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RAC1B Regulation of TGFB1 Reveals an Unexpected Role of Autocrine TGF?1 in the Suppression of Cell Motility.


ABSTRACT: Autocrine transforming growth factor (TGF)? has been implicated in epithelial-mesenchymal transition (EMT) and invasion of several cancers including pancreatic ductal adenocarcinoma (PDAC) as well as triple-negative breast cancer (TNBC). However, the precise mechanism and the upstream inducers or downstream effectors of endogenous TGFB1 remain poorly characterized. In both cancer types, the small GTPase RAC1B inhibits cell motility induced by recombinant human TGF?1 via downregulation of the TGF? type I receptor, ALK5, but whether RAC1B also impacts autocrine TGF? signaling has not yet been studied. Intriguingly, RNA interference-mediated knockdown (RNAi-KD) or CRISPR/Cas-mediated knockout of RAC1B in TGF?1-secreting PDAC-derived Panc1 cells resulted in a dramatic decrease in secreted bioactive TGF?1 in the culture supernatants and TGFB1 mRNA expression, while the reverse was true for TNBC-derived MDA-MB-231 cells ectopically expressing RAC1B. Surprisingly, the antibody-mediated neutralization of secreted bioactive TGF? or RNAi-KD of the endogenous TGFB1 gene, was associated with increased rather than decreased migratory activities of Panc1 and MDA-MB-231 cells, upregulation of the promigratory genes SNAI1, SNAI2 and RAC1, and downregulation of the invasion suppressor genes CDH1 (encoding E-cadherin) and SMAD3. Intriguingly, ectopic re-expression of SMAD3 was able to rescue Panc1 and MDA-MB-231 cells from the TGFB1 KD-induced rise in migratory activity. Together, these data suggest that RAC1B favors synthesis and secretion of autocrine TGF?1 which in a SMAD3-dependent manner blocks EMT-associated gene expression and cell motility.

SUBMITTER: Ungefroren H 

PROVIDER: S-EPMC7760153 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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RAC1B Regulation of <i>TGFB1</i> Reveals an Unexpected Role of Autocrine TGFβ1 in the Suppression of Cell Motility.

Ungefroren Hendrik H   Otterbein Hannah H   Wellner Ulrich F UF   Keck Tobias T   Lehnert Hendrik H   Marquardt Jens-Uwe JU  

Cancers 20201129 12


Autocrine transforming growth factor (TGF)β has been implicated in epithelial-mesenchymal transition (EMT) and invasion of several cancers including pancreatic ductal adenocarcinoma (PDAC) as well as triple-negative breast cancer (TNBC). However, the precise mechanism and the upstream inducers or downstream effectors of endogenous <i>TGFB1</i> remain poorly characterized. In both cancer types, the small GTPase RAC1B inhibits cell motility induced by recombinant human TGFβ1 via downregulation of  ...[more]

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