Quantitative proteome profiling of human myoma and myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention

Abstract

Uterine leiomyomas are benign tumors affecting a large proportion of the female population. Despite the very high prevalence, the molecular basis for understanding the onset and development of the disease are still poorly understood. In this study, we profiled the proteomes and kinomes of leiomyoma as well as myometrium samples from patients to a depth of >7000 proteins including 200 kinases. Statistical analysis identified a number of molecular signatures distinguishing healthy from diseased tissue. Among these, nine kinases (ADCK4, CDK5, CSNK2B, DDR1, EPHB1, MAP2K2, PRKCB, PRKG1, and RPS6KA5) representing a number of cellular signaling pathways showed particularly strong discrimination potential. Preliminary statistical analysis by receiver operator characteristics plots revealed very good performance for individual kinases (area under the curve, AUC of 0.70-0.94) as well as binary combinations thereof (AUC 0.70-1.00) that might be used to assess the activity of signaling pathways in myomas. Of note, the receptor tyrosine kinase DDR1 holds future potential as a drug target owing to its strong links to collagen signaling and the excessive formation of extracellular matrix typical for leiomyomas in humans.

A Proteomic Approach for the Identification of Up-Regulated Proteins Involved in the Metabolic Process of the Leiomyoma

“…Proteins GOT1, FABP5, CRABP2, isoform 2 of guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit β, isoform 3 of polymerase I and transcript release factor and isoform 5 of prelamin-A/C and FHL1 were further validated to confirm 2-DE data. The remaining 20 proteins have already been shown to be associated with leiomyoma using GeLC-MS/MS [ 14 ].…”

“…, β-actin and tubulin) are upregulated in leiomyoma and, thus, not adequate to be used as controls for normalization. Because we could not establish which proteins should be considered as housekeeping in our samples, we decided to apply a total protein content normalization method, as described by Lv et al and Lemeer et al [ 3 , 14 ].…”

“…Proteomics is a powerful tool for the analysis of complex mixtures of proteins. Lemeer et al performed quantitative proteome and kinome profiling of leiomyoma vs. myometrium using GeLC-MS/MS, identifying several dysregulated kinases [ 14 ]. The present study aimed at identifying upregulated proteins related to molecular mechanisms involved in leiomyoma development.…”

Dysregulated chaperones associated with cell proliferation and negative apoptosis regulation in the uterine leiomyoma

“…Leemer and colleagues (18) conducted an in-depth study on the proteomic profile of leiomyoma and myometrium samples by label-free GeLC-MS/MS, resulting in the identification and intensity-based label-free quantification of more than 7000 proteins. We compared our data with theirs.…”

Identificação de genes associados à atrofia muscular induzida pela privação de andrógeno

“…RPS6ka5 também foi demonstrada estar regulada positivamente em tecidos de mioma e miométrio em mulheres portadoras de leiomioma (neoplasia benigna de músculo liso) (Lemeer, Gholami et al 2015). Neste trabalho, foi observado o aumento dos níveis de RPS6Ka5 no grupo de animais castrados e quando tratados, sua expressão diminui-se em 4,79 vezes.…”