PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer
Ungefroren, H.; Reimann, J.; Konukiewitz, B.; Braun, R.; Wellner, U.F.; Lehnert, H.; Marquardt, J.U. RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer. Preprints2023, 2023091790. https://doi.org/10.20944/preprints202309.1790.v1
APA Style
Ungefroren, H., Reimann, J., Konukiewitz, B., Braun, R., Wellner, U.F., Lehnert, H., & Marquardt, J.U. (2023). RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer. Preprints. https://doi.org/10.20944/preprints202309.1790.v1
Chicago/Turabian Style
Ungefroren, H., Hendrik Lehnert and Jens U. Marquardt. 2023 "RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer" Preprints. https://doi.org/10.20944/preprints202309.1790.v1
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease due to early metastatic spread, late diagnosis and the lack of efficient therapies. A major driver of cancer progression and hurdle to successful treatment is the desmoplastic reaction of the tumor stroma, the formation of which is orchestrated by transforming growth factor (TGF)-β. Recent data from pancreatic cancer mouse models have shown that the TGF-β pathway is controlled by transcriptionally active p73 (TAp73) through secretion of biglycan (Bgn) via intermittent expression of the TGF-β signaling intermediates, Smad3 and Smad4. Genetic knockout of TP73, and, as a consequence, deficient induction of Smad3/Dpc4 and secretion of Bgn led to activation of TGF-β signaling through a (Smad-independent) ERK pathway, favoring epithelial-mesenchymal transition (EMT) and cell motility. Except for BGN, these functions of TAp73 have recently been shown to also operate in human PDAC cells and are reminiscent of what we previously observed for the small GTPase, RAC1b. This prompted us to hypothesize that TAp73 and RAC1b are part of the same tumor-suppressive pathway in human PDAC cells. The two objectives of this study, therefore, were to reveal i) if the regulatory interactions between TAp73 and Bgn previously discovered in murine PDAC-derived cells also operate in their human counterparts, and ii) if RAC1b collaborates with TAp73 in these tumor-suppressive activities in human PDAC cells. Using a variety of experimental approaches, including mutual rescue experiments, we were able to show that the previously proposed tumor-suppressive TAp73-Smad4-Bgn signaling also operates in human cells and that RAC1b is as an upstream activator of this pathway. Our findings highlight the complex role of TGF-β in pancreatic tumorigenesis and might have implications for therapeutic approaches targeting this growth factor for inhibition.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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