Abstract
Caveolin-1 (CAV1) is over-expressed in prostate cancer (PCa) and is associated with adverse prognosis, but the molecular mechanisms linking CAV1 expression to disease progression are poorly understood. Extensive gene expression correlation analysis, quantitative multiplex imaging of clinical samples, and analysis of the CAV1-dependent transcriptome, supported that CAV1 re-programmes TGFβ signalling from tumour suppressive to oncogenic (i.e. induction of SLUG, PAI-1 and suppression of CDH1, DSP, CDKN1A). Supporting such a role, CAV1 knockdown led to growth arrest and inhibition of cell invasion in prostate cancer cell lines. Rationalized RNAi screening and high-content microscopy in search for CAV1 upstream regulators revealed integrin beta1 (ITGB1) and integrin associated proteins as CAV1 regulators. Our work suggests TGFβ signalling and beta1 integrins as potential therapeutic targets in PCa over-expressing CAV1, and contributes to better understand the paradoxical dual role of TGFβ in tumour biology.
Highlights
Caveolin-1 (CAV1) is a cholesterol-binding scaffold protein which functions in membrane dynamics, uptake of certain viruses, lipid metabolism, signalling, mechano-sensing and membrane mechano-protection[18]
To gain further insight into the functional programs associated with CAV1 expression in prostate cancer (PCa), we queried extensive transcriptome datasets to find signatures exhibiting correlation with CAV1 expression
As we showed that integrin beta1 (ITGB1) is an upstream regulator of CAV1 expression and the two proteins are correlated in vitro, we asked if this correlation could be validated in a large clinical prostate cancer cohort
Summary
CAV1 expression associates with a mesenchymal gene signature. CAV1 expression has been shown to be up-regulated in PCa and to associate with poor prognosis[32,33,34]. Top GoTerm categories included cell adhesion (p = 6.9E-16), cell-substrate junction (p = 4.1E-16), and cytoskeletal protein binding (p = 4.2E-14) (Supplementary Table S6), which reflect functional annotations for CAV1 We curated these highly co-expressed gene sets as well as functionally-related genes and performed a targeted image-based RNAi screen in three different prostatic cell lines to detect the effect of specific gene-silencing on CAV1 (Supplementary Table S7 for gene list; Supplementary Table S8 for siRNAs). Neither CAV1 nor ITGB1 expression associated with Gleason score or pathological tumour stage (pT) (Tables 2 and 3) To support these data, a multiplexed 4-color IHC and automatic image analysis demonstrated that epithelial CAV1 correlates with ITGB1 and with ITGA2 and ITGA6 – alpha integrin subunits forming dimers with ITGB1 (Supplementary Fig. S5)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
