RESUMEN
Adiponectin (Acrp30) and leptin, adipokines produced and secreted mainly by the adipose tissue, are involved in human carcinogenesis. Thyroid carcinomas are frequent endocrine cancers, and several evidences suggest that they are correlated with obesity. In this study, we first analyzed the expression levels and prognostic values of Acrp30, leptin, and their receptors in thyroid cancer cells. Then, we investigated the role of Acrp30 and leptin in proliferation, migration, and invasion. We found that Acrp30 treatment alone inhibits cell proliferation and cell viability in a time and dose-dependent manner; leptin alone does not influence thyroid cancer cells (BCPAP and K1) proliferation, but the combined treatment reverts Acrp30-induced effects on cell proliferation. Additionally, through wound healing and Matrigel Matrix invasion assays, we unveiled that Acrp30 inhibits thyroid cancer cell motility, while leptin induces the opposite effect. Importantly, in the combined treatment, Acrp30 and leptin exert antagonizing effects on papillary thyroid cancer cells' migration and invasion in both BCPAP and K1 cell lines. Highlights of these studies suggest that Acrp30 and leptin could represent therapeutic targets and biomarkers for the management of thyroid cancer.
Asunto(s)
Adiponectina/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Leptina/farmacología , Adiponectina/genética , Adiponectina/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Colágeno/química , Combinación de Medicamentos , Regulación de la Expresión Génica , Humanos , Laminina/química , Leptina/genética , Leptina/metabolismo , Modelos Biológicos , Proteoglicanos/química , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transducción de Señal , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/metabolismo , Cáncer Papilar Tiroideo/patologíaRESUMEN
BACKGROUND: Aberrant expression of microRNAs (miR) has been proposed as non-invasive biomarkers for breast cancers. The aim of this study was to analyse the miR-622 level in the plasma and in tissues of breast cancer patients and to explore the role of miR-622 and its target, the NUAK1 kinase, in this context. METHODS: miR-622 expression was analysed in plasma and in tissues samples of breast cancer patients by q-RT-PCR. Bioinformatics programs, luciferase assay, public dataset analysis and functional experiments were used to uncover the role of miR-622 and its target in breast cancer cells. RESULTS: miR-622 is downregulated in plasma and in tissues of breast cancer patients respect to healthy controls and its downregulation is significantly associated with advanced grade and high Ki67 level. Modulation of miR-622 affects the motility phenotype of breast cancer cells. NUAK1 kinase is a functional target of miR-622, it is associated with poor clinical outcomes of breast cancer patients and is inversely correlated with miR-622 level. CONCLUSIONS: miR-622/NUAK1 axis is deregulated in breast cancer patients and affects the motility phenotype of breast cancer cells. Importantly, miR-622 and NUAK1 hold promises as biomarkers and as targets for breast cancers.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Regulación hacia Abajo , MicroARNs/genética , Proteínas Quinasas/genética , Proteínas Represoras/genética , Regiones no Traducidas 3' , Neoplasias de la Mama/sangre , Línea Celular Tumoral , Movimiento Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , MicroARNs/sangre , PronósticoRESUMEN
Thyroid carcinoma is the most common endocrine cancer and includes different forms. Among these, anaplastic thyroid carcinoma (ATC) is the rarest but the most lethal subtype, compared to papillary thyroid carcinoma (PTC) which shows an overall good prognosis. We have previously showed that Tumor Suppressor Candidate 2 (TUSC2), a known tumour suppressor gene, is downregulated in human PTC and ATC compared to normal thyroid samples. The aim of this study was to gain insight into the molecular mechanisms induced by TUSC2 in thyroid cancer cells. Here, we stably transfected TUSC2 in papillary (TPC-1) and in anaplastic (8505C) thyroid cancer cell lines and studied its effects on several biological processes, demonstrating that TUSC2 overexpression decreased thyroid cancer cell proliferation, migration and invasion. Through the proteome profiler apoptosis array, we observed that TUSC2 increased sensitivity to apoptosis by increasing the SMAC/DIABLO and CYTOCHROME C proteins. On the other hand, transient silencing of TUSC2, by siRNA, in an immortalized thyroid follicular epithelial cell line (Nthy-ori 3-1) showed the opposite effect. Finally modulation of SMAC/DIABLO partially rescued the biological effects of TUSC2. Thus, our data highlight a tumour suppressor role of TUSC2 in thyroid carcinogenesis, suggesting that it could be a promising target and biomarker for thyroid carcinoma.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Mitocondriales/metabolismo , Fenotipo , Neoplasias de la Tiroides/metabolismo , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/metabolismo , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Genes Supresores de Tumor , Humanos , ARN Interferente Pequeño , Cáncer Papilar Tiroideo , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides/patología , Proteínas Supresoras de Tumor/genéticaRESUMEN
Junctional adhesion molecule A (JAM-A) is a transmembrane protein that contributes to different biological process, including the epithelial to mesenchymal transition (EMT). Through an EMT profiler array, we explored the molecular players associated with human thyroid cancer progression and identified JAM-A as one of the genes mostly deregulated. The quantitative real-time polymerase chain reaction and immunohistochemistry analyses showed that downregulation of JAM-A occurred in anaplastic thyroid carcinoma (ATC) compared with normal thyroid (NT) and papillary thyroid carcinoma (PTC) tissues and correlated with extrathyroid infiltration, tumor size, and ATC histotype. In ATC cell lines, JAM-A restoration suppressed malignant hallmarks of transformation including cell proliferation, motility, and transendothelial migration. Accordingly, knockdown of JAM-A enhanced thyroid cancer cell proliferation and motility in PTC cells. Through the proteome profiler human phospho-kinase array, we demonstrated that higher expression of JAM-A was associated with a significant increased level of phosphorylation of p53 and GSK3 α/ß proteins. In conclusion, our findings highlight a novel role of JAM-A in thyroid cancer progression and suggest that JAM-A restoration could have potential clinical relevance in thyroid cancer treatment.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Receptores de Superficie Celular/metabolismo , Cáncer Papilar Tiroideo/patología , Carcinoma Anaplásico de Tiroides/patología , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/fisiología , Humanos , Interferencia de ARN , ARN Interferente Pequeño/genética , Neoplasias de la Tiroides/patologíaRESUMEN
PURPOSE: Aberrant expression of miRNAs is crucial in several tissues tumorigenesis including thyroid. Recent studies demonstrated that miR-650 plays different role depending on the cancer type. Herein, we investigated the role of miR-650 in thyroid carcinoma. METHODS: The expression of miR-650 was analyzed in human thyroid tissues by q-RT-PCR. Anaplastic (8505C, CAL62, SW1736) and papillary (TPC-1) thyroid cancer cell lines were used to dissect the role of miR-650 on malignant hallmarks of transformation. Label-free proteomic analysis was exploited to unravel the targets of miR-650, while luciferase reporter assay and functional experiments were performed to confirm a selected target. Spearman's rank correlation test was used to assess the association between miR-650 and its target in human thyroid cancer tissues. RESULTS: miR-650 is over-expressed in anaplastic (ATC) thyroid carcinoma where it enhances cell migration and invasion. Proteomic label-free and bioinformatics analysis revealed that the serine-threonine protein phosphatase 2 catalytic subunit alpha (PPP2CA) is a target of miR-650; these finding were confirmed by luciferase assay. Restoration of PPP2CA mRNA, deprived of its 3'UTR, is able to revert the malignant phenotype induced by miR-650 in HEK-293 cells. Importantly, PPP2CA is down-regulated in ATC tissues and is inversely correlated with miR-650. CONCLUSIONS: miR-650 displayed oncogenic activity in ATC cells through targeting PPP2CA phosphatase. These results suggest that miR-650/PPP2CA axis could be modulated to interfere with motile ability of thyroid carcinoma cells.