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Proteomics reveals the ribosome signaling pathway promoting prostate cancer progression and correlating with poor prognosis

ABSTRACT: Through digital rectal examinations and routine prostate-specific antigen (PSA) screening, early treatment of prostate cancer has become possible. However, prostate cancer is a complex and heterogeneous disease. In many patients, cancer cells can invade adjacent tissues and metastasize to other tissues, resulting in difficultly to cure. For the treatment of primary and metastatic prostate cancer, a significant problem is how to improve its survival time. Here, we collect 7 untreated primary and metastatic prostate cancer and 6 benign prostate hyperplasia samples under ultrasound guidance by experienced radiologists using the 18-G needle. Through mass spectrometry, we have completely depicted the protein atlas of primary and metastatic prostate cancer and benign prostate hyperplasia. Through bioinformatics analysis, experimental verification, and combined clinical data, we discover that the ribosome signaling pathway promotes the progression of prostate cancer and is associated with a poor prognosis. Among them, Mrpl1, Mrpl4, and Mrpl16 may be biomolecular markers for diagnosis and prognosis.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jiangbei Yuan

PROVIDER: PXD028211 | iProX | Sun Sep 05 00:00:00 BST 2021

REPOSITORIES: iProX

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Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS? prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study. Gene expression profiling and array CGH (aCGH) was performed on matched benign prostate tissues (n=28), localized prostate cancer (n=59), and metastatic castrate resistant prostate cancer (CRPC, n=35). For gene expression profiling, frozen prostate tissue samples (channel 2), were hybridized against a commercial pool of benign prostate tissue (Clontech, channel 1). For aCGH, frozen prostate tissue samples (channel 2) were hybridized against a commerical sample of Human Male Genomic DNA (Promega, channel 1).

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Proteomics reveals the ribosome signaling pathway promoting prostate cancer progression and correlating with poor prognosis

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