Function In Thyroid Cancer Research Articles

Knockdown of lncRNA-PANDAR suppresses the proliferation, cell cycle and promotes apoptosis in thyroid cancer cells.

Long non-coding RNAs (lncRNAs) have been found to show important regulatory roles in various human cancers. Lnc-RNA PANDAR is a novel identified lncRNA that was previously reported to show abnormal expression pattern in various cancers. However, little is known of its expression and biological function in thyroid cancer. Here, we used the quantitative real-time PCR (qRT-PCR) to determine the expression of PANDAR in 64 thyroid cancer tissues. We found that expression of PANDAR was up-regulated in thyroid cancer tissues compared with adjacent non-tumor tissues. Functional assays in vitro demonstrated that knockdown of PANDAR could inhibit proliferation, cell cycle progression, induces the apoptosis, inhibit invasion of thyroid cancer cells. Thus, our study provides evidence that PANDAR may function as a potential target for treatment for patients with thyroid cancer.

N-cadherin promotes thyroid tumorigenesis through modulating major signaling pathways.

Epithelial-mesenchymal transition (EMT), a crucial step in disease progression, plays a key role in tumor metastasis. N-cadherin, a well-known EMT marker, acts as a major oncogene in diverse cancers, whereas its functions in thyroid cancer remains largely unclear. This study was designed to explore the biological roles and related molecular mechanism of N-cadherin in thyroid tumorigenesis. Quantitative RT-PCR (qRT-PCR) and immunohistochemistry assays were used to evaluate N-cadherin expression. A series of in vitro studies such as cell proliferation, colony formation, cell cycle, apoptosis, migration and invasion assays were performed to determine the effect of N-cadherin on malignant behavior of thyroid cancer cells. Our results showed that N-cadherin was significantly upregulated in papillary thyroid cancers (PTCs) as compared with non-cancerous thyroid tissues. N-cadherin knockdown markedly inhibited cell proliferation, colony formation, cell migration and invasion, and induced cell cycle arrest and apoptosis. On the other hand, ectopic expression of N-cadherin promoted thyroid cancer cell growth and invasiveness. Mechanically, our data demonstrated that tumor-promoting role of N-cadherin in thyroid cancer was closely related to the activities of the MAPK/Erk, the phosphatidylinositol-3-kinase (PI3K)/Akt and p16/Rb signaling pathways in addition to affecting the EMT process. Altogether, our findings suggest that N-cadherin promotes thyroid tumorigenesis by modulating the activities of major signaling pathways and EMT process, and may represent a potential therapeutic target for this cancer.

Nc886, a non-coding RNA and suppressor of PKR, exerts an oncogenic function in thyroid cancer.

nc886 is a recently identified cellular non-coding RNA and its depletion leads to acute cell death via PKR (Protein Kinase RNA-activated) activation. nc886 expression is increased in some malignancies, but silenced in others. However, the precise role of nc886/PKR is controversial: is it a tumor suppressor or an oncogene? In this study, we have clarified the role of nc886 in thyroid cancer by sequentially generating PKR knockout (KO) and PKR/nc886 double KO cell lines from Nthy-ori 3-1, a partially transformed thyroid cell line. Compared to the wildtype, PKR KO alone does not exhibit any significant phenotypic changes. However, nc886 KO cells are less proliferative, migratory, and invasive than their parental PKR KO cells. Importantly, the requirement of nc886 in tumor phenotypes is totally independent of PKR. In our microarray data, nc886 KO suppresses some genes whose elevated expression is associated with poor survival confirmed by data from total of 505 thyroid cancer patients in the Caner Genome Atlas project. Also, the nc886 expression level tends to be elevated and in more aggressively metastatic tumor specimens from thyroid cancer patients. In summary, we have discovered nc886's tumor-promoting role in thyroid cancer which has been concealed by the PKR-mediated acute cell death.

The Role of STAT3 in Thyroid Cancer

Thyroid cancer is the most common endocrine malignancy and its global incidence rates are rapidly increasing. Although the mortality of thyroid cancer is relatively low, its rate of recurrence or persistence is relatively high, contributing to incurability and morbidity of the disease. Thyroid cancer is mainly treated by surgery and radioiodine remnant ablation, which is effective only for non-metastasized primary tumors. Therefore, better understanding of the molecular targets available in this tumor is necessary. Similarly to many other tumor types, oncogenic molecular alterations in thyroid epithelium include aberrant signal transduction of the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT (also known as protein kinase B), NF-кB, and WNT/β-catenin pathways. However, the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT3) pathway, a well-known mediator of tumorigenesis in different tumor types, is relatively less understood in thyroid cancer. Intriguingly, recent studies have demonstrated that, in thyroid cancer, the JAK/STAT3 pathway may function in the context of tumor suppression rather than promoting tumorigenesis. In this review, we provide an update of STAT3 function in thyroid cancer and discuss some of the evidences that support this hypothesis.

Abstract 3098: MiRNA-145 is a master regulator of the hallmarks of thyroid cancer.

Abstract microRNA-145 (miR-145) in an important member of the family of microRNAs which are downregulated in several types of tumors. However, miR-145 expression and function in thyroid cancer and in cellular differentiation is unknown. In our study, we performed miRNA profiling in normal, benign and malignant thyroid cancers including undifferentiated tumors with validation of differentially expressed miRNAs by quantitative RT PCR. We found significant downregulation of miR-145 in differentiated and undifferentiated thyroid cancer. We performed functional studies in thyroid cancer cell lines and found that miR-145 decreases cell proliferation, induces cell cycle arrest, decreases cell invasion and targets the PI3K/Akt pathway, one of the most commonly activated pathways in thyroid cancer and which is associated with epithelial-mesenchymal transition (EMT). Overexpression of miR-145 in cell lines also decreased the expression of EMT markers vimentin and N-cadherin. Furthermore, inhibition of miR-145 in normal primary thyroid cultured cells decreased NIS and PAX8 expression, key regulators of thyroid cell differentiation. miRNA-145 expression in tumor tissue was inversely correlated with VEGF serum levels in the same patients and overexpression of miR-145 in vitro decreased angiogenesis and VEGF secretion. MiRNA-145 has important regulatory effects on the hallmarks of thyroid cancer cells and thus may be involved in thyroid cancer progression. Citation Format: Myriem Boufraqech, Lisa Zhang, Meenu Jain, Neelam Gulati, Naris Nilubol, Mio Kitano, Yin Xiong, Electron Kebebew. MiRNA-145 is a master regulator of the hallmarks of thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3098. doi:10.1158/1538-7445.AM2013-3098

Abstract 4191: MiR-20a inhibits thyroid cancer cell growth and invasion through LIMK1.

Abstract There have been conflicting reports regarding the function of miR-20a in a variety of cancers. In this study, we evaluated the expression and function of miR-20a in thyroid cancer tissue and cell lines in vitro and in vivo. We found miR-20a was significantly downregulated in undifferentiated and aggressive thyroid cancer (p<0.05). Ectopic overexpression of miR-20a significantly inhibited thyroid cancer cell proliferation in vitro (p < 0.01) and in vivo (p < 0.01), tumor spheroid formation (p < 0.05), and invasion (p < 0.05) in multiple thyroid cancer cell lines. We performed integrated transcriptome analysis with and without miR-20a overexpression and target prediction analysis, and identified LIMK1 as a target of miR-20a. Luciferase assay demonstrated that LIMK1 was a direct target of miR-20a and that direct knockdown of LIMK1 recapitulated the effects of miR-20a in multiple thyroid cancer lines. Our findings suggest that miR-20a has a tumor suppressive function in thyroid cancer which is mediated through LIMK1 and that loss of miR-20a expression may be involved in thyroid cancer progression. Citation Format: Yin Xiong, Lisa Zhang, Electron Kebebew. MiR-20a inhibits thyroid cancer cell growth and invasion through LIMK1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4191. doi:10.1158/1538-7445.AM2013-4191

Expression and function of the novel proto-oncogene PBF in thyroid cancer: a new target for augmenting radioiodine uptake

Pituitary tumor-transforming gene (PTTG)-binding factor (PBF; PTTG1IP) was initially identified through its interaction with the human securin, PTTG. Like PTTG, PBF is upregulated in multiple endocrine tumours including thyroid cancer. PBF is believed to induce the translocation of PTTG into the cell nucleus where it can drive tumourigenesis via a number of different mechanisms. However, an independent transforming ability has been demonstrated both in vitro and in vivo, suggesting that PBF is itself a proto-oncogene. Studied in only a limited number of publications to date, PBF is emerging as a protein with a growing repertoire of roles. Recent data suggest that PBF possesses a complex multifunctionality in an increasing number of tumour settings. For example, PBF is upregulated by oestrogen and mediates oestrogen-stimulated cell invasion in breast cancer cells. In addition to a possible role in the induction of thyroid tumourigenesis, PBF overexpression in thyroid cancers inhibits iodide uptake. PBF has been shown to repress sodium iodide symporter (NIS) activity by transcriptional regulation of NIS expression through the human NIS upstream enhancer and further inhibits iodide uptake via a post-translational mechanism of NIS governing subcellular localisation. This review discusses the current data describing PBF expression and function in thyroid cancer and highlights PBF as a novel target for improving radioiodine uptake and thus prognosis in thyroid cancer.

Pharmacology of bovine and human thyrotropin: an historical perspective.

Before the induction of a brief period of hypothyroidism became the standard method for inducing 131I uptake in thyroid cancer diagnosis and therapy, several other methods were explored and used. At the dawn of this new era of recombinant human thyrotropin (TSH) it is of interest to reflect briefly on some of this work. Partially purified bovine TSH (bTSH) was supplied for many years by the Armour Company as Thytropar for intramuscular injection and was first used in thyroid cancer 50 years ago at the Montefiore Hospital and at the Memorial Sloan Kettering Cancer Center in New York City. Most of the patients were already hypothyroid and bTSH induced further 131I uptake in only a few. Experience over the next 30 years revealed frequent allergic reactions, occasionally serious ones, and in 1961 it was shown that prolonged use could result in resistance to both bTSH and human TSH. bTSH was, therefore, reserved for thyroid cancer patients unable to increase endogenous TSH when hypothyroid. bTSH also was used widely as a test to distinguish between hypothyroidism caused by thyroid or pituitary failure until it was replaced by thyrotropin-releasing hormone (TRH). In a few studies, TRH was also tested as an adjuvant to increase endogenous TSH and thus help to stimulate function in thyroid cancer, but this attracted little interest. Prolonged hypothyroidism, enhanced by antithyroid drugs, was used early on, but this very effective stimulant of thyroid cancer function was, for multiple reasons, discarded. Beginning interest 15 to 25 years ago in obtaining TSH from human pituitary glands, a byproduct of growth hormone production, was interrupted when this product was found to risk development of Creutzfeld-Jakob disease. Recombinant human TSH, a safe and effective substitute, is now ready for widespread use and development in thyroid cancer management.

Impaired cell-mediated immunity function in thyroid cancer.

Immunological parameters were studied in 31 patients with thyroid cancer. Serum immunoglobulin levels, T and B cell percentages in peripheral blood, showed no significant difference as compared with those of control group. The blastogenesis with phytohemagglutinin P (PHA) was significantly reduced, especially, in those having larger tumor size or metastasis or in those over age 60. The positive rate of skin test with purified-protein-derivative (PPD) and Streptokinase-Streptodornase (SK-SD) was also markedly reduced. The impaired blastogenesis of lymphocyte and reduced positive rate of skin test in those cancer patients suggested that the cell-mediated immunity function, in spite of adequate count of T-cells, was impaired.