Abstract
Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that the RNA-binding protein DDX5 binds to the mRNA transcripts of C3 and Fabp1 to augment their expressions posttranscriptionally. Knocking out DDX5 in epithelial cells protected mice from intestinal tumorigenesis and dextran sodium sulfate (DSS)-induced colitis. Identification of DDX5 as a common upstream regulator of tissue-specific oncogenic molecules provides an excellent therapeutic target for intestinal diseases.
Highlights
Tissue-specific oncogenic molecules drive tumorigenesis in different segments of the intestinal tract
We hypothesize that DDX5 may bind to target colonic intestinal epithelial cells (IECs) RNAs in the nucleus and regulate their expressions posttranscriptionally
Comparison of the RNA profile of colonic IECs isolated from steady-state WTIEC and DDX5ΔIEC mice revealed that knocking out DDX5 resulted in a down-regulation of 306 and upregulation of 174 colonic IEC transcripts (Fig 1D and Table S2)
Summary
Tissue-specific oncogenic molecules drive tumorigenesis in different segments of the intestinal tract. Ablation of FABP1 genetically protects against tumorigenesis in the small intestine [10]. C3 transcription is controlled by the twist basic helix–loop–helix transcription factor 1 (TWIST1), CCAAT/enhancer-binding protein β (C/EBPβ), nuclear receptors farnesoid X receptor, and peroxisome proliferator-activated receptor α in response to stimulation from pro-inflammatory cytokines, such as TNFα, IFNγ, and IL1β [11, 12, 13, 14, 15, 16, 17]. Fabp transcription is controlled by GATA-binding protein 4 (GATA4), C/EBP, peroxisome proliferator-activated receptor α, pancreatic and duodenal homeobox 1 (PDX1), and hypoxia-inducible factor (HIF1α) [18, 19, 20, 21, 22]. Little is known about how C3 and FABP1 expressions are regulated posttranscriptionally in intestinal epithelial cells (IECs)
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