Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/metabolism ; Pancreatic Neoplasms*/genetics ; Carcinoma, Pancreatic Ductal*/pathology ; Carcinoma, Pancreatic Ductal*/metabolism ; Carcinoma, Pancreatic Ductal*/genetics ; CCAAT-Enhancer-Binding Protein-delta*/metabolism ; CCAAT-Enhancer-Binding Protein-delta*/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit*/genetics; Animals ; Mice ; Humans ; Cell Line, Tumor ; Cell Proliferation ; Hypoxia/metabolism ; Cell Hypoxia ; Gene Expression Regulation, Neoplastic

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner. One such molecule is the transcription factor C/EBPδ, where we recently showed that C/EBPδ exerts tumor-suppressive effects in PDAC cells in vitro. To better understand the role of C/EBPδ in different contexts and the development of PDAC, we here build on these findings and assess the effect of C/EBPδ in a PDAC model in mice. We establish that the lack of oxygen in vivo-hypoxia-counteracts the tumor-suppressive effects of C/EBPδ, and identify a reciprocal feedback loop between C/EBPδ and HIF-1α. RNA sequencing of C/EBPδ-induced cells under hypoxia also suggests that the growth-limiting effects of C/EBPδ decrease with oxygen tension. Consequently, in vitro proliferation assays reveal that the tumor-suppressive activities of C/EBPδ are abrogated due to hypoxia. This study demonstrates the importance of considering major physiological parameters in preclinical approaches.

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Keywords: CEBPD; HIF1A; hypoxia; pancreatic cancer

142662-43-9 (CCAAT-Enhancer-Binding Protein-delta)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)

Date Created: 20240914 Date Completed: 20240914 Latest Revision: 20240916

20240916

PMC11394991

10.3390/ijms25179449

39273396