperative death due to massive hemorrhage; however, it is still considered an effective strategy for most cases. The lack of description for this challenging invasion in PTC warrants detailed characterization of its pattern, risk factors, optimal surgical method, and prognostic value. In total, 3127 patients diagnosed as having PTC were enrolled and categorized into two the following groups, namely the major vessel invasion (MVI) group (n = 30) and the control group (n = 3097). Data regarding clinicopathological and demographic characteristics, vascular invasion sites, postoperative complications, locoregional recurrence, distant metastasis, and surgical strategies were collected. Predictive disease-free survival (DFS) was also compared between the two groups. MVI was independently associated with invasion of the esophageal extension, age < 55years, tumor size > 1cm, lateral lymph node metastasis, and distant metastasis (P = 0.00; P = 0.01; 0.05; P = 0.00; P = 0.00, respectively). The difference in the predictive DFS between the two groups was significant (P = 0.00), and the difference remained significant even in patients with ETE when compared with patients without ETE (P = 0.00). Additionally, predictive DFS did not differ significantly between patients who received vessel repairment and those who received vessel resection (P = 0.28). This study first characterized the gross MVI pattern exhibited by PTC and the risk factors for MVI. Additionally, it demonstrated the DFS of patients with PTC. Extensive gross MVI significantly worsened the biological characteristics of PTC. Regardless of the high risk and difficulty of the operation, patients still benefited from the surgical intervention, and vessel repairment may be the optimal surgical strategy.

A novel necroptosis-related gene signature associated with immune landscape for predicting the prognosis of papillary thyroid cancer.

Background: Necroptosis, a type of programmed cell death, has been implicated in a variety of cancer-related biological processes. However, the roles of necroptosis-related genes in thyroid cancer yet remain unknown. Methods: A necroptosis-related gene signature was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis and Cox regression analysis. The predictive value of the prognostic signature was validated in an internal cohort. Additionally, the single-sample gene set enrichment analysis (ssGSEA) was used to examine the relationships between necroptosis and immune cells, immunological functions, and immune checkpoints. Next, the modeled genes expressions were validated in 96 pairs of clinical tumor and normal tissue samples. Finally, the effects of modeled genes on PTC cells were studied by RNA interference approaches in vitro. Results: In this study, the risk signature of seven necroptosis-related genes was created to predict the prognosis of papillary thyroid cancer (PTC) patients, and all patients were divided into high- and low-risk groups. Patients in the high-risk group fared worse in terms of overall survival than those in the low-risk group. The area under the curve (AUC) of the receiving operating characteristic (ROC) curves proved the predictive capability of created signature. The risk score was found to be an independent risk factor for prognosis in multivariate Cox analysis. The low-risk group showed increased immune cell infiltration and immunological activity, implying that they might respond better to immune checkpoint inhibitor medication. Next, GEO database and qRT-PCR in 96 pairs of matched tumorous and non-tumorous tissues were used to validate the expression of the seven modeled genes in PTCs, and the results were compatible with TCGA database. Finally, overexpression of IPMK, KLF9, SPATA2 could significantly inhibit the proliferation, invasion and migration of PTC cells. Conclusion: The created necroptosis associated risk signature has the potential to have prognostic capability in PTC for patient outcome. The findings of this study could pave the way for further research into the link between necroptosis and tumor immunotherapy.

Retracted] MicroRNA‑497 inhibits cellular proliferation, migration and invasion of papillary thyroid cancer by directly targeting AKT3.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the data shown for the cell migration and invasion assays in Figs.2C and 5C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 16: 5815‑5822, 2017; DOI: 10.3892/mmr.2017.7345].

Bone Marrow Mesenchymal Stem Cells (BMSCs) Promote the Metastasis of Thyroid Papillary Cancer by Inhibiting Poly-Pyrimidine Tract Binding Protein 1 (PTBP1)

We aimed to explore the mechanism underlying the role of bone marrow mesenchymal stem cells (BMSCs) in the invasion of papillary thyroid cancer (PTC) cells. BMSCs were co-cultured with PTC cells WRO or normal thyroid follicular epithelial cells T3TD followed by analysis of cell migration and proliferation by Transwell assay and MTT assay. Cells were transfected with shRNA or overexpression of PTBP1, followed by measuring cell proliferation and invasion and PTBP1 expression by RT-qPCR and Western blot. Co-cultivation with MSC promoted the malignant transformation of WRO, inhibited the RNA-binding protein PTBP1 and activation of GS3Kβ/Akt. In addition, silencing of PTBP1 accelerated cell invason and induced overexpression of EMT proteins, while overexpression of PTBP1 inhibited cell proliferation and migration. In conclusion, BMSCs might promote PTC invasion and metastasis by inhibiting PTBP1 expression, providing a novel insight into the treatment of PTC.

Clinical Predictors of Minimal Extrathyroid Invasion of Papillary Thyroid Cancer

extrathyroidal invasion (ETI) of papillary thyroid cancer (PTC) is a risk factor for lo-coregional metastasis. The clinical significance of minimal ETI depending on the primary tumor size&#x0D; has not been studied thoroughly. The combination of tumor diameter and minimal ETI can be used asa reliable prognostic factor for persistence of the disease. Given that the identification of the minimal&#x0D; ETI is possible only during the final histopathological study, there is a need to assess the existing pre-operative clinical predictors that increase the probability of minimal ETI of PTC. The aim of the study&#x0D; is to assess preoperative clinical predictors that increase the probability of minimal extrathyroidalinvasion of papillary thyroid cancer. A retro-prospective single-center study of preoperative clinicalpredictors that increase the probability of extrathyroidal invasion of thyroid cancer was conducted.Data from 514 patients aged 5 to 81 years were processed. Patients underwent surgery for papillarythyroid cancer for the first time. Scope of the operation: extrafascial thyroidectomy. Central neckdissection. Lymphadenectomy. All patients had clinical signs of low risk of recurrence. The meanage of patients was 44.4 ± 14.5 years. There were 91 men (17.7%) and 423 women (82.3%). Patientswere divided into two groups: group 1 with 169 patients with minimal extraorganic invasion aged 5to 71 years, group 2 with 345 patients without invasion aged 10 to 81 years. The following featureswere taken into account for the analysis: 1) age of patients; 2) their sex; 3) the size of the dominanttumor. The results were statistically processed using a specialized statistical program StatPlus Prov.7 (AnalystSoft Inc.) and Epitools statistical calculators (Ausvet, https://epitools.ausvet.com.au/).According to the results, both by age (mean age of patients in group 1 - 44.7 ± 14.4 years; meanage of patients in group 2 - 44.3 ± 14.6 years) and by sex (in group 1 – 30 men (17.8%), 139 women&#x0D; (82.2%), in group 2 – 61 men (17.7%), 284 women (82.3%), the groups were almost identical, bothgroups were significantly (p &lt;0.01) dominated by women. The size of the primary tumor in group1 - 15.0 (10.0; 20.0) mm - was statistically significantly higher (p &lt;0.001) than in the second - 10.0(7.0; 15.0) mm. Most of patients (71.0%) with invasion had a primary tumor size &gt; 10 mm, while ingroup 2 there were only 42.6% of such patients. Within the size ranges up to 10 mm, the probabilityof detection of invasion is 14.0% - 21.6%, while within the size ranges over 10 mm, it may be 41.9% -50.0%. A tumor size of PTC over 10 mm, with a diagnostic strength of 61.9%, increases the risk ofminimal extrathyroidal invasion. The average size of the primary tumor in the group of patients withminimal ETI is 15.0 (10.0; 20.0) mm, which is statistically significantly higher (p &lt;0.001) than thesame value in the group of patients without EIT - 10.0 (7.0; 15.0) mm. In patients with a PTC tumor&#x0D; size of less than 10 mm, the probability of minimal ETI ranges from 14.0% to 21.6%, while the prob-ability of minimal ETI in patients with a tumor size over 10 mm ranges from 41.9% to 50.0%. Given&#x0D; that minimal ETI may be one of the factors of increased risk of PTC locoregional metastasis, surgeryfor PTC patients with a tumor size over 10 mm should be supplemented with central neck dissection,lymphadenectomy. A tumor size of PTC over 10 mm, with a diagnostic strength of 61.9%, increases the risk of minimal extrathyroidal invasion, which is also an argument in favor of central neck dis-section, lymphadenectomy during surgery for patients with tumor size over 10 mm. The patients’ age and sex cannot be the factors that increase the risk of minimal extrathyroidal invasion of papillarythyroid cancer.

Abstract 767: Role of COL26A1 in papillary thyroid cancer invasion

Abstract Papillary thyroid cancer (PTC) accounts for 70-80% of all thyroid cancer cases and has been increasing in incidence over the last few decades. It is now the 8th most common cancer in women in the United States and the most common cancer in women under 25 years of age. PTC is often curable, as the tumors are most often slow-growing and surgically resectable and lymphatic spread does not worsen the generally favorable prognosis. However, there are aggressive forms of PTC that are not adequately treated by current therapeutic modalities and invasion into surrounding tissue next to the thyroid worsens the prognosis. Utilizing the NYMC biobank of PTC patient samples, meta-analysis of RNASeq data was performed, ranking differentially expressed genes between invasive vs noninvasive and lymph node positive vs lymph node negative samples. These genes were analyzed in conjunction with the GDC’s The Cancer Genome Atlas (TCGA) Thyroid Cancer (THCA) study, in which the Kaplan Meier survival curve identified genes with a significant impact on survival and those that were increased in metastatic tissue samples. Of the top differentially expressed genes that were increased in patients with extrathyroidal extension and lymph node metastasis, COL26A1 significantly inversely associated with survival (p = 0.0086). COL26A1 codes for collagen type XXVI α1 chain with known roles in degradation of the ECM and collagen chain trimerization. In TCGA datasets, COL26A1 expression was significantly correlated with clinical attributes including MACIS score (q = .001), differentiation score (q = 0.025), and tumor stage (q = 0.025). COL26A1 expression was increased 3-fold in papillary thyroid cancer cell line K1 when compared to normal thyroid cancer cells, NThy-ori 3-1. Two CRISPR guides designed to target COL26A1 were introduced into K1 resulting in repression of COL26A1 by 50% in both knockdowns. COL26A1 repression decreased the proliferation (33%), tumorigenicity (86%), invasion (33%), and migration capacity (73%). Furthermore, knockdown of COL26A1 leads to decreased cell-to-cell adhesion in culture. Thus, COL26A1 may have potential use as a prognostic marker and actionable therapeutic target for small molecule inhibitors. Long noncoding RNAs (lncRNAs) have vast implications in different cancer types with roles in gene expression via modulation of coding and noncoding RNAs. lncRNAs are tissue- and stage- specific and stable in serum alluding to their ability to be used in thyroid cancer prognosis and diagnosis. Therefore, we investigated the mRNA-miRNA-lncRNA axis involved in regulation of COL26A1 utilizing Qiagen Ingenuity Pathway Analysis (IPA). We have identified potential pathways linking COL26A1 with PTC, highlighting those involved in proliferation, migration, invasion, and adhesion. Investigation into these molecular interactions and pathways can elucidate the role of COL26A1 and allow for its optimal targeting for treatment of invasive papillary thyroid cancer. Citation Format: Michelle Carnazza, Danielle Quaranto, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Raj K. Tiwari, Jan Geliebter. Role of COL26A1 in papillary thyroid cancer invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 767.

A novel prognostic model for papillary thyroid cancer based on epithelial-mesenchymal transition-related genes.

The frequent incidence of postsurgical recurrence issues in papillary thyroid cancer (PTC) patients is a primary concern considering the low cancer-related mortality. Previous studies have demonstrated that epithelial-mesenchymal transition (EMT) activation is closely related to PTC progression and invasion. In this study, we aimed to develop a novel EMT signature and ancillary nomogram to improve personalized prediction of progression-free interval (PFI). First, we carried out a differential analysis of PTC samples and pairwise normal thyroid samples to explore the differentially expressed genes (DEGs). The intersection of the DEGs with EMT-related genes (ERGs) were identified as differentially expressed EMT-related genes (DE-ERGs). We determined PFI-related DE-ERGs by Cox regression analysis and then established a novel gene classifier by LASSO regression analysis. We validated the signature in external datasets and in multiple cell lines. Further, we used uni- and multivariate analyses to identify independent prognostic characters. We identified 244 prognosis-related DE-ERGs. The 244 DE-ERGs were associated with several pivotal oncogenic processes. We also constructed a novel 10-gene signature and relevant prognostic model for recurrence prediction of PTC. The 10-gene signature had a C-index of 0.723 and the relevant nomogram had a C-index of 0.776. The efficacy of the signature and nomogram was satisfying and closely correlated with relevant clinical parameters. Furthermore, the signature also had a unique potential in differentiating anaplastic thyroid cancer (ATC) samples. The novel EMT signature and nomogram are useful and convenient for personalized management for thyroid cancer.

Circular RNA VANGL1 Facilitates Migration and Invasion of Papillary Thyroid Cancer by Modulating the miR-194/ZEB1/EMT Axis.

Circular RNAs (circRNAs) are often aberrantly expressed in human tumors and also serve a critical regulatory role in papillary thyroid cancer (PTC). The aim of this study is to investigate the expression pattern and biological role of circVANGL1 in PTC. The results revealed that circVANGL1 was significantly upregulated in human PTC samples. In addition, high circVANGL1 expression was closely associated with adverse clinical parameters of PTC patients. Our in vitro experiments further indicated that the knockdown of circVANGL1 using siRNA obviously repressed migration, proliferation, EMT, and invasion of PTC cells, while opposite effects were induced by its overexpression. We further noted that circVANGL1 could interact with miR-194 directly in PTC, and serve as a ceRNA to regulate ZEB1 function. Moreover, miR-194 inhibition markedly abrogated the effects of circVANGL1 knockdown in PTC cells. Therefore, our results provide convincing evidence that circVANGL1 may exert oncogenic effects in PTC, partly via regulating the miR-194/ZEB1 axis.