SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells

Abstract

Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a matricellular protein that modulates interactions between cells and their microenvironment. SPARC is expressed during extracellular matrix remodeling and is abundant in bone marrow and high-grade prostate cancer (PCa). In PCa, SPARC induces changes associated with epithelial–mesenchymal transition (EMT), enhancing migration and invasion and increasing the expression of EMT transcriptional factor Zinc finger E-box-binding homeobox 1 (ZEB1), but not Zinc finger protein SNAI1 (Snail) or Zinc finger protein SNAI2 (Slug). It is unknown whether the SPARC-induced downregulation of E-cadherin in PCa cells depends on ZEB1. Several integrins are mediators of SPARC effects in cancer cells. Because integrin signaling can induce EMT programs, we hypothesize that SPARC induces E-cadherin repression through the activation of integrins and ZEB1. Through stable knockdown and the overexpression of SPARC in PCa cells, we demonstrate that SPARC downregulates E-cadherin and increases vimentin, ZEB1, and integrin β3 expression. Knocking down SPARC in PCa cells decreases the tyrosine-925 phosphorylation of FAK and impairs focal adhesion formation. Blocking integrin αvβ3 and silencing ZEB1 revert both the SPARC-induced downregulation of E-cadherin and cell migration enhancement. We conclude that SPARC induces E-cadherin repression and enhances PCa cell migration through the integrin αvβ3/ZEB1 signaling pathway.

Pauperization of Emerin from nuclear envelope during chromatin bridge resolution drives prostate cancer cell migration and invasiveness

“…Our data from the tumor samples collected from PCa patients and 3D PC-3 cell spheroid culture suggests that cells with EMD pauperization share common transcriptomic signature. Mostly genes involved in cell migration and invasion were up-regulated, many of them were previously linked with prostate cancer progression (41)(42)(43)47). We also observed that the set of genes up-regulated in cells with EMD pauperization could indicate patients with worse prognosis.…”

“…Based on immunofluorescent staining for EMD, tumors were divided in two groups: normal EMD NE staining and pauperized EMD from NE (presence of EMD-rich MN or EMD loss in cancer cells, Fig 5A). Tumors with EMD pauperized form NE had up-regulated 33 genes (Supplementary Table S4) including the ones encoding proteins involved in prostate cancer migration and invasion as vimentin (41), SPARC (42), or invasion as MMP2 (43), as presented in Fig 5A and Extended Fig. 5B.…”

Pauperization of Emerin from nuclear envelope during chromatin bridge resolution drives prostate cancer cell migration and invasiveness

“…Based on immunofluorescent staining for EMD, tumors were divided in two groups: normal EMD NE staining and pauperized EMD from NE (presence of EMD-rich MN or EMD loss in cancer cells, Fig 5A). Tumors with EMD pauperized form NE had up-regulated 33 genes (Supplementary Table S4) including the ones encoding proteins involved in prostate cancer migration and invasion as vimentin (Lang et al , 2002), SPARC (López-Moncada et al , 2022), or invasion as MMP2 (Trudel et al , 2003), as presented in Fig 5A and Extended Fig. 5B.…”

“…Our data from the tumor samples collected from PCa patients and 3D PC-3 cell spheroid culture suggests that cells with EMD pauperization share common transcriptomic signature. Mostly genes involved in cell migration and invasion were up-regulated, many of them were previously linked with prostate cancer progression (Lang et al , 2002; López-Moncada et al , 2022; Trudel et al , 2003; Lu et al , 2007). We also observed that the set of genes up-regulated in cells with EMD pauperization could indicate patients with worse prognosis.…”

HnRNPAB is an independent prognostic factor in non‑small cell lung cancer and is involved in cell proliferation and metastasis

“…In the process of EMT, the expressions of many mesenchymal related proteins are often increased, especially Vimentin (33). Cells in EMT acquire stem cell-like properties, in which the protein expression changed from E-cadherin to N-cadherin, ZEB1 and SNAI1, of which ZEB1 and SNAI1 directly suppressed the expression of E-cadherin by binding to its promoter (34)(35)(36). Our results showed that hnRNPAB knockdown increased the expression of E-cadherin and reduced the expressions of ZEB1, N-cadherin, Vimentin, and SNAI1, indicating EMT was reversed.…”