RAC1b Collaborates with TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

被引:1
作者
Ungefroren, Hendrik [1 ,2 ]
Reimann, Julissa [1 ]
Konukiewitz, Bjoern [2 ]
Braun, Ruediger [3 ]
Wellner, Ulrich F. [3 ]
Lehnert, Hendrik [4 ]
Marquardt, Jens-Uwe [1 ]
机构
[1] Univ Hosp Schleswig Holstein UKSH, Dept Med 1, Campus Lubeck, D-23538 Lubeck, Germany
[2] Univ Hosp Schleswig Holstein UKSH, Inst Pathol, Campus Kiel, D-24105 Kiel, Germany
[3] Univ Hosp Schleswig Holstein UKSH, Dept Surg, Campus Lubeck, D-23538 Lubeck, Germany
[4] Univ Salzburg, A-5020 Salzburg, Austria
关键词
biglycan; cell migration; epithelial-mesenchymal transition; PDAC; RAC1b; SMAD3; SMAD4; TAp73; transforming growth factor-beta; LEADS; EMT;
D O I
10.3390/biomedicines12010199
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type characterized by a marked desmoplastic tumor stroma that is formed under the influence of transforming growth factor (TGF)-beta. Data from mouse models of pancreatic cancer have revealed that transcriptionally active p73 (TAp73) impacts the TGF-beta pathway through activation of Smad4 and secretion of biglycan (Bgn). However, whether this pathway also functions in human PDAC cells has not yet been studied. Here, we show that RNA interference-mediated silencing of TAp73 in PANC-1 cells strongly reduced the stimulatory effect of TGF-beta 1 on BGN. TAp73-mediated regulation of BGN, and inhibition of TGF-beta signaling through a (Smad-independent) ERK pathway, are reminiscent of what we previously observed for the small GTPase, RAC1b, prompting us to hypothesize that in human PDAC cells TAp73 and RAC1b are part of the same tumor-suppressive pathway. Like TAp73, RAC1b induced SMAD4 protein and mRNA expression. Moreover, siRNA-mediated knockdown of RAC1b reduced TAp73 mRNA levels, while ectopic expression of RAC1b increased them. Inhibition of BGN synthesis or depletion of secreted BGN from the culture medium reproduced the promigratory effect of RAC1b or TAp73 silencing and was associated with increased basal and TGF-beta 1-dependent ERK activation. BGN also phenocopied the effects of RAC1b or TAp73 on the expression of downstream effectors, like the EMT markers E-cadherin, Vimentin and SNAIL, as well as on negative regulation of the ALK2-SMAD1/5 arm of TGF-beta signaling. Collectively, we showed that tumor-suppressive TAp73-Smad4-Bgn signaling also operates in human cells and that RAC1b likely acts as an upstream activator of this pathway.
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页数:17
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