There have been conflicting reports regarding the function of miR-20a in a variety of cancer types and we previously found it to be dysregulated in sporadic versus familial papillary thyroid cancer. ...In this study, we studied the expression of miR-20a in normal, benign and malignant thyroid samples, and its effect on thyroid cancer cells in vitro and in vivo.
The expression of miR-20a in normal, benign and malignant thyroid tissue was determined by quantitative RT-PCR. Thyroid cancer cells were transfected with miR-20a and the effect on cellular proliferation, tumor spheroid formation, and invasion was evaluated. Target genes of miR-20 were determined by genome-wide mRNA expression analysis with miR-20a overexpression in thyroid cancer cells and target prediction database. Target genes were validated by quantitative PCR and immunoblotting, and luciferase assays. MiR-20a expression was significantly higher in anaplastic thyroid cancer than in differentiated thyroid cancer, and benign and normal thyroid tissues. 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 found that LIMK1 was a target of miR-20a in thyroid cancer cell lines and direct knockdown of LIMK1 recapitulated the effect of miR-20a in thyroid cancer cells.
To our knowledge, this is the first study to demonstrate that miR-20a plays a role as a tumor suppressor in thyroid cancer cells and targets LIMK1. Our findings suggest the upregulated expression of miR-20a in anaplastic thyroid cancer counteracts thyroid cancer progression and may have therapeutic potential.
Opinion statement
Anaplastic thyroid cancer (ATC) is a rare but very aggressive form of undifferentiated thyroid cancer. Due to its rapid rate of progression and invasive nature, ATC poses ...significant risks of morbidity and mortality. The cornerstone in the management of ATC remains a prompt diagnosis of the disease and timely management of complications depending on the stage of disease. Surgery continues to offer a higher chance of a cure, although not all patients are candidates for surgical management. Patients with advanced disease may be considered for palliative surgery to reduce morbidity and complications from advanced disease. With the advent of new molecular testing and improved methods of diagnosis, novel therapeutic targets have been identified. Systemic therapy (chemotherapy and radiation therapy) as well as novel immunotherapy have shown some promise in patients with targetable genetic mutations. Patients should therefore have molecular testing of their tumor—if it is unresectable—and be tested for mutations that are targetable. Mutation-targeted therapy may be effective and may result in a significant response to allow surgical intervention for exceptional responders. Overall, patients who receive all three modalities of therapy (surgery, chemotherapy, and radiation therapy) have the highest overall survival.
Cancer gender disparity in incidence, disease aggressiveness and prognosis has been observed in a variety of cancers. Thyroid cancer is one of the fastest growing cancer diagnoses worldwide. It is ...2.9-times more common in women than men. The less aggressive histologic subtypes of thyroid cancer are more common in women, whereas the more aggressive histologic subtypes have similar gender distribution. The gender disparity in incidence, aggressiveness and prognosis is well established for thyroid cancer but the cause of the disparity is poorly understood. The aim of this article is to evaluate the current evidence on the cause of thyroid cancer gender disparity. Dietary and environmental factors do not appear to have a significant role in thyroid cancer gender disparity. Common somatic mutations in BRAF, rearranged in transformation/papillary thyroid carcinomas (RET/PTC) and neurotrophin receptor-tyrosine kinase (NTRK) also do not account for the gender disparity in thyroid cancer. While reproductive factors would seem a logical hypothesis to account for the gender disparity, there appears to be no conclusive effect on the risk of developing thyroid cancer. Recent studies on estrogen receptor status in thyroid cancer show a difference in the receptor subtypes expressed based on the histology of thyroid cancer. Moreover, the response to estrogen is dependent on the specific estrogen receptor expressed in thyroid cancer cells. However, what determines the tumor-specific sex hormone receptor expression is unclear. No established molecular factors appear to explain gender differences in thyroid cancer. Therefore, the application of high-throughput genomic and proteomic approaches to the study of thyroid cancer gender disparity could be helpful for better understanding the molecular basis for gender differences in thyroid and other cancers.
Through diagnostic imaging and peptide receptor radionuclide therapy, nuclear medicine has earned a major role in gastroenteropancreatic neuroendocrine tumors (GEP NETs). GEP NETs are diagnosed ...fortuitously or on the basis of symptoms or hormonal syndrome. The functional tumor characteristics shown by radionuclide imaging allow for more accurate staging and treatment selection. Tumor grade helps determine which tracer should be selected. In the past,
In-pentetreotide has been successful in well-differentiated (G1 and G2) tumors. However, PET/CT imaging with novel somatostatin analogs (e.g.,
Ga-DOTATOC,
Ga-DOTATATE,
Ga-DOTANOC, and
Cu-DOTATATE) now offers improved sensitivity.
F-fluorodihydroxyphenylalanine (
F-FDOPA) is another interesting radiopharmaceutical.
F-FDOPA sensitivity is influenced by a tumor's capacity to take up, decarboxylate, and store amine precursors.
F-FDOPA sensitivities are highest in ileal NETs and may also be helpful in insulinomas. A high uptake of
F-FDG with a low uptake of somatostatin analog usually indicates poorly differentiated tumors (G3). Starting from these principles, this article discusses theranostic approaches to GEP NETs, taking into account both primary and metastatic lesions.
Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is ...molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37-57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.
There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer-related deaths. Driver ...mutations in the
and
pathways are common in ATC and PDTC. Histone deacetylases (HDAC) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent and to evaluate biomarkers of treatment response.
CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its antiproliferative effect
and
CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G
-M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase-3/7 activity and decreased survivin levels and decreased cellular migration and invasion. CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Finally, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.
Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer.
.
Patients with succinate dehydrogenase subunit B(SDHB) mutation-related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current ...therapeutic approaches are limited, but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of (68)Ga-DOTA(0)-Tyr(3)-octreotate ((68)Ga-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities (18)F-fluorodopamine ((18)F-FDA), (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA), (18)F-fluoro-2-deoxy-d-glucose ((18)F- FDG) PET/CT as well as CT/MRI.
(68)Ga-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent (18)F-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving (18)F-FDOPA and (18)F-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator.
(68)Ga-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% 95% confidence interval (CI), 96.5%-99.5%, (18)F-FDG, (18)F-FDOPA, (18)F-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI, 81.3%-89.4%; P < 0.01), 61.4% (CI, 55.6%-66.9%; P < 0.01), 51.9% (CI, 46.1%-57.7%; P < 0.01), and 84.8% (CI, 80.0%-88.5%; P < 0.01), respectively.
(68)Ga-DOTATATE PET/CT showed a significantly superior detection rate to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL.
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