ITGB1-dependent upregulation of Caveolin-1 switches TGFβ signalling from tumour-suppressive to oncogenic in prostate cancer

Teijo Pellinen, Sami Blom, Sara Sánchez, Katja Välimäki, John-Patrick Mpindi, Hind Azegrouz, Raffaele Strippoli, Raquel Nieto, Mariano Vitón, Irene Palacios, Riku Turkki, Yinhai Wang (+8 others)
2018 Scientific Reports  
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,
more » ... 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. Epithelial-to-mesenchymal transition (EMT) is associated with the disruption of the normal structure of the epithelium and the invasion of carcinoma cells into the surrounding stroma 1 . EMT-associated epithelial plasticity is a relevant phenomenon in prostate cancer (PCa) progression 2 . A hallmark of EMT is the decreased or aberrant expression of the adherens junction protein E-cadherin 3 . In PCa, decreased E-cadherin expression has been shown to correlate with clinical disease progression in multiple independent studies [4] [5] [6] [7] [8] . A pivotal regulator of EMT is transforming growth factor beta (TGFβ) 9 . Shutdown of canonical TGFβ signalling through down-regulation or deletion of the transcriptional effector protein, SMAD4, promotes cell growth and proliferation in epithelium, and can therefore lead to carcinogenesis 10 . However, in advanced stages of cancer, the growth-suppressive function of TGFβ is often subverted to promote invasion and EMT, independent of SMAD proteins 11 . Indeed, there is evidence that TGFβ expression correlates with PCa progression and poor clinical outcome 12, 13 . Also, TGFβ signalling promotes invasive growth and metastasis of PCa [14] [15] [16] [17] . However, and despite its outstanding relevance, the principles determining this "Janus" behaviour of the TGFβ pathway have not been fully elucidated.
doi:10.1038/s41598-018-20161-2 pmid:29402961 pmcid:PMC5799174 fatcat:ttgringf3rdgreaa3xavkz6ati