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Insights into the Evolution of Spermatogenesis-Related Ubiquitin-Proteasome System Genes in Abdominal Testicular Laurasiatherians.

ABSTRACT: During embryonic development in mammals, the testicles generally descend into the scrotum, making the testicular temperature 2-4 °C lower than the core temperature via heat exchange and clearance, and thus more beneficial for normal spermatogenesis. Failure to descend, known as cryptorchidism, carries a series of risks such as infertility and testicular cancer. However, some mammals have evolved abdominal testes while maintaining healthy reproduction. To explore the underlying molecular mechanism, we conducted comparative genomic analyses and functional assays on the spermatogenesis-related ubiquitin-proteasome system (UPS) genes essential to sperm formation in representative laurasiatherians. Here, positive selection and rapid evolution of spermatogenesis-related UPS genes were identified in the abdominal testicular laurasiatherians. Moreover, potential convergent amino acids were found between distantly related species with similar abdominal testicles and functional analyses showed RNF8 (V437I) in abdominal testicular species (437I) has a stronger ubiquitination ability, which suggests that the mammals with abdominal testes might exhibit enhanced sperm cell histone clearance to maintain sperm formation. This evidence implies that, in response to "cryptorchidism injury", spermatogenesis-related UPS genes in the abdominal testicular species might have undergone adaptive evolution to stabilize sperm formation. Thus, our study could provide some novel insights into the reproductive adaptation in abdominal testicular mammals.

SUBMITTER: Ding X

PROVIDER: S-EPMC8620446 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dysregulation of the ubiquitin-proteasome system (UPS) pathway greatly affects uncontrolled proliferation, genomic instability, and carcinogenesis, particularly in those with renal papillary cell carcinoma (PRCC). However, there is little information at the molecular level about the full link between changes in the genes involved in ubiquitin-mediated proteolysis and PRCC.MethodsThe Cancer Genome Atlas (TCGA) and GeneCards databases were utilized to find the clinical data and gene expression patterns of patients with PRCC. Univariate Cox regression analysis and absolute shrinkage and selection operator (LASSO) analyses identified a risk signature formed by ten optimal UPS genes. The predictive value of the risk signature in TCGA-PRCC cohorts was evaluated using Kaplan-Meier analysis and receiver operating characteristic (ROC) curves. By utilizing GO enrichment and the KEGG pathway, the interactions of differentially expressed genes connected to ubiquitin-mediated proteolysis were functionally examined. The protein expression of the hub genes was affirmed using the Human Protein Atlas (HPA) database. The effectiveness of particular CDC20 and UBE2C in vitro was confirmed by experimental research.ResultsTen of the best ubiquitin-mediated proteolysis genes (UBE2C, DDB2, CBLC, BIRC3, PRKN, UBE2O, SIAH1, SKP2, UBC, and CDC20) were detected to create a risk signature. The high-risk score group stratified was associated with advanced tumor status and poor survival of PRCC patients. 10 genes were also found to be associated with the cell cycle pathway and ubiquitin-mediated proteolysis to GO and KEGG analysis. Of these 10 genes, CDC20 and UBE2C are highly expressed in tumor tissue and correlated with cancer immunity founded on the analyses of the expression of human protein atlas and TISIDB. The downregulation of UBE2C facilitated tumor inhibition and the anti-immune effect was confirmed by in vitro experiments.ConclusionOur results indicate that the risk model created from the ubiquitin-mediated proteolysis genes can be reliably and accurately predict the prognosis of PRCC patients, highlighting its targeted value for PRCC treatment. Particularly, the expression of UBE2C may be crucial for the prognosis and immunological treatment of renal cancer.

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Insights into the Evolution of Spermatogenesis-Related Ubiquitin-Proteasome System Genes in Abdominal Testicular Laurasiatherians.

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