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1.
Apoptosis ; 28(9-10): 1315-1331, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37336836

RESUMEN

Thyroid cancer (TC) is one of the most common endocrine system cancers, and its incidence is elevating. There is an urgent need to develop a deeper understanding of TC pathogenesis and explore new therapeutic target for its treatment. This study aimed to investigate the effects of pleckstrin homology and RhoGEF domain containing G4 (PLEKHG4) on the progression of TC. Herein, 29 pairs of TC and adjacent tissues were used to assess the expression of PLEKHG4. A xenograft model of mouse was established by subcutaneously injected with TC cells. Lung metastasis model was established through left ventricular injection. The results revealed that PLEKHG4 was up-regulated in human TC tissues. PLEKHG4 level was correlated with clinicopathological parameters of TC patients. In vitro assays revealed that PLEKHG4 promoted TC cell proliferation, migration, invasion, and epithelial-mesenchymal transformation. Knockdown of PLEKHG4 led to the opposite effects, and the loss of PLEKHG4 enhanced the apoptosis ability and inhibited the stemness properties of TC cells. These findings were further confirmed by the in vivo growth and lung metastasis of TC tumor. Mechanistically, PLEKHG4 promoted the activation of RhoGTPases RhoA, Cdc42, and Rac1. The inhibitors of these RhoGTPases reversed the PLEKHG4-induced malignant phenotypes. Additionally, ubiquitin-conjugating enzyme E2O (UBE2O), a large E2 ubiquitin-conjugating enzyme acted as an ubiquitin enzyme of PLEKHG4, facilitated its ubiquitination and degradation. In conclusion, PLEKHG4, regulated by UBE2O, promoted the thyroid cancer progression via activating the RhoGTPases pathway. UBE2O/PLEKHG4/RhoGTPases axis is expected to be a novel a therapeutic target for TC treatment.


Asunto(s)
Neoplasias de la Tiroides , Enzimas Ubiquitina-Conjugadoras , Humanos , Animales , Ratones , Apoptosis/genética , Proliferación Celular , Factores de Intercambio de Guanina Nucleótido Rho , Línea Celular Tumoral , Movimiento Celular/genética
2.
Cell Biol Toxicol ; 39(5): 1979-1994, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-35066776

RESUMEN

MicroRNA-497 (miR-497) has been reported to be a tumor-suppressive miRNA in thyroid cancer (TC), yet the mechanism is not clearly defined. In this study, we aim to determine the mechanism by which miR-497-3p affects the progression of TC. After characterization of low miR-497-3p expression pattern in TC and normal tissues, we assessed the correlation between miR-497-3p expression and clinicopathological features of TC patients. Its low expression shared associations with advanced tumor stage and lymph node metastasis. ChIP and methylation-specific PCR provided data showing that downregulation of miR-497-3p in TC tissues was induced by DNA methyltransferase-mediated hypermethylation. By performing dual-luciferase reporter assay, we identified that miR-497-3p targeted PAK1 while PAK1 could inhibit ß-catenin expression. Through this mechanism, miR-497-3p exerted the anti-proliferative, anti-invasive, pro-apoptotic, and anti-tumorigenic effects on TC cells on the strength of the results from gain-of-function and rescue experiments. This study suggested that hypermethylation of miR-497-3p resulted in upregulation of ß-catenin dependent on PAK1 and contributed to cancer progression in TC, which highlighted one of miR-mediated tumorigenic mechanism.


Asunto(s)
MicroARNs , Neoplasias de la Tiroides , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Quinasas p21 Activadas/genética
3.
J Cell Physiol ; 237(1): 1057-1069, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34750830

RESUMEN

Atherosclerosis (AS) is a common disease that seriously threatens human health. So far, the pathogenesis of AS has not been fully understood. This project investigates the effects of circARHGAP12 on AS and its regulatory mechanism. ApoE-/- knockout mice (ApoE) were adopted and reared with a high-fat diet to construct an AS model. Lentivirus was established to knock down the expression of circARHGAP12 in mice. After 12 weeks, the aorta was removed and the expression of circARHGAP12 was detected. Vascular oil red O staining was used to detect the degree of AS. The expression of inflammatory factors was detected by ELISA. Aortic smooth muscle cells (MASMCs) were cultured to evaluate the effects of circARHGAP12 on the phenotype of MASMCs. RNA pull-down and luciferase assay were used to verify the downstream target genes of circARHGAP12. In addition, the effects of circARHGAP12 on MASMCs proliferation and migration were detected by MTT and transwell assay. Compared with the normal group, the expression of circARHGAP12 in the MASMCs under ox-LDL treatment was elevated, and circARHGAP12 silencing could inhibit AS in vitro and in vivo. The results of the mechanism study showed that circARHGAP12 can directly bind with miR-630. In addition, miR-630 can also target EZH2 to modulate the transcription of TIMP2 and to influence the migration of MASMCs. circARHGAP12 is upregulated in AS. CircARHGAP12 knockdown can inhibit the progression of AS. This study expands on the role of circRNA in AS and provides potential targets for the treatment of AS.


Asunto(s)
Aterosclerosis , MicroARNs , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/patología , Movimiento Celular/genética , Proliferación Celular/genética , Células Cultivadas , Lipoproteínas LDL/metabolismo , Ratones , Ratones Noqueados para ApoE , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo
4.
Cancer Immunol Immunother ; 70(8): 2235-2245, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33486611

RESUMEN

BACKGROUND: LncRNAs play an important role in the regulation of the killing effect of cytotoxic CD8 + T cells in various cancers. However, the role and underlying mechanisms of UCA1 in the killing effect of cytotoxic CD8 + T cells in anaplastic thyroid carcinoma (ATC) are not clear. METHODS: UCA1, miR-148a, and PD-L1 expression were detected by quantitative real-time PCR and/or Western blot. The ratio of PD-L1+ATC cells/ATC cells was determined using flow cytometry. The ability of CD8 + T cells to kill target ATC cells was detected by Chromium-51 (51Cr) release assay. The targeted relationship between UCA1 and miR-148a was confirmed by dual-luciferase reporter gene assay. RESULTS: UCA1 and PD-L1 expression levels were elevated in ATC tissues and cells. Silencing UCA1 and PD-L1 enhanced the killing effect of cytotoxic CD8 + T cells on ATC cells. UCA1 negatively regulated the expression of miR-148a, and miR-148a targeted PD-L1 to down-regulate its expression. Besides, we found that UCA1 attenuated the killing effect of cytotoxic CD8 + T cells and reduced cytokine secretion through PD-L1 and miR-148a. Finally, silencing UCA1 or PD-L1 in ATC cells restored the suppression of the killing effect of CD8 + T cells in vivo. CONCLUSION: UCA1 attenuated the killing effect of cytotoxic CD8 + T cells on ATC cells through the miR-148a/PD-L1 pathway.


Asunto(s)
Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/inmunología , MicroARNs/inmunología , ARN Largo no Codificante/inmunología , Carcinoma Anaplásico de Tiroides/inmunología , Neoplasias de la Tiroides/inmunología , Animales , Apoptosis/inmunología , Línea Celular Tumoral , Movimiento Celular/inmunología , Proliferación Celular/fisiología , Regulación hacia Abajo/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Transducción de Señal/inmunología
5.
Exp Cell Res ; 387(2): 111785, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31877303

RESUMEN

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy with an increasing occurrence and recurrence. MicroRNAs (miRNAs) have been widely acknowledged to be participated in human cancers. However, how these miRNAs exert roles and potential mechanisms in PTC regulatory networks is still lacking. The purpose of our study lies in discovering the regulatory basis of miR-200b/c and Rap1b for PTC tumorigenesis and malignant progression, as well as the underlying molecular mechanisms. Herein, miR-200b/c expression was sharply dropped and Rap1b expression was up-regulated in PTC cells and tissues samples when compared to normal thyroid epithelial cells and normal tissues. miR-200b/c targeted Rap1 directly and negatively regulated its expression. miR-200b/c overexpression suppressed proliferative, colony forming, migratory and invasive capabilities and EMT as well as elevated apoptosis of PTC cells through inhibiting Rap1b. Furthermore, xenograft experiments showed miR-200b/c overexpression constrained growth of PTC xenograft and EMT. miR-200b/c inhibited NF-κB/Twist1 signals via regulating the Rap1b expression in cells and animal models. Taken together, our study suggested that upregulation of miR-200b/c-RAP1B axis constrained PTC cell proliferation, invasion, migration and EMT. Also, the upregulation of miR-200b/c-RAP1B leaded to elevated apoptosis through inhibiting the NF-κB/Twist1 pathway, thus inhibiting PTC tumorigenesis and malignant progression.


Asunto(s)
Carcinogénesis/genética , MicroARNs/genética , FN-kappa B/genética , Proteínas Nucleares/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Proteína 1 Relacionada con Twist/genética , Proteínas de Unión al GTP rap/genética , Animales , Línea Celular , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Regulación hacia Arriba/genética
6.
Exp Cell Res ; 392(1): 112024, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32335029

RESUMEN

Papillary thyroid carcinoma (PTC) is the most common malignancy in thyroid. miR-744-5p plays an efficient role in various cancers, but its role in PTC remains unknown. In this work, we aimed to explore the function of miR-744-5p and the mechanism by which miR-744-5p acted in PTC. We observed that miR-744-5p expression was significantly declined in PTC tissues and cell lines. The high level of miR-744-5p is significantly associated with a better clinical picture of PTC patients. Overexpression of miR-744-5p inhibited the proliferation, arrested the cell cycle, and promoted the apoptosis in PTC cells. Oppositely, down-regulation of miR-744-5p reversed the above tendencies. We also found that miR-744-5p down-regulated its downstream genes c-myc and attenuated cell proliferation induced by c-myc. Long non-coding RNA (lncRNA) HOTTIP was found to be up-regulated and to act as an oncogene in PTC. In this study, miR-744-5p bound to HOTTIP and was negatively regulated by HOTTIP. In conclusion, miR-744-5p acts as a tumor suppressor to inhibit proliferation and promotes the apoptosis of PTC cells via targeting c-myc. Moreover, miR-744-5p expression interferes with lncRNA HOTTIP ability to promote proliferation and downregulate apoptosis in papillary thyroid carcinoma.


Asunto(s)
Apoptosis/genética , Proliferación Celular/genética , MicroARNs/fisiología , ARN Largo no Codificante/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética
7.
Cancer Cell Int ; 20: 294, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32669970

RESUMEN

BACKGROUND: Thyroid cancer (TC) is the most frequent endocrine malignancy. Long noncoding RNAs (lncRNAs) have been confirmed to act as significant roles in tumor development. The role of lncRNA TMPO-AS1 in TC is still unclear, so it remains to be explored. The aim of the research is to investigate the role and regulatory mechanism of TMPO-AS1 in TC. METHODS: TMPO-AS1 and TMPO expression in TC tumors and cells was detected by TCGA database and QRT-PCR assay respectively. CCK-8, EDU, TUNEL and western blot assays were conducted to identify the biological functions of TMPO-AS1 in TC. Luciferase reporter and RNA pull down assays were conducted to measure the interaction among TMPO-AS1, TMPO and miR-498. RESULTS: TMPO-AS1 was overexpressed in TC tissues and cell lines. Knockdown of TMPO-AS1 suppressed cell growth and accelerated cell apoptosis in TC. Furthermore, downregulation of TMPO-AS1 suppressed TMPO expression in TC. The data suggested that TMPO expression was upregulated in TC tissues and cell lines and was positively correlated with TMPO-AS1 expression in TC. Furthermore, the expression of miR-498 presented low expression in TC cells. And miR-498 expression was negatively regulated by TMPO-AS1, meanwhile, TMPO expression was negatively regulated by miR-498 in TC cells. Besides, it was confirmed that TMPO-AS1 could bind with miR-498 and TMPO in TC cells. In addition, it was validated that TMPO-AS1 elevated the levels of TMPO via sponging miR-498 in TC cells. CONCLUSIONS: TMPO-AS1 promotes cell proliferation in TC via sponging miR-498 to modulate TMPO.

8.
Cell Physiol Biochem ; 45(5): 2044-2053, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29533940

RESUMEN

BACKGROUND/AIMS: To investigate the clinical significance and functional mechanisms of deubiquitinase USP33 in papillary thyroid carcinoma (PTC). METHODS: Immunohistochemistry staining was conducted to explore the expression of USP33 in PTC tissues and adjacent normal thyroid tissues. Patients' prognosis was evaluated by disease-free survival. The prognostic role of USP33 was tested by univariate and multivariate analyses. To confirm the effect of USP33 in cell proliferation and invasion, overexpression and knockdown of USP33 were performed in two PTC cell lines. Besides, cell cycle, immunoprecipitation, and apoptosis experiments were conducted to further explore the signaling pathways. RESULTS: By analyzing series of 158 PTC tissues, we found that USP33 was down-regulated in tumor tissue compared with normal thyroid tissues, which was closely associated with lymph node metastasis (P<0.001). In particular, univariate and multivariate analyses indicated that USP33 was an independent prognostic biomarker for PTC, low USP33 expression indicated high recurrence risk. Cellular studies with TPC-1 and BCPAP cells demonstrated that USP33 can attenuate the cell capacities of proliferation, migration and invasion. Fluorescence-activated cell sorting experiment found no significant effect of USP33 on cell cycle, whereas the apoptotic caspase proteins were activated by USP33-overexpression. Moreover, the interaction between USP33 and Robo1 protein was identified, and knockdown of Robo1 enhancing the oncogenic effect upon USP33-knockdown, suggesting that USP33 may inhibit tumor progression through Robo1 signaling. CONCLUSIONS: Our data demonstrated that USP33 downregulation in PTC tissues was correlated with poor clinical outcome, which may serve as a novel biomarker and potential therapeutic target.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Papilar/patología , Neoplasias de la Tiroides/patología , Ubiquitina Tiolesterasa/metabolismo , Adulto , Carcinoma Papilar/metabolismo , Carcinoma Papilar/mortalidad , Caspasas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Supervivencia sin Enfermedad , Regulación hacia Abajo , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Transducción de Señal , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/mortalidad , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/genética , Proteínas Roundabout
9.
J Cell Biochem ; 118(12): 4745-4752, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28513866

RESUMEN

The distance metastases of papillary thyroid carcinoma (PTC) were a major threaten for PTC patients, thus, to study the potential mechanism for the treatment of PTC was essential. Previous studies have shown that PTCSC3 (Thyroid Carcinoma Susceptibility Candidate 3), miR-574-5p and Wnt/ß-catenin were involved in PTC, but the potential pathogenic mechanism among them was still unclear. Real-time PCR and Western blot were used to detect genes expression. Luciferase reporter assay was used to detect the combination of miR-574-5p and suppressor of cancer cell invasion (SCAI), as well as the ratio of TOP/FOP. RNA Pull-down assay verified the bound of PTCSC3 and miR-574-5p. MTT assay, Transwell assay, and wound scratch assay were used to detect cell viability and cell migration. The expression of PTCSC3 and SCAI were decreased, while miR-574-5p and ß-catenin were increased in PTC tissues and cells. Overexpressed PTCSC3 suppressed cell proliferation and migration, promoted the expression of SCAI, but inhibited ß-catenin. PTCSC3 absorbed miR-574-5p, and miR-574-5p targeted to SCAI; SCAI could regulate the activity of Wnt/ß-catenin. PTCSC3/miR-574-5p regulated the activity of Wnt/ß-catenin via SCAI and mediated cell proliferation and migration of PTC-1. In vivo experiments verified the fact that overexpressed PTCSC3 inhibited tumor growth. The signaling PTCSC3-miR-574-5p-SCAI-Wnt/ß-catenin mediated the proliferation and migration of PTC-1 cells, which was vital for the further PTC therapy and prognosis. J. Cell. Biochem. 118: 4745-4752, 2017. © 2017 Wiley Periodicals, Inc.


Asunto(s)
Carcinoma Papilar/metabolismo , Proliferación Celular , MicroARNs/metabolismo , ARN no Traducido/metabolismo , Neoplasias de la Tiroides/metabolismo , Vía de Señalización Wnt , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Línea Celular Tumoral , Femenino , Humanos , Masculino , MicroARNs/genética , Pronóstico , ARN no Traducido/genética , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología
10.
J Surg Res ; 189(1): 68-74, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24650454

RESUMEN

BACKGROUND: Our recent study has found that microRNA-21 (miRNA-21) was significantly upregulated in papillary thyroid carcinoma (PTC) tissues compared with nontumor tissues by using miRNA microarray chip. However, the function of miRNA-21 is unknown in PTC. The aim of this study was to investigate the roles of miRNA-21 in PTC and the mechanism of gene regulation by it. METHODS: We transfected PTC cell line (TPC-1) with pEZX-eGFP-miRNA-21 plasmid to determine the biological functions of miRNA-21. Western blot assay was applied to investigate the correlation between miRNA-21 and programmed cell death 4 (PDCD4) expression in TPC-1 cell line. RESULTS: Overexpression of miRNA-21 could significantly enhance proliferation and invasion and inhibit the apoptosis of TPC-1 cells. In addition, miRNA-21 and PDCD4 expression showed a significantly negative correlation in TPC-1 cells. CONCLUSIONS: These data suggest that miRNA-21 may play an oncogenic role by directly targeting PDCD4 in the cellular processes of PTC. In addition, the findings in our present study also may represent new clues for the diagnostic and therapeutic strategies in the treatment of PTC.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Carcinoma/metabolismo , MicroARNs/fisiología , Proteínas de Unión al ARN/genética , Neoplasias de la Tiroides/metabolismo , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores de Tumor/genética , Carcinoma/genética , Carcinoma/patología , Carcinoma Papilar , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Proteínas de Unión al ARN/biosíntesis , Proteínas de Unión al ARN/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología
11.
Int J Med Sci ; 10(5): 585-92, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23533107

RESUMEN

OBJECTIVE: To elucidate the mechanisms undergoing the pathogenesis of PTC, this study try to find stage specific microRNAs (miRNAs) using microarray chip in stage I, II and III papillary thyroid carcinoma (PTC) tissues as well predict miRNAs binding target genes and their molecular functions. METHODS: PTC specimens of stage I, II, and III and their paired adjacent non-tumor tissue (one patient for each stage) were collected. The expressions of miRNAs were examined using miRNA microarray chip. The most significant changed miRNAs from microarray were verified by using quantitative RT-PCR. The Potential miRNAs regulating target genes and their preliminary biological functions were forecasted with variety function prediction software. RESULTS: Ten miRNAs exhibited sequential up regulation expression profiles and five miRNAs performed sequential down regulation throughout stage I to III (p<0.05). After normalization, Fifteen miRNAs showed significant different compared to adjacent non-tumor tissues (p<0.05). Among of them, the most significant up regulation and down regulation miRNAs were miR-146b-5p and miR-335, respectively. Both of them were verified with qRT-PCR. 34 target genes for miR-146-5p and 36 target genes for miR-335 was predicted. CONCLUSION: MicroRNA profile assay successfully detected a branch of differential expression miRNAs between PTC and normal tissue. Some of them also showed stage specific. Biological function analysis showed that target genes were involved in five aspects including cell proliferation, differentiation, apoptosis, cycle, and signaling transduction pathway, suggesting the regulatory role of abnormal expression of critical miRNAs in the pathogenesis of PTC.


Asunto(s)
Carcinoma/genética , Diferenciación Celular , Proliferación Celular , MicroARNs/biosíntesis , Transducción de Señal/genética , Neoplasias de la Tiroides/genética , Anciano , Apoptosis/genética , Carcinoma/metabolismo , Carcinoma/patología , Carcinoma Papilar , Ciclo Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología
12.
Front Endocrinol (Lausanne) ; 14: 1200855, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37780622

RESUMEN

Background: Whether familial thyroid cancer is more aggressive than sporadic thyroid cancer remains controversial. Additionally, whether the number of affected family members affects the prognosis is unknown. This study focused mainly on the comparison of the clinicopathological characteristics and prognoses between papillary thyroid cancer (PTC) patients with and without family history. Methods: A total of 626 familial papillary thyroid cancer (FPTC) and 1252 sporadic papillary thyroid cancer (SPTC) patients were included in our study. The clinical information associated with FPTC and SPTC was recorded and analyzed by univariate analysis. Results: Patients in the FPTC group had a higher rate of multifocality (p=0.001), bilaterality (p=0.000), extrathyroidal invasion (p=0.000), distant metastasis (p=0.012), lymph node metastasis (p=0.000), recurrence (p=0.000), a larger tumor size (p=0.000) and more malignant lymph nodes involved (central: p=0.000; lateral: p=0.000). In addition, our subgroup analysis showed no significant difference (p>0.05) between patients with only one affected family member and those with two of more group in all clinicopathological characteristics. In papillary thyroid microcarcinoma (PTMC) subgroup analysis, we found that FPTMC patients harbored significantly larger tumors (p=0.000), higher rates of multifocality (p=0.014), bilaterality (p=0.000), distant metastasis (p=0.038), lymph node metastasis (p=0.003), greater numbers of malignant lymph nodes (central: p=0.002; lateral: p=0.044), higher rates of I-131 treatment (p=0.000) and recurrence (p=0.000) than SPTMC patients. Conclusion: Our results indicated that PTC and PTMC patients with a positive family history had more aggressive clinicopathological behaviors, suggesting that more vigilant screening and management for FPTC may be helpful.


Asunto(s)
Radioisótopos de Yodo , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Metástasis Linfática , Relevancia Clínica , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología
13.
Front Immunol ; 14: 1187160, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37854594

RESUMEN

Background: The incidence of thyroid carcinoma (THCA), the most common endocrine tumor, is continuously increasing worldwide. Although the overall prognosis of THCA is good, patients with distant metastases exhibit a mortality rate of 5-20%. Methods: To improve the diagnosis and overall prognosis of patients with thyroid cancer, we screened specific candidate neoantigen genes in early- and late-stage THCA by analyzing the transcriptome and somatic cell mutations in this study. Results: The top five early-stage neoantigen-related genes (NRGs) were G protein-coupled receptor 4 [GPR4], chondroitin sulfate proteoglycan 4 [CSPG4], teneurin transmembrane protein 1 [TENM1], protein S 1 [PROS1], and thymidine kinase 1 [TK1], whereas the top five late-stage NRGs were cadherin 6 [CDH6], semaphorin 6B [SEMA6B], dysferlin [DYSF], xenotropic and polytropic retrovirus receptor 1 [XPR1], and ABR activator of RhoGEF and GTPase [ABR]. Subsequently, we used machine learning models to verify their ability to screen NRGs and analyze the correlations among NRGs, immune cell types, and immune checkpoint regulators. The use of candidate antigen genes resulted in a better diagnostic model (the area under the curve [AUC] value of the early-stage group [0.979] was higher than that of the late-stage group [0.959]). Then, a prognostic model was constructed to predict NRG survival, and the 1-, 3- and 5-year AUC values were 0.83, 0.87, and 0.86, respectively, which were closely related to different immune cell types. Comparison of the expression trends and mutation frequencies of NRGs in multiple tumors revealed their potential for the development of broad spectrum therapeutic drugs. Conclusion: In conclusion, the candidate NRGs identified in this study could potentially be used as therapeutic targets and diagnostic biomarkers for the development of novel broad spectrum therapeutic agents.


Asunto(s)
Adenocarcinoma , Neoplasias de la Tiroides , Humanos , Exoma , Transcriptoma , Neoplasias de la Tiroides/genética
14.
Front Endocrinol (Lausanne) ; 13: 857057, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35464061

RESUMEN

Background and Purpose: This study aimed to analyze the diagnostic ability of the combination of stimulated thyroglobulin (sTg) and antithyroglobulin antibody (TgAb) in predicting the efficacy and prognosis of radioactive iodine (131I) therapy (RAIT) in patients with differentiated thyroid carcinomas (DTCs) after total thyroidectomy (TT). Methods: This retrospective study comprised 409 DTC patients who underwent 131I treatment following TT in the First Affiliated Hospital of Zhengzhou University from January 2019 to August 2020, and they were followed up to November 2021. Patients were divided into the successful ablation and the unsuccessful ablation group based on the classification of the efficacy of RAIT in the 2015 American Thyroid Association guidelines. The clinical characteristics and the efficacy of the initial RAIT were evaluated. The cutoffs of preablation sTg, sTg/thyroid-stimulating hormone (TSH) ratio, and sTg×TgAb product were calculated to predict the efficacy of RAIT. Univariate and multivariate logistic regression analyses were used to identify the independent risk factors for unsuccessful ablation. Kaplan-Meier curves were used to estimate the prognostic value of sTg×TgAb product affecting progression-free survival (PFS). Results: The cohort consisted of 222 cases in the successful ablation group and 187 cases in the unsuccessful ablation group. Between the two groups, preablation sTg, sTg/TSH ratio, and sTg×TgAb product were significantly higher in the unsuccessful ablation group. The area under the curve (AUC) of the sTg×TgAb product was the highest among the above three factors. The cutoffs for the worse therapeutic effect of the initial RAIT in sTg, sTg/TSH ratio, and sTg×TgAb were >2.99 ng/ml, >0.029 mg/IU, and >34.18, respectively. STg >2.99 ng/ml and sTg×TgAb product >34.18 were independent risk factors for unsuccessful ablation. Patients with sTg×TgAb product >34.18 had shorter PFS than that of patients with sTg×TgAb product ≤34.18. In separate analyses of TgAb-negative and TgAb-positive subgroups, higher sTg×TgAb was both associated with a lower success rate of RAIT and a shorter PFS. Conclusion: STg×TgAb product predicted the efficacy and prognosis of 131I therapy for both TgAb-negative and TgAb-positive DTC patients before the initial 131I treatment following TT. Thus, it can be used as a clinical reference indicator for the surveillance of DTC patients.


Asunto(s)
Adenocarcinoma , Neoplasias de la Tiroides , Adenocarcinoma/tratamiento farmacológico , Autoanticuerpos , Humanos , Radioisótopos de Yodo/uso terapéutico , Pronóstico , Estudios Retrospectivos , Tiroglobulina , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Tirotropina
15.
Front Endocrinol (Lausanne) ; 13: 850457, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35663321

RESUMEN

Purpose: This study aimed to explore a visual model for predicting the prognosis of patients with parathyroid carcinoma (PC) and analyze related biochemistries in different groups of stage. Methods: The training dataset of 342 patients with PC was obtained from the Surveillance, Epidemiology, and End Results (SEER) database, and the validation dataset included 59 patients from The First Affiliated Hospital of Zhengzhou University. Univariate and multivariate Cox regression analyses were performed to evaluate significant independent prognostic factors. Based on those factors, nomograms and Web-based probability calculators were constructed to evaluate the overall survival (OS) and the cancer-specific survival (CSS) at 3, 5, and 8 years. The concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram in the training set and validation set. Moreover, biochemistries from the validation set were retrospectively analyzed in different groups of stage by Kruskal-Wallis test. Results: Age, marital status, tumor size, stage, lymph node status, and radiation were identified as prognostic factors of OS. In contrast, only tumor size and stage were predictive for CSS. The nomogram was developed based on these independent factors. The C-index, ROC curve, calibration curve, and DCA of the nomogram in both training and validation sets showed that the nomogram had good predictive value, stability, and clinical benefit in predicting 3-, 5-, and 8-year OS and CSS in PC patients. Among the 59 PC patients from our hospital, lower albumin (ALB) levels and higher postoperative parathyroid hormone (PTH) levels were found in patients with distant metastasis (Distant vs. Regional ALB levels: p = 0.037; Distant vs. Local ALB levels: p = 0.046; Distant vs. Regional postoperative PTH levels: p = 0.002; Distant vs. Local postoperative PTH: p = 0.002). Conclusion: The established nomogram application can provide accurate prognostics for patients with PC in the Chinese population, but it must be validated on prospectively collected real-world data.


Asunto(s)
Nomogramas , Neoplasias de las Paratiroides , Humanos , Estadificación de Neoplasias , Estudios Retrospectivos , Programa de VERF , Tasa de Supervivencia
16.
Front Endocrinol (Lausanne) ; 13: 1062571, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36605945

RESUMEN

Purpose: To create an ultrasound -based deep learning radiomics nomogram (DLRN) for preoperatively predicting the presence of RET rearrangement among patients with papillary thyroid carcinoma (PTC). Methods: We retrospectively enrolled 650 patients with PTC. Patients were divided into the RET/PTC rearrangement group (n = 103) and the non-RET/PTC rearrangement group (n = 547). Radiomics features were extracted based on hand-crafted features from the ultrasound images, and deep learning networks were used to extract deep transfer learning features. The least absolute shrinkage and selection operator regression was applied to select the features of nonzero coefficients from radiomics and deep transfer learning features; then, we established the deep learning radiomics signature. DLRN was constructed using a logistic regression algorithm by combining clinical and deep learning radiomics signatures. The prediction performance was evaluated using the receiver operating characteristic curve, calibration curve, and decision curve analysis. Results: Comparing the effectiveness of the models by linking the area under the receiver operating characteristic curve of each model, we found that the area under the curve of DLRN could reach 0.9545 (95% confidence interval: 0.9133-0.9558) in the test cohort and 0.9396 (95% confidence interval: 0.9185-0.9607) in the training cohort, indicating that the model has an excellent performance in predicting RET rearrangement in PTC. The decision curve analysis demonstrated that the combined model was clinically useful. Conclusion: The novel ultrasonic-based DLRN has an important clinical value for predicting RET rearrangement in PTC. It can provide physicians with a preoperative non-invasive primary screening method for RET rearrangement diagnosis, thus facilitating targeted patients with purposeful molecular sequencing to avoid unnecessary medical investment and improve treatment outcomes.


Asunto(s)
Aprendizaje Profundo , Neoplasias de la Tiroides , Humanos , Nomogramas , Cáncer Papilar Tiroideo/diagnóstico por imagen , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/cirugía , Estudios Retrospectivos , Aberraciones Cromosómicas , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Proteínas Proto-Oncogénicas c-ret
17.
Front Oncol ; 12: 872033, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35463310

RESUMEN

Purpose: Long noncoding RNAs (LncRNAs) play complex but important roles in the progression of various tumors. This study aimed to elucidate the functional mechanisms of the HLA complex group 11 (HCG11) in nasopharyngeal carcinoma (NPC). Patients and Methods: HCG11 levels in NPC specimens were determined by fluorescence in situ hybridization (FISH) and qPCR. Proliferation, apoptosis, and metastasis of NPC cells were determined using CCK8, colony formation, annexin V-PI, and transwell assays. A murine tumor xenograft model was used to investigate the regulatory function of HCG11 in NPC in vivo, and immunohistochemical staining was used to determine the Ki-67 level in tumors. The target relationships between HCG11, microRNA miR-490-3p, and MAPK kinase kinase 9 (MAP3K9) were detected using bioinformatics, qPCR, western blotting, and luciferase reporter assays. Results: HCG11 was highly expressed in NPC tissues and was positively associated with tumor stage, lymphatic metastasis, and poor prognosis. Functionally, HCG11 knockdown inhibited proliferation and migration and induced apoptosis of NPC cells. Mechanistically, miR-490-3p is a direct target of HCG11, oncogenic functions of HCG11 in NPC cell proliferation and migration can be partially reversed by the miR-490-3p inhibitor. HCG11 significantly increased mitogen-activated protein kinase MAPK kinase 9 (MAP3K9) levels by inhibiting miR-490-3p. Conclusion: HCG11 facilitates NPC progression via MAP3K9 signaling by sponging miRNA-490-3p, which may contribute to new prognostic markers and promising therapeutic targets.

18.
Cell Death Dis ; 13(2): 157, 2022 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-35173149

RESUMEN

Papillary thyroidal carcinoma (PTC) is a common endocrine cancer that plagues people across the world. The potential roles of long non-coding RNAs (lncRNAs) in PTC have gained increasing attention. In this study, we aimed to explore whether lncRNA ROR affects the progression of PTC, with the involvement of tescalcin (TESC)/aldehyde dehydrogenase isoform 1A1 (ALDH1A1)/ßIII-tubulin (TUBB3)/tensin homolog (PTEN) axis. PTC tumor and adjacent tissues were obtained, followed by measurement of lncRNA ROR and TESC, ALDH1A1, and TUBB3 expression. Interactions among lncRNA ROR, TESC, ALDH1A1, TUBB3, and PTEN were evaluated by ChIP assay, RT-qPCR, or western blot analysis. After ectopic expression and depletion experiments in PTC cells, MTT and colony formation assay, Transwell assay, and flow cytometry were performed to detect cell viability and colony formation, cell migration and invasion, and apoptosis, respectively. In addition, xenograft in nude mice was performed to test the effects of lncRNA ROR and PTEN on tumor growth in PTC in vivo. LncRNA ROR, TESC, ALDH1A1, and TUBB3 were highly expressed in PTC tissues and cells. Overexpression of lncRNA ROR activated TESC by inhibiting the G9a recruitment on the promoter of TESC and histone H3-lysine 9me methylation. Moreover, TESC upregulated ALDH1A1 expression to increase TUBB3 expression, which then reduced PTEN expression. Overexpression of lncRNA ROR, TESC, ALDH1A1 or TUBB3 and silencing of PTEN promoted PTC cell viability, colony formation, migration, and invasion while suppressing apoptosis. Moreover, overexpression of lncRNA ROR increased tumor growth by inhibiting PTEN in vivo. Taken together, the current study demonstrated that lncRNA ROR mediated TESC/ALDH1A1/TUBB3/PTEN axis, thereby facilitating the development of PTC.


Asunto(s)
ARN Largo no Codificante , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Familia de Aldehído Deshidrogenasa 1/genética , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Ratones Desnudos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , ARN Largo no Codificante/genética , Retinal-Deshidrogenasa/genética , Retinal-Deshidrogenasa/metabolismo , Cáncer Papilar Tiroideo/metabolismo , Neoplasias de la Tiroides/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
20.
Hum Cell ; 34(2): 457-467, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33098545

RESUMEN

Forkhead box (FOX) proteins have been identified as key transcription factors in diverse biological processes involved in tumor progression. A large number of FOX proteins are implicated in tumorigenesis of papillary thyroid carcinoma (PTC). Here we investigated the role of Forkhead box K1 (FOXK1) in PTC progression. First, we found that FOXK1 was elevated in both PTC tissues (N = 68) and cell lines. Moreover, up-regulated FOXK1 was associated with shorter overall survival of PTC patients. Second, in vitro functional assays showed that FOXK1 promoted progression of PTC. Mechanistically, FOXK1 could bind to the promoter of cysteine-rich angiogenic inducer 61 (CYR61) and regulate connective tissue growth factor (CTGF) expression through CYR61. Notably, over-expression of CTGF weakened suppression of PTC progression induced by FOXK1 knockdown. Finally, in vivo xenotransplant tumor model indicated that knockdown of FOXK1 suppressed PTC growth. In conclusion, our results indicate that FOXK1 exerts oncogenic roles in PTC via CYR61/CTGF axis, which suggests FOXK1 might act as a potential therapeutic target.


Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factores de Transcripción Forkhead/fisiología , Regulación Neoplásica de la Expresión Génica/genética , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Línea Celular , Proteína 61 Rica en Cisteína/metabolismo , Progresión de la Enfermedad , Factores de Transcripción Forkhead/metabolismo , Humanos , Terapia Molecular Dirigida , Unión Proteica/genética
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