cyclin-d1 and Thymus-Neoplasms

Thymic epithelial tumors are the most common adult mediastinal tumors; however, their growth mechanism remains relatively unknown. Among the JAK/STAT pathway-related proteins, which control various intracellular events, STAT3 is deeply involved in cell proliferation. Constitutive activation of STAT3 and the resulting overexpression of cyclin D1 have been confirmed in various tumors, but have not been thoroughly investigated in thymic epithelial tumors. In this study, we immunohistochemically examined STAT3 activation, cyclin D1 expression, and JAK3 activation in thymic epithelial tumors and statistically analyzed their correlation with clinicopathological features.. Formalin-fixed paraffin-embedded specimens of 94 thymic epithelial tumors surgically resected at Kyorin University Hospital between 2005 and 2018 were included in this study. pSTAT3, cyclin D1, and pJAK3 were immunohistochemically examined, and the correlation with histology, Masaoka stage, and survival time was statistically analyzed.. Cyclin D1 was found to be significantly overexpressed in the STAT3-activated group. This phenomenon was associated with histology and Masaoka stage. JAK3 was also activated in thymic epithelial tumors; however, JAK3 and STAT3 activation were not always correlated. Using survival time analysis, the STAT3-activated group, cyclin D1-expressed group, and JAK3-activated group had significantly lower progression-free survival times than those for both the non-activated and non-expressed groups.. STAT3 activation may promote cyclin D1 overexpression in thymic epithelial tumors, and intracellular signaling pathways other than JAK3 may be involved in STAT3 activation. STAT3 activation, cyclin D1 overexpression, and JAK3 activation are biomarker candidates that indicate clinically poor prognosis.

Topics: Cyclin D1; Humans; Janus Kinase 3; Neoplasms, Glandular and Epithelial; STAT3 Transcription Factor; Thymus Neoplasms

Lysosome-associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2) are implicated in a variety of normal and pathological processes. LAMP-2 is proposed to participate in chaperone-mediated autophagy.Autophagy regulates T-lymphocyte homeostasis by promoting both survival and proliferation. The biological importance of this process in the thymic gland and especially the involvement of LAMPs are far from being elucidated. The aim of the study was to examine the parallel expression of LAMPs and ubiquitin, a key molecule in autophagy, in normal human thymic glands and thymomas. The immunohistochemical expression of both markers was compared with that of cyclin D1--an important regulator of cell cycle progression. Novel evidence for differential expression of LAMPs and ubiquitin is presented. Most Hassal's corpuscules in thymoma were negative for LAMPs, but positive in normal thymus.Both lymphocytes and epithelial cells in pathological thymus showed higher intensity for LAMP-2 compared with LAMP-1. In thymoma, ubiquitin was more intensively positive in these cell types compared with the normal thymus, suggesting activated autophagy in the course of this pathological state. A deregulation in cyclin D1 expression in thymoma is also reported. The functional importance of these molecules in autophagy accompanying normal and pathological processes in the thymic gland is reviewed.

Topics: Child; Child, Preschool; Cyclin D1; Humans; Immunohistochemistry; Infant; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Thymoma; Thymus Gland; Thymus Neoplasms; Ubiquitin

Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antibiotics, Antineoplastic; Ataxia Telangiectasia Mutated Proteins; Carrier Proteins; Cell Cycle Proteins; Cyclin D1; DNA Replication; DNA-Binding Proteins; Eukaryotic Initiation Factors; Lymphoma; Mice; Mice, Knockout; Phosphoproteins; Phosphotransferases (Alcohol Group Acceptor); Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; Thymus Neoplasms; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

There have been few reports on genetic alterations in thymomas. To investigate the expression of p16INK4A, RB, p53 and cyclin D1 in thymomas, we first examined 36 thymomas (non-invasive type, 16 cases; invasive type, 20 cases) and 3 thymic carcinomas, using immunohistochemistry. Abnormal expression of p16INK4A, RB, p53 and cyclin D1 was observed in 18, 8, 10 and 7 cases, respectively. Only a subgroup of invasive thymomas and thymic carcinomas showed an inverse correlation between p16INK4A and RB expression. Subsequently, we examined the 36 thymomas and 4 thymic carcinomas for mutations in p53 and CDKN2 genes, using PCR-SSCP and direct-sequencing analyses. No mutation of these genes was detected in the thymomas and thymic carcinomas examined. A polymorphism in the 3' untranslated region of exon 3 of CDKN2 was detected in 5 cases of thymoma. We searched for hypermethylation in the promoter region of CDKN2, observing it in 4 thymomas and 1 thymic carcinoma. Our data suggest that, unlike other more common cancers, alteration of the p53 gene may not play a significant role in the tumorigenesis of thymoma. However, inactivation of p16INK4A and RB may play a role in the progression of thymoma and thymic carcinoma.

Topics: Blotting, Southern; Carcinoma; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; DNA Mutational Analysis; DNA Primers; DNA-Binding Proteins; DNA, Neoplasm; Genes, p16; Genes, p53; Humans; Immunohistochemistry; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Retinoblastoma Protein; Thymoma; Thymus Neoplasms; Tumor Suppressor Protein p53