MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

Increased serum interleukin-37 (IL-37) levels correlate with oxidative stress parameters in Hashimoto's thyroiditis.

PURPOSE: Interleukin-37 (IL-37), member of the IL-1 family, is a natural suppressor of immune and inflammatory responses. Increased serum IL-37 levels were observed in several autoimmune diseases, including Graves' disease. To our knowledge, no data on Hashimoto's thyroiditis (HT) are available in the literature. METHODS: Aim of our study was to measure serum IL-37 levels and evaluate their relationship, if any, with oxidative stress markers in HT patients. We enrolled 45 euthyroid HT patients (5 M e 40 F, median age 40 years) and 50 age- and sex-matched healthy controls. None was under L-thyroxine therapy. Serum IL-37 levels were measured by ELISA. Specific serum tests, such as derived reactive oxygen metabolites (d-ROMs), and biological anti-oxidant potential (BAP) test were performed in all subjects to investigate the changes in oxidative balance, and advanced glycation end products (AGEs) were determined as a specific marker of oxidative stress. RESULTS: IL-37 levels were significantly higher in HT than in controls (median 475 vs. 268 pg/ml, P = 0.018). In the same patients, serum oxidants (d-ROMs) were increased and anti-oxidants (BAP) decreased compared with controls (P = 0.011 and < 0.0001, respectively), clearly indicating an enhanced oxidative stress. In addition, AGEs levels were higher in HT patients than in controls (210 vs. 140 AU/g prot, P < 0.0001) and directly correlated with IL-37 levels (P = 0.048). At multivariate analysis, the main independent predictors that influenced IL-37 levels were both anti-thyroid antibodies (P = 0.026) and AGEs levels (P = 0.001). CONCLUSIONS: IL-37 is up-regulated in HT and may exert a protective role by counteracting oxidative stress and inflammation.

Serum interleukin-6 levels are increased in HIV-infected patients that develop autoimmune disease during long-term follow-up.

BACKGROUND: Elevated IL-6 levels have been associated with both autoimmune diseases and treated HIV-seropositive (HIV+) subjects. However, few data on classic and trans-signaling IL-6 in autoimmune thyroid diseases and HIV+ subjects developing autoimmune disorders are currently available. MATERIALS AND METHODS: A total of 102 patients were included in the study. They were subdivided into two groups. Group A consisted in 51 HIV+ patients, who were followed-up for a period of five years in search of possible occurrence of autoimmune diseases. Ten of them, treated with antiretroviral therapy (ART), developed an autoimmune disorder, namely Hashimoto's thyroiditis, and psoriasis. Group B consisted in 51 patients affected by Hashimoto's thyroiditis (HT). Serum levels of the free form of IL-6 were analyzed by ELISA in all patients and for HIV+ patients at the beginning of the follow-up, before initiation of ART. RESULTS: Mean serum levels of IL-6 were similar in Group A and in Group B. In Group B, IL-6 levels showed a 5.8% increase compared with assay minimum detectable dose corresponding to 1% of full serum IL-6 level. However, serum levels of free IL-6 were increased in those HIV+ patients who developed autoimmune disorders (5.8±2.8pg/ml) and in these patients, the highest levels of free IL-6 correlated with age and CD4 cellular counts. CONCLUSIONS: The present study indicates a correlation between serum free IL-6 levels and the occurrence of autoimmune disease in HIV+ population, treated with ART during a long-term follow-up. The increased levels of serum free IL-6 were observed before ART treatment was initiated, indicating that IL-6 measurement in such patients may represent an early predictor of development of autoimmune disease.

TP53 polymorphism may contribute to genetic susceptibility to develop Hashimoto's thyroiditis.

PURPOSE: p53, which is encoded by the tumor suppressor gene TP53, plays a crucial role in the regulation of mechanisms of cell cycle arrest and apoptosis. Some SNPs of TP53, involving a different apoptotic ability of p53, have been associated with increased susceptibility to develop autoimmune diseases as well as cancer. We investigated the genotypic distribution of TP53 exon 4 SNPs in a cohort of Caucasian patients affected by Hashimoto's thyroiditis (HT). METHODS: Peripheral blood for DNA extraction was collected from 109 Caucasian unrelated subjects, 79 HT patients and 30 healthy controls. SNPs analysis was carried out by amplification and sequencing of exon 4 TP53. RESULTS: For the Pro72Arg (rs 1042522) SNP we found these rates in HT patients: 11.4% wild-type C/C (Pro72Pro), 24.0% heterozygous G/C (Pro72Arg), 64.6% homozygous G/G (Arg72Arg). The corresponding rates in healthy controls were 10, 46.7 and 43.3%, respectively. Thus, significantly different were G/C heterozygosity (24.0 vs 46.7 %, p = 0.039) and G/G homozygosity (64.6 vs 43.3%, p = 0.042). These differences were also confirmed when comparing our study population to published Caucasian control groups. The other described SNPs (Pro34Pro rs 11575998, Pro36Pro rs1800370, Pro47Ser rs1800371, and Arg110Leu rs 11540654) were absent or very rare in our study population. CONCLUSIONS: Our preliminary data, the first on a Caucasian population, indicate an increased prevalence of the homozygous genotype Arg/Arg and a decreased prevalence of heterozygous genotype Arg/Pro of rs 1042522 in HT patients compared to controls, suggesting that such SNP may contribute to confer susceptibility to HT.