Treatment Of Papillary Thyroid Carcinoma Research Articles

Detection of Circulating BRAFV600E in Patients with Papillary Thyroid Carcinoma

BRAF(V600E) is a common mutation in papillary thyroid carcinoma (PTC) correlated with aggressive features. Our objective was to assess the feasibility and accuracy of a novel RNA-based blood assay to identify individuals with a high-risk tumor mutation in patients with PTC. Patients with benign or malignant thyroid disorders were included between September 2013 and July 2014 before either thyroidectomy (n=62) or treatment of recurrent or metastatic PTC (n=8). RNA was isolated from peripheral blood lymphocytes and reverse transcribed and followed by two rounds of nested PCR amplification with a restriction digest specific for wild-type BRAF. BRAF(V600E) levels were quantified with standardization curves. Circulating BRAF(V600E) levels were compared with BRAF mutation status from surgical pathologic DNA-based tissue assays. Testing characteristics and receiving-operator curve using tissue results as the gold standard were assessed. Matched blood and tissue assays for BRAF(V600E) were performed on 70 patients with PTC (stages I to IV, n = 48) or other (n = 22) thyroid tumors. Sixty-three percent of PTC patients tested positive for BRAF(V600E) with conventional tissue assays on surgical specimens. The correlation between the RNA-based blood assay and tissue BRAF status was 0.71. PTC patients harbor detectable BRAF(V600E) circulating tumor cells. This blood assay is feasible and has potential as a biomarker for prognosis, surveillance, clinical decision making, and assessment of treatment response to BRAF-targeted therapies.

Evaluation of thyroid isthmusectomy as a potential treatment for papillary thyroid carcinoma limited to the isthmus: A clinical study of 73 patients.

There are no specific therapeutic guidelines for thyroid cancers confined to the isthmus. To determine whether isthmic papillary thyroid carcinoma (PTC) can be treated with thyroid isthmusectomy and limited neck dissection, we analyzed factors related to central lymph node (CLN) metastasis in patients with clinically node-negative (cN0), solitary, isthmic PTC. We retrospectively reviewed 73 consecutive patients who underwent surgery for solitary isthmic, PTC. The frequency, pattern, and risk factors of CLN metastasis were analyzed. Occult CLN metastasis and paratracheal lymph node (PTLN) metastasis were detected in 34 patients (46.6%) and 28 patients (38.4%), respectively. On multivariate logistic regression analysis, male sex and tumor size >0.7 cm were associated with CLN metastasis, and age ≤38 years, tumor size >0.6 cm, and pretracheal lymph node positivity were associated with PTLN metastasis. Thyroid isthmusectomy for solitary isthmic PTC may be insufficient in patients with tumors >0.6 cm, those aged ≤38 years, and male patients. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1510-E1514, 2016.

Identification of potential therapeutic targets for papillary thyroid carcinoma by bioinformatics analysis.

The aim of the present study was to identify potential therapeutic targets for papillary thyroid carcinoma (PTC) and to investigate the possible mechanism underlying this disease. The gene expression profile, GSE53157, was downloaded from the Gene Expression Omnibus database. Only 10 chips, including 3 specimens of normal thyroid tissues and 7 specimens of well-differentiated thyroid carcinomas, were analyzed in the present study. Differentially-expressed genes (DEGs) between PTC patients and normal individuals were identified. Next, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of DEGs were performed. Modules in the protein-protein interaction (PPI) network were identified. Significant target genes were selected from the microRNA (miRNA) regulatory network. Furthermore, the integrated network was constructed with the miRNA regulatory and PPI network modules, and key target genes were screened. A total of 668 DEGs were identified. Modules M1, M2 and M3 were identified from the PPI network. From the modules, DEGs of cyclin-dependent kinase inhibitor 1A, S100 calcium binding protein A6 (S100A6), dual specificity phosphatase 5, keratin 19, met proto-oncogene (MET) and lectin galactoside-binding soluble 3 were included in the Malacards database. In the miRNA regulatory and integrated networks, genes of cyclin-dependent kinase inhibitor 1C (CDKN1C), peroxisome proliferator-activated receptor γ, aryl hydrocarbon receptor, basic helix-loop-helix family, member e40 and reticulon 1 were the key target genes. S100A6, MET and CDKN1C may exhibit key roles in the progression and development of PTC, and may be used as specific therapeutic targets in the treatment of PTC. However, further experiments are required to confirm these results.

MiR-29a suppresses growth and metastasis in papillary thyroid carcinoma by targeting AKT3.

MicroRNA-29a (miR-29a) has been reported to play important roles in tumor initiation, development, and metastasis in various cancers. However, the biological function and potential mechanisms of miR-29a in papillary thyroid carcinoma (PTC) remain unclear. In the present study, we discovered that miR-29a was frequently downregulated in PTC tissues, and its expression was significantly associated with tumor size, TNM stage, and lymph node metastasis. Functional assays showed that overexpression of miR-29a markedly suppressed PTC cell proliferation, migration, and invasion and promoted PTC apoptosis and cell cycle arrest at G0/G1 phase. In vivo, miR-29a overexpression decreased tumor growth in a xenograft mouse model. Luciferase reporter assay showed that miR-29a can directly bind to the 3' untranslated region (UTR) of AKT3 in PTC cells. Overexpreesion of miR‑29a obviously decreased AKT3 expression, thereby suppressing phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation. We also confirmed that AKT3 expression was increased in PTC tissue and was inversely correlated miR-29a expression in PTC tissues. In addition, downregulation of AKT3 by siRNA mimicked the effects of miR-29a overexpression, and upregulation of AKT3 partially reversed the inhibitory effects of miR-29a. These results suggested that miR-29a could act as a tumor suppressor in PTC by targeting AKT3 and that miR-29a may potentially serve as an anti-tumor agent in the treatment of PTC.

BRAF V600E mutation: Differential impact on central lymph node metastasis by tumor size in papillary thyroid carcinoma.

The necessity of prophylactic central neck dissection is one of debating issues in the treatment of papillary thyroid carcinoma (PTC). In a previous study, the predictive value of BRAF mutation for lymph node metastasis was only significant in 0.5 to 1.0 cm PTC. Thus, we assess the predictive value of BRAF mutation for central lymph node metastasis according to tumor size. Medical records of 3107 patients with PTC who underwent thyroidectomy with central neck dissection were retrospectively reviewed. BRAF mutation was a predictor for central lymph node metastasis in 2.0 to 4.0 cm PTC (odds ratio [OR] = 3.494; p = .002). Although BRAF mutation was associated with central lymph node metastasis in 0.5 to 1.0 cm PTC in univariate analysis (OR = 1.334; p = .047), this significance was not observed in multivariate analysis (OR = 1.232; p = .163). BRAF mutation was not associated with central lymph node metastasis in other tumor sizes. Prophylactic central neck dissection could be considered in 2.0 to 4.0 cm PTC with positive BRAF mutation. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1203-E1209, 2016.

Expression of Pax8 is decreased and bortezomib does not increase the iodine uptake in thyroid carcinoma cells.

Fundamental treatment for papillary thyroid carcinoma (PTC) involves total or subtotal thyroidectomy. Iodine-131 (131I) is routinely utilized to target remnant thyroid cancer and metastasis after thyroidectomy. The effectiveness of other therapeutic modalities remains unsatisfactory; thus, these patients have a poor prognosis. The manner in which the ability of 131I uptake can be improved is vital for their prognosis. Bortezomib has been used as a re-differentiation agent for the treatment of patients with multiple myeloma; however, little is reported about the role of bortezomib in thyroid cancer. To evaluate the therapeutic potential of bortezomib in a human PTC cell line, expression of paired-box 8 (Pax8) protein was determined using Western blot in PTC, normal thyroid, and anaplastic/undifferentiated thyroid carcinoma (ATC) cells. The expression of Pax8 protein in PTC cells pretreated with bortezomib was determined using the same method. Iodine uptake was determined using 131I radioactivity assay. The level of Pax8 protein in normal thyroid cells was significantly higher than in PTC (P < 0.05) and ATC cells (P < 0.05); its expression in PTC cells was also significantly higher than in ATC cells (P < 0.05). The PTC cells in the bortezomib-treated group showed a higher expression of Pax8 protein than the control group (P < 0.05). These findings indicate that bortezomib can increase the expression of Pax8, but does not significantly increase the iodine uptake of PTC cells.

High aldehyde dehydrogenase 1A1 (ALDH1A1) expression correlated with risk of lymph node metastasis in papillary thyroid carcinoma

To investigate the relationship between ALDH1A1 expression and lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). One hundred and fifty-three paraffin-embedded specimens of PTC treated in the Beijing Tongren Hospital of Capital Medical University were selected from January 2006 to December 2013. The expression of ALDH1A1 was detected in both tumor tissues and adjacent non-tumor tissues by immunohistochemistry and several clinicopathological parameters (size, bilaterality, multifocality, tumor border and extrathyroidal extensions) were assessed by HE staining. The correlation of ALDH1A1 expression with LNM was analyzed. In 153 cases of PTC, there were 82 cases with LNM, 126 cases with high ALDH1A1 expression in tumor tissues, and 112 cases with high ALDH1A1 expression in adjacent non-tumor tissues. On univariate analysis, patient age < 45 years, tumor size of 10 mm or more, invasive tumor border, and high ALDH1A1 expression in tumor tissues predicted LNM in PTC (P < 0.05), whereas gender, bilaterality, multifocality, extra-thyroidal extensions and high ALDH1A1 expression in adjacent non-tumor border did not (P > 0.05). On multivariate analysis, invasive tumor border, high ALDH1A1 expression in tumor tissues were found to be independent predictive factors for LNM in PTC (P < 0.05). After a follow-up of 42 months (median time), four patients developed locoregional recurrences, but no distance recurrence or disease related death were seen in 82 patients of follow up. The estimated 5-year locoregional recurrence was 4.88%. Of these four logcoregional recurrences, three involved lymph nodes and one involved the remaining thyroid. The ALDH1A1 expression in tumor tissues was high in all of recurrence cases. High ALDH1A1 expression in tumor tissues is correlated with lymph node metastasis in PTC and may be used as an independent predictive factor of LNM, and may improve treatment and follow-up strategies for PTC.

Review of survival rates 20-years after conservative surgery for papillary thyroid carcinoma

IntroductionA less extensive thyroidectomy could be used for patients in the low risk group. ObjectiveTo perform a critical follow-up after lobectomy with isthmusectomy for the treatment of papillary thyroid carcinoma in patients with a single nodule limited to the periphery of the lobe. MethodsThirty-one patients with thyroid papillary carcinoma operated on till 1993 were selected. They had undergone lobectomy with isthmusectomy. This is a retrospective cohort study in which the oncological outcome (contralateral and regional recurrence) and the reoperation complications (recurrent nerve paralysis/paresis and hypoparathyroidism) were evaluated. Descriptive analysis was employed. ResultsIn the last decade (2003–2013), 6 (20%) contralateral recurrences were observed in the remaining lobe and in 1 of these cases (3%), contralateral lymph node metastases were noted. A completion thyroidectomy plus lymphadenectomy was performed, without modification of global survival. ConclusionBecause of the rate of 20% of contralateral recurrence after a 20-year follow-up, we suggest modification of the surgical paradigm for total thyroidectomy as an initial therapy.

Expression and significance of haptoglobin mRNA and protein in papillary thyroid carcinoma

Objective To explore the expression and significance of haptoglobin(Hp)in papillary thyroid carcinoma. Methods Reverse transcriptase-polymerase chain reaction(RT-PCR) and Western blotting were applied to detect the expression of Hp in 112 cases of papillary thyroid carcinoma,67 cases of benign thyroid node and 50 cases of normal thyroid tissues. Results The relative expression value of Hp mRNA was(0. 913±0. 102)in papillary thyroid carcinoma tissues, which were over-expressed comparing with benign thyroid node(0. 357±0. 009)and normal thyroid tissue(0. 296±0. 008) groups(P 0. 05).In addition,although the level of Hp mRNA increased with the higher clinical stages, there were no statistical significance(P> 0. 05). Conclusion Our results suggested that Hp might play a key role in papillary thyroid carcinoma occurrence.Moreover, findings in the present study also provided evidence for the diagnostic and therapeutic strategies in the treatment of papillary thyroid carcinoma. Key words: Haptoglobin; Papillary thyroid carcinoma

Quality Control and Telemedicine for BRAF V600E Mutations in Papillary Thyroid Carcinomas

The assessment of BRAF V600E mutations is important for prognosis and treatment of Papillary Thyroid Carcinomas (PTC), the standard methods for their identification are molecular biology techniques. In this study, the potential of image morphometry applied to cell nuclei and sequentially the use of a Classification And Regression Tree (CART) is investigated, in order to: identify morphometric features useful to characterize BRAF mutations, and to eventually produce an algorithm identifying BRAF mutation status. The 140 studied cases had histological confirmation and known BRAF mutation status identified via real-time PCR. The analysis revealed that nuclear features contributing to BRAF mutation status identification via the CART model are related mostly to nuclear color. According to the results there is evidence that BRAF V600E mutations can be identified by measurable image features. Therefore, the proposed method is useful for quality control of BRAF V600E mutations on cytological slides, can serve as alternative to PCR method and may be used for remote assessment.

MiR-204-5p suppresses cell proliferation by inhibiting IGFBP5 in papillary thyroid carcinoma

microRNAs (miRNAs) are frequently dysregulated in human malignancies. It was recently shown that miR-204-5p is downregulated in papillary thyroid carcinoma (PTC); however, the functional significance of this observation is not known. This study investigated the role of miR-204-5p in PTC. Overexpressing miR-204-5p suppressed PTC cell proliferation and induced cell cycle arrest and apoptosis. The results of a luciferase reporter assay showed that miR-204-5p can directly bind to the 3′ untranslated region (UTR) of insulin-like growth factor-binding protein 5 (IGFBP5) mRNA, and IGFBP5 overexpression partially reversed the growth-inhibitory effects of miR-204-5p. These results indicate that miR-204-5p acts as a tumor suppressor in PTC by regulating IGFBP5 expression and that miR-204-5p can potentially serve as an antitumorigenic agent in the treatment of PTC.

Silencing NOB1 enhances doxorubicin antitumor activity of the papillary thyroid carcinoma in vitro and in vivo

Doxorubicin (DOX), a broad‑spectrum anthra-cyclin, is in wide clinical use for the treatment and prevention of thyroid cancer. However, the effectiveness of the treatment remains limited due to inherent tumor resistance to DOX. Results of a previous study demonstrated that downregulation of NIN1/RPN12 binding protein 1 homolog (NOB1) expression via adenovirus expression vector carrying NOB1 siRNA (Ad/sh-NOB1) induced cancer apoptosis and increased the radiosensitivity of papillary thyroid carcinoma (PTC) cells. However, whether knockout NOB1 can decrease DOX resistance remains unclear. Therefore, in the present study, the effect of Ad/sh-NOB1 infection, independently or in combination with DOX, was determined in a PTC cell line to identify more effective therapeutics against PTC cancer. Furthermore, tumor growth ability in nude mice was determined to identify the combination treatment effect in tumorigenesis in vivo. The results showed that Ad/sh-NOB1 combined with DOX treatment in PTC cells significantly suppressed proliferation, colony formation, migration and invasion, and induced cell apoptosis and arrest in the G0/G1 stage as compared to Ad/sh-NOB1 or DOX monotherapy. We also found that this combination suppressed the tumor growth of a nude mouse model as compared to Ad/sh-NOB1 or DOX monotherapy. In addition, Ad/sh-NOB1 combined with DOX treatment significantly increased activation of the p38 MAPK pathway, which may contribute to inhibition of PTC cell growth and decreased DOX resistance. Taken together, the experimental results indicate that Ad/sh-NOB1 combined with DOX treatment is a potential drug candidate for the treatment of papillary thyroid carcinoma.

Bilateral central lymph node dissection with thyroidectomy for papillary thyroid cancer

Objectives The aims of the study were to evaluate the frequency and pattern of central neck lymph node metastasis in papillary thyroid cancer and its relation to the lateral neck lymph node metastasis. Also, this study aimed to evaluate the complications of central neck dissection. Background The indications and extent of central lymph node dissection (CLND) in the treatment of papillary thyroid carcinoma remain controversial, and its therapeutic effect remains debatable. Patients and methods A total of 30 patients diagnosed with papillary thyroid cancer were treated from 2011 to 2013. All patients underwent total thyroidectomy and bilateral central neck dissection. In patients with positive central lymph node metastases in frozen section, we performed ipsilateral lateral lymph node dissection removing levels II to V. Central lymph node metastases were analyzed. In addition, we investigated postoperative complications after total thyroidectomy and CLND. Results Among 30 patients, 12 (40%) had central lymph node metastases, with the ipsilateral paratracheal lymph nodes most commonly affected (40%). Of the 12 patients with positive central lymph node metastases, only two had positive lateral lymph node metastases. The frequency of temporary hypocalcemia, permanent hypocalcemia, and temporary vocal cord paralysis was 16.7, 6.7, and 6.7%, respectively. Conclusion CLND prevents nodal recurrence in the central compartment, which carries a high incidence of morbidity during surgery for recurrence. In addition, CLND, in good hands, does not contribute to the morbidity of total thyroidectomy (hypoparathyroidism and recurrent laryngeal nerve injury). We propose that total thyroidectomy and bilateral CLND are the least-recommended surgical treatments. Also, in clinically negative lateral nodes, we conclude that lateral lymph node dissection is not important even if central lymph nodes were positive for metastases.

Factors Associated with Metastatic Lymph Node Ratio, Extranodal Extension in the Central Compartment Node-Positive Papillary Thyroid Carcinoma

Received February 12, 2015 Revised March 27, 2015 Accepted March 31, 2015 Address for correspondence Kang Dae Lee, MD, PhD Department of OtolaryngologyHead and Neck Surgery, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea Tel +82-51-990-6470 Fax +82-51-245-8539 E-mail kdlee59@gmail.com Background and ObjectivesZZLymph node (LN) metastasis occurs in 30-80% of patients presenting for initial treatment of papillary thyroid carcinoma (PTC). The presence of LN metastasis is an independent risk factor for recurrence, which can add significant treatment morbidity. The LN ratio (LNR) and extranodal extension (ENE) have been shown to be important prognostic factors in PTC. The purpose of this study was to assess the characteristic features of LNR and ENE. Subjects and MethodZZWe undertook a retrospective study of 411 patients treated between January, 2011 and December, 2013 for central compartment node-positive PTC by thyroidectomy and central compartment neck dissection (CCND) at our institution. We compared various clinicopathologic parameters such as age, gender, tumor size, multifocality, bilaterality, local invasion, extrathyroidal extension and aggressive variants between LNR and ENE. ResultsZZThe significant associated factors for high LNR (defined as higher than 0.5) in multivariate analysis were gender (p=0.001, odds ratio=2.285) and multifocality (p=0.027, odds ratio=2.092). On the other hand, the significant associated factors for ENE in multivariate analysis were primary tumor size (p=0.023, odds ratio=1.965) and local invasion (p=0.043, odds ratio=1.870). ConclusionZZBeing male, multifocality, large primary tumor size (defined as larger than 1 cm) and local invasion were revealed as associated factors for LNR and ENE. Therefore, elective CCND should be considered for patients with PTC, for whom a thorough investigation of associative factors should be made before surgery. Korean J Otorhinolaryngol-Head Neck Surg 2015;58(7):475-80

Pattern and Distribution of Lymph Node Metastases in Papillary Thyroid Cancer

Background: The indications and extent of lymph node dissection in the treatment of papillary thyroid carcinoma remains controversial, and benefit from therapy is debatable. This study was designed to identify the pattern and distribution of lymph node metastases and to establish an optimal strategy for neck dissection for those patients. Methods: A total of 44 patients diagnosed with papillary thyroid cancer were treated from 2006 to 2013. All patients underwent total thyroidectomy, central neck dissection, and ipsilateral selective neck dissection removing lymphatic structures in levels II through V. The frequency of cervical lymph node metastases in each level, and the presence of capsular invasion were analysed. In addition, we investigated postoperative complications after total thyroidectomy and central lymph node dissection. Results: Lymph node metastases were found in 18 patients (40.9%); all of them had ipsilateral level VI nodal involvement. 7 patients had level V involvement, 2 patients had level II affection, 3 patients had level III & IV affection and 2 patients had contralateral level VI lymph node affection. We also found extracapsular invasion in 6 (13.6%) patients and grade I, II, III in 2, 40, 2 patients respectively. The frequency of temporary hypocalcaemia, permanent hypocalcaemia and temporary vocal cord paralysis were 6.8%, 2.3% and 4.5%, respectively. Conclusion: We recommend total thyroidectomy and central compartment lymph node dissection. If ipsilateral central lymph nodes are positive for metastases in frozen section, we proceed to ipsilateral selective neck dissection removing lymphatic structures in levels II through V even in the absence of clinically evident lymph node metastasis irrespective of tumor size. The technique had a low rate of complications; namely laryngeal nerve injury and hypoparathyroidism.

Central neck compartment dissection in papillary thyroid carcinoma: An update

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, accounting for approximatley 90% of thyroid malignancies in areas of the world without deficit of Iodine. It’s universally accepted that total thyroi­ dectomy is the minimal surgical treatment for patients with PTC higher than 1 cm. When a quality surgery is performed, the prognosis for PTC is excellent with 10 and 20-year overall survival rates around 90% and 85%, respectively. Lymph node metastases are very frequent in PTC, occurring in 50%-80% of PTC patients, the most of them being located in the central compartment of the neck (CCN) and with a high rate of occult or clinically undetectable disease. A lot of controversy exists regarding how to treat the central nodal compartment disease of PTC. The first problem is the lack of standardization of the terminology and concepts related to the CCN, which are clearly established and defined in this paper according to the most recent consensus documents of endocrine societies. This uniformity will provide a more consistent and clear communicaction between all the specialist involved in the treatment of PTC. CCN can be performed to treat patients with clinically detectable, radiologically suspected of intraoperative visualized nodal disease (this is defined as therapeutic) or when these findings are absent (also called prophylactic). Indicactions, advantages and disadvantages of both therapeutic and prophylactic CCN dissection are widely discussed and clear recommendations provided.

A Case of Pyriform Sinus Fistula Concurrent with Papillary Thyroid Carcinoma in a 72-Year-Old Patient

Since branchial anomalies are developmental disorders, pyriform sinus fistula (PSF) has been considered as a pediatric disease, and most reports of PSF with clinical symptoms have thus been on neonatal and young children. There are only a few case reports worldwide, of PSF found in adult patients. Here, we report a case where the patient’s initial symptom of PSF occurred at the age of 72. Interestingly, papillary thyroid carcinoma (PTC) was concurrently identified on computed tomography during the evaluation for PSF. Chemical cauterization and total thyroidectomy was performed for the treatment of PSF and PTC, respectively. This case report may contribute to increased awareness of PSF in adult patients and the possible coexistence of thyroid cancer in these patients.

The Warthin-Like Variant of Papillary Thyroid Carcinoma: A Comparison with Classic Type in the Patients with Coexisting Hashimoto's Thyroiditis.

Background. The Warthin-like variant of papillary thyroid (WLPTC) is a rare subtype of papillary thyroid carcinoma (PTC) resembling Warthin tumors of the salivary glands. Due to its rarity, the clinicopathologic and molecular features of WLPTC remain unclear. Methods. Of the 2,139 patients who underwent surgical treatment for PTC from 2012 to 2013, 40 patients with WLPTC were identified and compared to 200 consecutive patients with classic PTC. BRAF mutation was tested with pyrosequencing. Results. There were no significant differences in age, predilection for women, multifocality, extrathyroidal extension, or lymph node metastasis between WLPTC and classic PTC. However, WLPTCs were more commonly associated with Hashimoto's thyroiditis than classic PTCs (93% versus 36%, resp., P < 0.001) and showed significantly lower rate of BRAF mutation when compared to classic PTCs (65% versus 84%, resp., P = 0.007). In classic PTC, the frequency of BRAF mutations was negatively correlated with coexisting Hashimoto's thyroiditis. When we compared WLPTC and classic PTC in the patients with coexisting Hashimoto's thyroiditis, there were no significant differences in clinicopathologic characteristics or the BRAF mutational rate between the two groups. Conclusions. Patients with WLPTC have similar demographic, clinical, pathologic, and molecular characteristics to those with classic PTC coexisting with Hashimoto's thyroiditis.

MiR-146b-5p Promotes Metastasis and Induces Epithelial-Mesenchymal Transition in Thyroid Cancer by Targeting ZNRF3

Background/Aims: Micro-RNA (miR)-146b-5p is overexpressed in papillary thyroid carcinoma (PTC) and associated with extrathyroidal invasion and advanced tumor stage. In the present study, we showed that miR-146b-5p is upregulated in PTC with lymph node metastasis. Methods: A computational search and luciferase assay identified zinc RING finger 3 (ZNRF3), a negative regulator of Wnt/β-catenin signaling, as a direct target of miR-146b-5p in PTC. Results: MiR-146b-5p promoted migration and invasiveness and induced epithelial-mesenchymal transition (EMT) of PTC cells, whereas ZNRF3 overexpression reversed this effect. MiR-146b-5p increased the cell surface levels of the Wnt receptors Frizzled-6 and LRP6 and enhanced Wnt/β-catenin signaling by downregulating ZNRF3, whereas an inhibitor of Wnt/β-catenin suppressed the effect of miR-146b-5p on migration, invasiveness and EMT of PTC cells. Conclusion: These results indicate that miR-146b-5p induces EMT and may promote PTC metastasis through the regulation of Wnt/β-catenin signaling, and suggest novel potential therapeutic targets for the treatment of PTC.

Clinicopathological factors in risk prediction of lymph node metastasis in papillary thyroid carcinoma

To explore the relationship between histomorphological factors and lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). A total of 153 paraffin-embedded specimens of PTC treated at Beijing Tongren Hospital, Capital Medical University were collected from January 1, 2006 to December 31, 2013 and assessed by hematoxylin and eosin staining. The tumor growth patterns (infiltrative tumor border, lateral tubular growth and intraglandular dissemination), histomorphological characteristics (hobnail features, loss of cohesiveness/polarity (LOCP) and micropapillary structures) and several clinicopathological parameters were evaluated for their values in LNM. Among them, there were infiltrative tumor border (n = 128), lateral tubular growth (n = 34), intraglandular dissemination (n = 30), extrathyroidal extensions (n = 53), hobnail features (n = 37), LOCP (n = 59) and micropapillary structures (n = 70). According to univariate analysis, patient age < 45 years, tumor size of 10 mm or more, infiltratve tumor border, lateral tubular growth, intraglandular dissemination, hobnail features, LOCP and micropapillary structures predicted LNM for PTC (P < 0.05); whereas gender, multifocality and extrathyroidal extensions did not (P > 0.05). According to multivariated analysis, tumor size of 1 cm or more, infiltratve tumor border, hobnail features, LOCP and micropapillary structures were independent predictive factors of LNM for PTC (P < 0.05). After a median follow-up period of 42 months, 4/82 patients suffered from locoregional recurrence. The estimated 5-year locoregional recurrence was 4.88%. Among 4 logcoregional recurrence cases, 3 involved in lymph nodes and 1 in remaining thyroid. Among 3 lymph node metastasis cases, there were hobnail feature (n = 1), LOCP (n = 1) and LOCP and micropapillary structure (n = 1). None of hobnail feature, LOCP or micropapillary structure was found in recurrent case of remaining thyroid. Correlated with lymph node metastasis in PTC, hobnail features, LOCP and micropapillary structures may be used as independent predictive factors of LNM so as to improve treatment and follow-up strategies for PTC.