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We describe three cases of primary mediastinal seminoma, a rare neoplasm histologically similar to the testicular form, which mainly affects men between 30-60 yrs of age. Case No. 1--a 45 year old patient was treated with a combination of radiotherapy and chemotherapy. Twenty six months after the diagnosis, the patient shows a limited residual lesion, a good general health status and was asymptomatic. Case No. 2--a 56 year old patient was admitted for suspected epithelial lung cancer, with subsequent histological diagnosis of seminoma on surgical sample. The exeresis of the lesion was followed by radiotherapy and chemotherapy, the latter interrupted owing to the onset of thrombotic complications resulting in the patient's death. Case No. 3--a 35 year old patient was subjected to diagnostic and therapeutic thoracotomy, with diagnosis of primary mediastinal seminoma. The surgical therapy was followed by a cycle of radiotherapy. Five years later, the general health of the patient is good and he is still asymptomatic. In the discussion we consider the embryogenesis, clinical picture, radiological and anatomicopathological aspects, typical biomarkers of cancer, diagnostic procedures and therapeutic protocols currently followed.
A case of metastatic seminoma to the ureter is presented. The metastasis formed a polypoid intraluminal mass that led to complete obstruction of the ureter, leading to advanced hydronephrosis of the kidney. This is the second case in the world literature of a primary testicular tumor metastasizing to the ureter.
A 7-year-old stallion with progressive left testicular enlargement was presented. Grossly, the excised testicle measured 25 × 15 × 12 cm and weighed 3.7 kg. It was multinodular with a gray-white surface; however, the right testis was normal. Histologically, the neoplastic cells were disseminated diffusely in the tumoral stroma with a minimal fibrovascular stroma. Neoplastic cells were round to polygonal with abundant eosinophilic cytoplasm and large round to oval vesicular or hyperchromatic nucleous with a single prominent nucleolus. Immunohistochemically, the neoplastic cells were positive nuclear immunostaining for C-KIT and negative for OCT3/4. According to gross, histopathological, and immunohistochemical characteristics, the diffuse type of seminoma was diagnosed. Nine months later, the follow-up observation of the case showed that the tumor had no recurrence and metastasis.
Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TF-gene/miRNA and miRNA-gene/TF pairs with regulation direction. Subsequently, we determined 288 and 664 dysregulated TF-miRNA-gene FFLs in SE and NSE, respectively. By constructing dysregulated FFL networks, we found that many hub nodes (12 out of 30 for SE and 8 out of 32 for NSE) in the top ranked FFLs could predict subtype-classification (Random Forest classifier, average accuracy ≥90%). These hub molecules were validated by an independent dataset. Our network analysis pinpointed several SE-specific dysregulated miRNAs (miR-200c-3p, miR-25-3p, and miR-302a-3p) and genes (EPHA2, JUN, KLF4, PLXDC2, RND3, SPI1, and TIMP3) and NSE-specific dysregulated miRNAs (miR-367-3p, miR-519d-3p, and miR-96-5p) and genes (NR2F1 and NR2F2). This study is the first systematic investigation of TF and miRNA regulation and their co-regulation in two major TGCT subtypes.
Several studies have demonstrated that the p75NTR low-affinity receptor of Nerve Growth Factor (NGF), is produced in abnormally large amounts in several human cancer types. However, the role of p75NTR varies substantially depending on cell context, so that a dual role of this receptor protein in tumor cell survival and invasion, as well as cell death, has been supported in recent studies. Herein we explored for the first time the expression of p75NTR in human specimens (nr = 40) from testicular germ cell tumors (TGCTs), mostly seminomas. Nuclear overexpression of p75NTR was detected by immunohistochemistry in seminoma tissue as compared to normal tissue, whereas neither NGF nor its high-affinity TrkA receptor was detected. An increased nuclear staining of phospho-JNK, belonging to the p75NTR signaling pathway and its pro-apoptotic target gene, p53, was concomitantly observed. Interestingly, our analysis revealed that decreased expression frequency of p75NTR, p-JNK and p53 was related to staging progression, thus suggesting that p75NTR may represent a specific marker for seminoma and staging in TGCTs.
A characteristic feature of testicular seminoma is the abundance of immune cells in the tumor microenvironment, raising the possibility that immune checkpoint inhibitors may serve as a therapeutic option in these types of tumors. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor in analogy to PD-1, and drugs targeting TIGIT are currently being investigated in clinical trials. Little is known about the expression of these proteins in testicular seminomas. Therefore the present study performed immunohistochemical analysis to determine the relative abundance of TIGIT and PD-1 in relation to the total CD3+ immune cell infiltration in a tissue microarray (TMA) constructed from 78 seminoma patients. The fraction of TIGIT+ and PD-1+ lymphocytes was highly variable in individual cancers and ranged from 2.3 to 69.4% (mean: 32.2±14.7%) for TIGIT and from 0.8 to 56.5% (mean: 21.6±13.2%) for PD-1. The same high degree of variability was also identified for the ratio of PD-1 to TIGIT positive cells, which varied from a dominance of TIGIT (PD-1: TIGIT ratio=0.02) in 74% of patients, to a predominance of PD-1 (PD-1: TIGIT ratio=12.5) in 23% of patients. In summary, the immune checkpoint receptors TIGIT and PD-1 are abundantly expressed in human seminomas. Once available, anti-TIGIT antibodies, possibly in combination with anti-PD-1 drugs, may be a reasonable therapeutic strategy for this type of cancer.
Background: Seminoma accounts for the most part of cases of testicular germ cell tumor, which is the most common malignancy among males between ages 15 and 44 years. Understanding the molecular mechanism of tumorigenesis is important for better clinical diagnosis and treatment. Purpose: We performed bioinformatics analysis to better understand seminoma at the genetic level and to explore potential candidate genes or molecules for diagnosis, treatment, and prognosis. Methods: A gene expression profile (GSE8607), containing 40 seminoma samples and three healthy testes samples, was analyzed to identify differentially expressed genes (DEGs) associated with the occurrence of seminoma. Functional annotation was then performed using gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Cytoscape with Search Tool for the Retrieval of Interacting Genes was used to construct a protein-protein interaction (PPI) network of the DEGs and select hub genes. Moreover, validation of expression level and Kaplan-Meier analysis for overall survival were conducted to those hub genes. Results: A total of 1,636 DEGs were identified between seminoma and healthy samples, including 701 up-regulated in seminoma that were enriched in the regulation of immune responses, defense responses, receptor activity, and signal transducer activity; 935 were down-regulated in seminoma and were associated with reproductive processes, kinase activity, and carbohydrate derivative binding. Five hub genes were selected from the PPI network according to the degree of connectivity: IL6, VEGFA, IL10, CCR5, and CXCR4. Among them, high expression levels of CCR5 and CXCR4 were associated with poor prognosis for seminoma patients. Four modules selected from the PPI network revealed that seminoma was connected with the Janus kinase-signal transducers and activators of transcription signaling pathway, chemokine signaling pathway, endocytosis, and cytokine-cytokine receptor interaction. Conclusion: These identified DEGs and hub genes facilitate our knowledge of the underlying molecular mechanism of seminoma and have the potential to be used as diagnostic biomarkers or therapeutic targets for seminoma.
Although in past decades the adipokine leptin and its own receptor have been considered as significant cancer biomarkers, their potential involvement in human testicular seminoma growth and progression remains unexplored. Here, we showed that the expression of leptin and its receptor was significantly higher in human testicular seminoma compared with normal adult testis. Human seminoma cell line TCam-2 also expressed leptin along with the long and short isoforms of leptin receptor, and in response to leptin treatment showed enhanced activation of its downstream effectors. In line with these results, leptin stimulation significantly increased the proliferation and migration of TCam-2 cells. Treatment of TCam-2 cells with the peptide Leu-Asp-Phe-Ile (LDFI), a full leptin-receptor antagonist, completely reversed the leptin-mediated effects on cell growth and motility as well as reduced the expression of several leptin-induced target genes. More importantly, the in vivo xenograft experiments showed that LDFI treatment markedly decreased seminoma tumor growth. Interestingly, LDFI-treated tumors showed reduced levels of the proliferation marker Ki-67 as well as decreased expression of leptin-regulated genes. Taken together, these data identify, for the first time, leptin as a key factor able to affect testicular seminoma behavior, highlighting leptin receptor as a potential target for novel potential treatments in this type of cancer.
(1) Background: PTTG1 sustains the EMT process and the invasiveness of several neoplasms. We previously showed the role of nuclear PTTG1 in promoting invasiveness, through its transcriptional target MMP2, in seminoma in vitro models. Here, we investigated the key players involved in PTTG1-mediated EMT in human seminoma. (2) Methods: Two seminoma cell lines and four human seminoma tumor specimens were used. E-Cadherin gene regulation was investigated using Western blot, real-time PCR, and luciferase assay. Immunoprecipitation, ChIP, RE-ChIP, and confocal microscopy analysis were performed to evaluate the interplay between PTTG1 and ZEB1. Matrigel invasion and spheroid formation assays were applied to functionally investigate PTTG1 involvement in the EMT of seminoma cell lines. RNA depletion and overexpression experiments were performed to verify the role of PTTG1/ZEB1 in E-Cadherin repression and seminoma invasiveness. E-Cadherin and ZEB1 levels were analyzed in human testicular tumors from the Atlas database. (3) Results: PTTG1 transcriptionally represses E-Cadherin in seminoma cell lines through ZEB1. The cooperation of PTTG1 with ZEB1 has a significant impact on cell growth/invasion properties involving the EMT process. Analysis of the Atlas database of testicular tumors showed significantly lower E-Cadherin levels in seminoma, where PTTG1 showed nuclear staining. Finally, PTTG1 and ZEB1 strongly localize together in the periphery of the tumors. (4) Conclusions: These results strengthen the evidence for a role of PTTG1 in the EMT process in human seminomas through its cooperation with the transcriptional repressor ZEB1 on the E-Cadherin gene. Our data enrich the molecular characterization of seminoma, suggesting that PTTG1 is a prognostic factor in seminoma clinical management.
Seminoma is the most common subtype of testicular germ cell tumor, with an increasing incidence worldwide. Clusterin (CLU) expression was found to be downregulated in testicular seminoma in our previous study. We now expanded the sample size, and further indicated that CLU expression correlates with tumor stage. Tcam-2 cell line was used to investigate the CLU function in testicular seminoma, and CLU was found to inhibit the proliferation and metastasis abilities. Besides, extracellular matrix protein COL15a1 was demonstrated as the downstream of CLU to affect the epithelial-mesenchymal transition (EMT) process via competitively binding to DDR1 with COL1A1 and inhibiting the phosphorylation of PYK2. MEF2A was found to interact with CLU and bind to the promoter of COL15a1 and so upregulate its expression. This is the first study using testicular xenografts in situ to simulate testicular seminoma metastatic and proliferative capacities. In conclusion, CLU acts as a tumor suppressor to inhibit the metastasis of testicular seminoma by interacting with MEF2A to upregulate COL15a1 and blocking the EMT process.
KIF3b is a protein of the kinesin-2 family which plays an important role in intraflagellar transport. Testis cancer is a common cancer among young men. Its diagnostic rate is increasing and over half of the cases are seminomas. Many aspects of the mechanism and gene expression background of this cancer remain unclear. Using western-blotting and semi-quantitative PCR we found high protein levels of KIF3b enrichment in seminoma tissue despite the mRNA levels remaining equivalent to that of normal testicular tissues. The distribution of KIF3b was mainly in cells with division potential. Wound-healing assays and cell counting kit assays showed that the knockdown of KIF3b significantly suppressed cell migration ability, viability and number in HeLa cells. Immunofluorescence images during the cell cycle revealed that KIF3b tended to gather at the spindles and was enriched at the central spindle. This indicated that KIF3b may also have direct impacts upon spindle formation and cytokinesis. By counting the numbers of nuclei, spindles and cells, we found that the rates of multipolar division and multi-nucleation were raised in KIF3b-knockdown cells. In this way we demonstrate that KIF3b functions importantly in mitosis and may be essential to seminoma cell division and proliferation as well as being necessary for normal cell division.
Testicular germ cell tumors (TGCTs) are common in young males, and seminoma accounts for a large proportion of TGCTs. However, there are limited records on the exploration of novel biomarkers for seminoma. Hence, we aimed to identify new biomarkers associated with overall survival in seminoma. mRNA-seq and clinical traits of TGCTs were downloaded from UCSC XENA and analyzed by weighted gene co-expression network analysis. After intersection with differentially expressed genes in GSE8607, common genes were subjected to protein-protein interaction (PPI) network construction and enrichment analyses. Then, the top 10 common genes were investigated by Kaplan-Meier (KM) survival analyses and univariate Cox regression analyses. Ultimately, TYROBP, CD68, and ITGAM were considered three prognostic biomarkers in seminoma. Based on correlation analysis between these genes and immune infiltrates, we suggest that the three biomarkers influence the survival of seminoma patients, possibly through regulating the infiltration of immune cells. In conclusion, our study demonstrated that TYROBP, CD68, and ITGAM could be regarded as prognostic biomarkers and therapeutic targets for seminoma patients.
Silencing of genes by DNA methylation is a common phenomenon in many types of cancer. However, the genome-wide effect of DNA methylation on gene expression has been analysed in relatively few cancers. Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. Previous analyses have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. The genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours' biology have not yet been established. In this study, genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data from primary tumours to address this question. Genome methylation was analysed using the Illumina infinium HumanMethylome450 bead chip system and gene expression was analysed using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Regulation by methylation was confirmed by demethylation using 5-aza-2-deoxycytidine and reverse transcription-quantitative PCR. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested played a role in their silencing in yolk sac tumour cells and many of these genes were also differentially expressed in primary tumours. Genes silenced by methylation in the various GCT cell lines were identified. Several pluripotency-associated genes were identified as a major functional group of silenced genes.
Testicular seminoma is one of the most common tumours in the field of urology, and its aetiology is still unclear. The aim of the present study was to identify the factors responsible for the development of testicular cancer and to investigate whether mutations in these genes were primarily congenital or acquired. To identify the key genes and miRNAs linked to testicular seminoma, as well as their potential molecular mechanisms, the GSE15220, GSE1818 and GSE59520 microarray datasets were analysed. A total of 5,195 and 1,163 differentially expressed genes (DEGs) were identified after analysing the GSE15220 and GSE1818 datasets, respectively. Among them, 287 genes were common between the two datasets. Of these, 110 were upregulated and 177 were downregulated. Five differentially expressed microRNAs (miRs; DEMs) that were downregulated in seminoma were identified after analysing the GSE59520 dataset. Following protein‑protein interaction network and Gene Ontology analysis, the five nodes with the highest degrees were screened as hub genes. Among them, the high expression of hub genes, such as protein tyrosine phosphatase receptor type C (PTPRC), was associated with worse overall survival. We also predicted the potential target genes of the DEMs. DNA topoisomerase II α (TOP2A), marker of proliferation Ki‑67 (MKI67), PTPRC and ubiquitin conjugating enzyme E2 C were associated with the PI3K/AKT and Wnt/β‑catenin signalling pathways. In addition, hsa‑miR‑650 and hsa‑miR‑665 were associated with the PI3K/AKT and Wnt/β‑catenin signalling pathways. Additionally, TOP2A and MKI67 were strongly associated with the target genes hsa‑miR‑650 and hsa‑miR‑665, respectively. We proposed that the hub genes reported in the present study may have a certain impact on cellular proliferation and migration in testicular seminoma. The roles of these hub genes in seminoma may provide novel insight to improve the diagnosis and treatment of patients with seminoma.
Testicular germ cell tumours (TGCTs) rank as the most common malignancy in men aged 20-34 years, and seminomas are the most type of TGCTs. As a crucial anti-tumour agent with explicit toxicity, cisplatin may render resistance through intertwined mechanisms, even in disease entities with high curative ratio, such as seminoma. Previously, we established cisplatin-resistant seminoma TCam-2 (TCam-2/CDDP) cells and showed that epigenetic regulations, such as non-coding RNA (ncRNA) interactions, might orchestrate cell fate decisions in the cisplatin treatment context in seminoma. N6-methyladenosine (m6A) is the most prevalent internal modification in mRNA. In the present study, we assessed cisplatin resistance in seminoma from the perspective of m6 A, another manner of epigenetic modification. The global m6 A enrichment of TCam-2 and TCam-2/CDDP was depicted. Then, we elucidated whether transcription factor-activating enhancer-binding protein 2C (TFAP2C) was functionally m6 A-modified by methyltransferase-like protein 3 (METTL3), which acted as an m6 A 'writer', and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which acted as an m6 A 'reader'. Enhanced stability of TFAP2C mRNA promoted seminoma cell survival under cisplatin treatment burden probably through up-regulation of DNA repair-related genes. Hopefully, this study will help improve our understanding of the subtleties of the tumour cellular coping strategy in response to chemotherapy. Targeting factors that are involved in m6 A methylation may be an effective strategy for circumventing cisplatin resistance in seminoma.
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