Radiation-induced senescence and thyroid cancer: a barrier or a driving force = Senescência e câncer de tiróide induzido por radiação: uma barreira ou uma força motriz

Objetivos: O principal objetivo deste artigo de revisão foi lançar luz sobre o impacto da senescência na carcinogênese da tiroide, um campo promissor, mas ainda negligenciado. Fonte dos dados: pesquisa nos bancos de dados PubMed e Google Scholar realizada para artigos em inglês com os termos: exposição à radiação ionizante, câncer de tireoide, radiação assinatura, RET/PTC, senescência e senescência induzida por radiação. Não houve restrições quanto a data. Resumo das constatações: radiação ionizante (IR) é, sem dúvida, o fator de risco mais bem caracterizado para o câncer de tireoide de histotipo papilar e seu papel central como indutor de senescência tem sido proposto. Um papel paradoxal da senescência na carcinogênese – uma barreira a proliferação celular cancerígena em etapas precoces e uma força motriz para a progressão do câncer através de secreção de citocinas pró-inflamatórias e enzimas matriz degradantes – é o foco principal sobre o câncer relacionado à idade e trazem à vida novos insights para a investigação do câncer de tiroide. Este artigo de revisão mostra brevemente as principais conclusões que apontam a radiação ionizante à carcinogênese de tireoide, destacando as alterações moleculares mediadas pela exposição aguda e crônica à radiação em células da tireoide. Conclusões: Evidências fornecidas por nosso grupo e outros poucos relatos sugerem que, tal como outros estímulos oncogênicos em diferentes tipos de células, IR induz um fenótipo senescente em células da tireoide, o que poderia representar uma barreira inicial a transformação. No entanto, como a senescência poderia contribuir para a progressão do tumor ainda permanece indefinida. A compreensão destes mecanismos não só poderia ajudar a elucidar a iniciação e progressão do câncer de tireoide, mas também pode indicar novos alvos terapêutico

Ionizing Radiation deregulates the microRNA expression profile in differentiated thyroid cells

Ionizing Radiation (IR) is a well-known risk factor for papillary thyroid cancer, and it has been reported to deregulate microRNA expression, which is important to thyroid carcinogenesis. Therefore, we have investigated the impact of IR on microRNA expression profile of the normal thyroid cell line (FRTL-5 CL2) and as well as its effect on radiosensitivity of thyroid cancer cell lines, especially the human anaplastic thyroid carcinoma cell line (8505c)

HMGA1-Regulating microRNAs Let-7a and miR-26a are Downregulated in Human Seminomas

Background: Recent studies have underlined HMGA protein’s key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the HMGA1 transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a—two HMGA1-targeting microRNAs. Methods: HMGA1 mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities. Results: an inverse correlation was found between the expression of miR-26a and Let-7a and HMGA1 expression levels in seminomas samples, suggesting a critical role of these microRNAs in HMGA1 levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2. Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is—at least in part—due to the downregulation of HMGA1-targeting microRNAs

The Long Non-Coding RNA RP5-1024C24.1 and Its Associated-Gene MPPED2 Are Down-Regulated in Human Thyroid Neoplasias and Act as Tumour Suppressors

Background: Well-differentiated papillary thyroid carcinoma (PTC) represents the thyroid neoplasia with the highest incidence. Long non-coding RNAs (lncRNAs) have been found deregulated in several human carcinomas, and hence, proposed as potential diagnostic and prognostic markers. Therefore, the aim of our study was to investigate their role in thyroid carcinogenesis. Methods: We analysed the lncRNA expression profile of 12 PTC and four normal thyroid tissues through a lncRNA microarray. Results: We identified 669 up- and 2470 down-regulated lncRNAs with a fold change >2. Among them, we focused on the down-regulated RP5-1024C24.1 located in an antisense position with respect to the MPPED2 gene which codes for a metallophosphoesterase with tumour suppressor activity. Both these genes are down-regulated in benign and malignant thyroid neoplasias. The restoration of RP5-1024C24.1 expression in thyroid carcinoma cell lines reduced cell proliferation and migration by modulating the PTEN/Akt pathway. Inhibition of thyroid carcinoma cell growth and cell migration ability was also achieved by the MPPED2 restoration. Interestingly, RP5-1024C24.1 over-expression is able to increase MPPED2 expression. Conclusions: Taken together, these results demonstrate that RP5-1024C24.1 and MPPED2 might be considered as novel tumour suppressor genes whose loss of expression contributes to thyroid carcinogenesis

NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells

Abstract Background NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer. Methods The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990–1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3). Results NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter. Conclusions In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis

Intrinsic LINE-1 Hypomethylation and Decreased Brca1 Expression are Associated with DNA Repair Delay in Irradiated Thyroid Cells

Exposure to ionizing radiation greatly increases the risk of developing papillary thyroid carcinoma (PTC), especially during childhood, mainly due to gradual inactivation of DNA repair genes and DNA damages. Recent molecular characterization of PTC revealed DNA methylation deregulation of several promoters of DNA repair genes. Thus, epigenetic silencing might be a plausible mechanism for the activity loss of tumor suppressor genes in radiation-induced thyroid tumors. Herein, we investigated the impact of ionizing radiation on global methylation and CpG islands within promoter regions of homologous recombination (HR) and non-homologous end joining (NHEJ) genes, as well as its effects on gene expression, using two well-established normal differentiated thyroid cell lines (FRTL5 and PCCL3). Our data reveal that X-ray exposure promoted G(2)/M arrest in normal thyroid cell lines. The FRTL5 cells displayed a slower kinetics of double-strand breaks (DSB) repair and a lower long interspersed nuclear element-1 (LINE-1) methylation than the PCCL3 cells. Nevertheless, acute X-ray exposure does not alter the expression of genes involved in HR and NHEJ pathways, apart from the downregulation of Brca1 in thyroid cells. On the other hand, HR and NHEJ gene expressions were upregulated in radiation-induced senescent thyroid cells. Taken together, these data suggest that FRTL5 cells intrinsically have less efficient DNA DSB repair machinery than PCCL3 cells, as well as genomic instability, which could predispose the FRTL5 cells to unrepaired DSB lesions and, therefore, gene mutation

Genetically proxied impaired GIPR signaling and risk of 6 cancers

Summary: Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention

Role of <i>Dicer1</i> in thyroid cell proliferation and differentiation

<p><i>DICER1</i> plays a central role in the biogenesis of microRNAs and it is important for normal development. Altered microRNA expression and <i>DICER1</i> dysregulation have been described in several types of tumors, including thyroid carcinomas. Recently, our group identified a new somatic mutation (c.5438A>G; E1813G) within <i>DICER1</i> gene of an unknown function. Herein, we show that <i>DICER1</i> is overexpressed, at mRNA level, in a significant-relative number of papillary (70%) and anaplastic (42%) thyroid carcinoma samples, whereas is drastically downregulated in all the analyzed human thyroid carcinoma cell lines (TPC-1, BCPAP, FRO and 8505c) in comparison with normal thyroid tissue samples. Conversely, <i>DICER1</i> is downregulated, at protein level, in PTC in comparison with normal thyroid tissues. Our data also reveals that <i>DICER1</i> overexpression positively regulates thyroid cell proliferation, whereas its silencing impairs thyroid cell differentiation. The expression of <i>DICER1</i> gene mutation (c.5438A>G; E1813G) negatively affects the microRNA machinery and cell proliferation as well as upregulates <i>DICER1</i> protein levels of thyroid cells but has no impact on thyroid differentiation. In conclusion, <i>DICER1</i> protein is downregulated in papillary thyroid carcinomas and affects thyroid proliferation and differentiation, while <i>DICER1</i> gene mutation (c.5438A>G; E1813G) compromises the <i>DICER1</i> wild-type-mediated microRNA processing and cell proliferation.</p