Small RNAs in Seminal Plasma as Novel Biomarkers for Germ Cell Tumors.
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ABSTRACT:
SUBMITTER: Morup N
PROVIDER: S-EPMC8152278 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:miR-371a-3p is currently the most informative reported biomarker for germ cell tumors (GCTs). Another developmental-related biomarker, CRIPTO, is involved in the regulation of pluripotency and germ cell fate commitment. We aimed to assess the value of CRIPTO as a diagnostic and prognostic biomarker of testicular GCTs (TGCTs) and also to assess its presence in seminal plasma samples, compared with miR-371a-3p. In total, 217 and 94 serum/seminal plasma samples were analyzed. CRIPTO was quantified using ELISA and miR-371a-3p using bead-based isolation followed by RT-qPCR. Methylation profiling (EPIC array) for the CRIPTO promoter region was undertaken in 35 TGCT tissues plus four (T)GCT cell lines. Significantly higher CRIPTO concentration was found in sera of non-seminomas compared to controls (p = 0.0297), and in stage II/III disease compared to stage I (p = 0.0052, p = 0.0097). CRIPTO concentration was significantly positively correlated with miR-371a-3p levels in serum (r = 0.16) and seminal plasma (r = 0.40). CRIPTO/miR-371a-3p levels were significantly higher in seminal plasma controls when compared to serum controls (p = 0.0001, p < 0.0001). CRIPTO/miR-371a-3p were detected both in normospermic and azoospermic males, and levels were higher in TGCTs compared to GCNIS-only. We have provided the largest dataset of evaluation of CRIPTO in serum and seminal plasma of GCTs, showing its potential value as a biomarker of the disease.
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Project description:PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that bind PIWI family proteins exclusively expressed in the germ cells of mammalian gonads. MIWI2-associated piRNAs are essential for silencing transposons during primordial germ cell development, and MIWI-bound piRNAs are required for normal spermatogenesis during adulthood in mice. Although piRNAs have long been regarded as germ cell-specific, increasing lines of evidence suggest that somatic cells also express piRNA-like RNAs (pilRNAs). Here, we report the detection of abundant pilRNAs in somatic cells, which are similar to MIWI-associated piRNAs mainly expressed in pachytene spermatocytes and round spermatids in the testis. Based on small RNA deep sequencing and quantitative PCR analyses, pilRNA expression is dynamic and displays tissue specificity. Although pilRNAs are similar to pachytene piRNAs in both size and genomic origins, they have a distinct ping-pong signature. Furthermore, pilRNA biogenesis appears to utilize a yet to be identified pathway, which is different from all currently known small RNA biogenetic pathways. In addition, pilRNAs appear to preferentially target the 3'-UTRs of mRNAs in a partially complementary manner. Our data suggest that pilRNAs, as an integral component of the small RNA transcriptome in somatic cell lineages, represent a distinct population of small RNAs that may have functions similar to germ cell piRNAs.
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Project description:Extracellular vesicles (EVs) regulate multiple physiological processes. Seminal plasma contains numerous EVs that may deliver functional molecules such as small RNAs (sRNAs) to the sperm. However, the RNA profiles in the boar seminal plasma extracellular vesicles (SP-EVs) and its function have not been characterized. The aim of this study was to characterize the functions and sRNA profiles in the boar SP-EVs using deep sequencing technology. Briefly, boar SP-EVs were isolated by differential ultracentrifugation and confirmed with a transmission electron microscope (TEM), nanoparticle tracking analysis (NTA), and Western blot. The isolated boar SP-EVs contained numerous and diverse sRNA families, including microRNAs (miRNAs, 9.45% of the total reads), PIWI-interacting RNAs (piRNAs, 15.25% of the total reads), messenger RNA fragments (mRNA, 25.30% of the total reads), and tRNA-derived small RNAs (tsRNA, 0.01% of the total reads). A total of 288 known miRNAs, 37 novel miRNA, and 19,749 piRNAs were identified in boar SP-EVs. The identified ssc-miR-21-5p may confer negative effects on sperm fertility based on a dual-luciferase reporter experiment. This study therefore provides an effective method to isolate SP-EVs and characterizes the sRNA profile.
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Project description:Testicular germ cell tumors (TGCTs) are the most common tumors in adolescent and young men. Recently, genome-wide studies have made it possible to progress in understanding the molecular mechanisms underlying the development of tumors. It is becoming increasingly clear that aberrant regulation of RNA metabolism can drive tumorigenesis and influence chemotherapeutic response. Notably, the expression of non-coding RNAs as well as specific splice variants is deeply deregulated in human cancers. Since these cancer-related RNA species are considered promising diagnostic, prognostic and therapeutic targets, understanding their function in cancer development is becoming a major challenge. Here, we summarize how the different expression of RNA species repertoire, including non-coding RNAs and protein-coding splicing variants, impacts on TGCTs' onset and progression and sustains therapeutic resistance. Finally, the role of transcription-associated R-loop misregulation in the maintenance of genomic stability in TGCTs is also discussed.
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Project description:Germ cell tumours predominantly of the testis ((T)GCTs) are remarkably chemotherapy sensitive. However, a small proportion of patients fail to be cured with cisplatin-based combination chemotherapy. miR-371a-3p is a new liquid biopsy biomarker for (T)GCTs. The aim of this study was to evaluate clinical utility of plasma miR-371a-3p level in patients starting systemic chemotherapy. Patients were included before the first cycle (N = 180) and second cycle (N = 101) of systemic first line chemotherapy, treated between July 2010 and May 2017. Plasma miR-371a-3p levels were measured with the ampTSmiR test and compared to disease characteristics and outcome. Pretreatment plasma miR-371a-3p levels were increased in 51.7% of cases and associated with number of metastatic sites, presence of lung, retroperitoneal, and mediastinal lymph node metastases, S - stage, IGCCCG risk group, and response to therapy. Patients with a negative pretreatment plasma level had better progression-free survival (PFS) and overall survival (OS) compared to patients being positive for miR-371a-3p (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.09-0.71, P = 0.02 for PFS and HR = 0.21, 95% CI 0.07-0.67, P = 0.03 for OS, respectively). Patients negative for miR-371a-3p in both samples had a superior PFS (HR = 0.10, 95% CI 0.01-21.49, P = 0.02) and OS (HR = 0.08, 95% CI 0.01-27.81, P = 0.008) compared to patients with miR-371a-3p positive in both samples (multivariate analyses were non-significant). In total 68% of the patients were S0. This study demonstrates clinical value of plasma miR-371a-3p level in chemotherapy naïve (T)GCT patients starting first line of chemotherapy to predict prognosis.
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Project description:Testicular germ cell tumors are unique among solid cancers. Historically, this disease was deadly if progressed beyond the stage I. The implementation of cisplatin-based chemotherapy regimens has drastically changed the clinical outcome of metastatic testicular cancer. Several biomarkers were established to refine the prognosis by International Germ Cell Collaborative Group in 1997. Among these, the most significant were primary tumor site; metastatic sites, such as non-pulmonary visceral metastases; and the amplitude of serum tumor markers ?-fetoprotein, ?-chorionic gonadotropin, and lactate dehydrogenase. Since then, oncology has experienced discoveries of various molecular biomarkers to further refine the prognosis and treatment of malignancies. However, the ability to predict the prognosis and treatment response in germ cell tumors did not improve for many years. Clinical trials with novel targeting agents that were conducted in refractory germ cell tumor patients have proven to have negative outcomes. With the recent advances and developments, novel biomarkers emerge in the field of germ cell tumor oncology. This review article aims to summarize the current knowledge in the research of novel prognostic biomarkers in testicular germ cell tumors.
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Project description:Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men ages 15 to 44 years. Embryonal carcinomas (EC) comprise a subset of TGCTs that exhibit pluripotent characteristics similar to embryonic stem (ES) cells, but the genetic drivers underlying malignant transformation of ECs are unknown. To elucidate the abnormal genetic events potentially contributing to TGCT malignancy, such as the existence of fusion genes or aberrant fusion transcript expression, we performed RNA sequencing of EC cell lines and their nonmalignant ES cell line counterparts. We identified eight novel fusion transcripts and one gene with alternative promoter usage, ETV6. Four out of nine transcripts were found recurrently expressed in an extended panel of primary TGCTs and additional EC cell lines, but not in normal parenchyma of the testis, implying tumor-specific expression. Two of the recurrent transcripts involved an intrachromosomal fusion between RCC1 and HENMT1 located 80 Mbp apart and an interchromosomal fusion between RCC1 and ABHD12B. RCC1-ABHD12B and the ETV6 transcript variant were found to be preferentially expressed in the more undifferentiated TGCT subtypes. In vitro differentiation of the NTERA2 EC cell line resulted in significantly reduced expression of both fusion transcripts involving RCC1 and the ETV6 transcript variant, indicating that they are markers of pluripotency in a malignant setting. In conclusion, we identified eight novel fusion transcripts that, to our knowledge, are the first fusion genes described in TGCT and may therefore potentially serve as genomic biomarkers of malignant progression.
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Project description:The origin and contribution of seminal plasma RNAs into the whole semen RNA repertoire are poorly known, frequently being overlooked or neglected. In this study, we used high-throughput sequencing and RT-qPCR to profile microRNA (miRNA) constituents in the whole semen, as well as in fractionated spermatozoa and seminal plasma of Atlantic salmon (Salmo salar). We found 85 differentially accumulated miRNAs between spermatozoa and the seminal plasma. We identified a number of seminal plasma-enriched and spermatozoa-enriched miRNAs. We localized the expression of some miRNAs in juvenile and mature testes. Two abundant miRNAs, miR-92a-3p and miR-202-5p, localized to both spermatogonia and somatic supporting cells in immature testis, and they were also highly abundant in somatic cells in mature testis. miR-15c-5p, miR-30d-5p, miR-93a-5p, and miR-730-5p were detected only in mature testis. miRs 92a-3p, 202-5p, 15c-5p, and 30d-5p were also detected in a juvenile ovary. The RT-qPCR experiment demonstrated lack of correlation in miRNA transcript levels in seminal plasma versus blood plasma. Our results indicate that salmon semen is rich in miRNAs, which are present in both spermatozoa and seminal plasma. Testicular-supporting somatic cells are likely the source of seminal plasma enrichment, whereas blood plasma is unlikely to contribute to the seminal plasma miRNA repertoire.
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Project description:Incidental detection of urogenital tumors has increased in recent decades owing to the greater use of ultrasonography and cross-sectional imaging. For patients with low-risk prostate cancer or small renal masses, active surveillance represents a valid treatment option. Similarly, for men with small testicular masses <10 mm, active surveillance has been discussed as an alternative to surgery, although little is known regarding the behavior of small testicular germ cell tumors (GCTs). In the Swiss Austrian German Testicular Cancer Cohort Study we identified 849 patients (546 seminoma, 303 nonseminoma) treated with radical inguinal orchiectomy for GCT with a median tumor diameter of 35 mm. A tumor diameter <10 mm was observed in 25 patients (13 seminoma, 12 nonseminoma). Of these, five patients (20%) presented with primary metastatic disease, all of whom had elevated tumor markers and nonseminomatous GCTs. Two patients (8%) with initially localized disease (1 seminoma, 1 nonseminoma) and without elevated tumor markers experienced relapse at 4 mo (nonseminoma) and 14 mo (seminoma) after orchiectomy, despite the fact that the latter had received adjuvant chemotherapy. These findings highlight the metastatic potential of small testicular GCTs and raise the question of whether active surveillance for small testicular masses is safe.Patient summaryThis study on testicular cancer assesses the metastatic potential of small testicular germ cell tumors. Men with small testicular masses should be counseled about the malignant potential of small testicular germ cell tumors.
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