Introduction This study aimed to investigate the molecular pathogenesis of Uterine Leiomyosarcoma (ULMS), a highly lethal gynecologic malignancy with limited treatment options, and identify potential therapeutic strategies. ULMS is characterized by chromosomal instability (CIN), and its molecular mechanisms remain poorly understood.
Methods We conducted Whole Genome and Target Region Sequencing to investigate genomic alterations in ULMS. mRNA profiling analysis identified differential expression of genes involved in mitosis and nuclear division pathways, including MELK. In vitro and in vivo experiments assessed the effects of MELK overexpression on cellular proliferation, migration, and invasion.
Results Our study revealed that global chromosomal instability (CIN) was more prevalent than nucleotide alterations in ULMS. Additionally, mRNA profiling analysis showed differential expression of many genes involved in mitosis and nuclear division pathways, including MELK. We demonstrated that MELK promotes cellular proliferation, migration, and invasion in ULMS by phosphorylating MAD2L1 at the S170 site, causing its dissociation from CDC20 and subsequent conversion to its inactive form, O-MAD2, leading to uneven chromosomal distribution in daughter cells. MELK also promotes cell cycle progression by phosphorylating RB1 at the S252 site, leading to high cellularity and nuclear atypia formation in vitro and in vivo.
Conclusion/Implications Our study provides a comprehensive analysis of genomic alterations underlying CIN in ULMS and identifies MELK as a potential therapeutic target. The MELK-mediated molecular mechanism of CIN in ULMS provides insight into developing new therapies targeting this pathway. Further research is needed to develop effective therapeutic strategies for treating ULMS.
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