Neuroproteins in Cancer: Assumed Bystanders Become Culprits.

Recent breakthrough discoveries have highlighted the stimulatory role of nerves in cancer initiation and progression, through the release of neurotransmitters and growth factors by nerve terminals in the tumor microenvironment. Intriguingly, neuroproteins such as neuronal membrane proteins, synaptic proteins, neurotransmitters, and neurotrophic growth factors as well as their corresponding receptors, to name only a few, are frequently found in proteomic analyses of cancer tissues external to the brain and central nervous system. While the usual explanation was that neuroproteins were actually not specific to the nervous system and were therefore also expressed in cancer cells, it now appears that the presence of neuroproteins in cancer is largely due to the infiltration of nerves in the tumor microenvironment. Given the newly identified function of nerves as promoters of cancer growth and metastasis, neuroproteins should be considered with great attention because they may actually represent innovative biomarkers and therapeutic targets in oncology.

Proteomic Profiling of Human Uterine Fibroids Reveals Upregulation of the Extracellular Matrix Protein Periostin.

The central characteristic of uterine fibroids is excessive deposition of extracellular matrix (ECM), which contributes to fibroid growth and bulk-type symptoms. Despite this, very little is known about patterns of ECM protein expression in fibroids and whether these are influenced by the most common genetic anomalies, which relate to MED12. We performed extensive genetic and proteomic analyses of clinically annotated fibroids and adjacent normal myometrium to identify the composition and expression patterns of ECM proteins in MED12 mutation-positive and mutation-negative uterine fibroids. Genetic sequencing of tissue samples revealed MED12 alterations in 39 of 65 fibroids (60%) from 14 patients. Using isobaric tagged-based quantitative mass spectrometry on three selected patients (n = 9 fibroids), we observed a common set of upregulated (>1.5-fold) and downregulated (<0.66-fold) proteins in small, medium, and large fibroid samples of annotated MED12 status. These two sets of upregulated and downregulated proteins were the same in all patients, regardless of variations in fibroid size and MED12 status. We then focused on one of the significant upregulated ECM proteins and confirmed the differential expression of periostin using western blotting and immunohistochemical analysis. Our study defined the proteome of uterine fibroids and identified that increased ECM protein expression, in particular periostin, is a hallmark of uterine fibroids regardless of MED12 mutation status. This study sets the foundation for further investigations to analyze the mechanisms regulating ECM overexpression and the functional role of upregulated ECM proteins in leiomyogenesis.

Protein interaction screening identifies SH3RF1 as a new regulator of FAT1 protein levels.

Mutations and ectopic FAT1 cadherin expression are implicated in a broad spectrum of diseases ranging from developmental disorders to cancer. The regulation of FAT1 and its downstream signalling pathways remain incompletely understood. We hypothesized that identification of additional proteins interacting with the FAT1 cytoplasmic tail would further delineate its regulation and function. A yeast two-hybrid library screen carried out against the juxtamembrane region of the cytoplasmic tail of FAT1 identified the E3 ubiquitin-protein ligase SH3RF1 as the most frequently recovered protein-binding partner. Ablating SH3RF1 using siRNA increased cellular FAT1 protein levels and stabilized expression at the cell surface, while overexpression of SH3RF1 reduced FAT1 levels. We conclude that SH3RF1 acts as a negative post-translational regulator of FAT1 levels.