UXT-V1 contributes to the malignant phenotypes of colorectal cancer via GSK3β by activating Wnt/β-catenin pathway

Abstract

Background: Colorectal cancer (CRC) is one of malignant tumors that seriously threatening human health. β-catenin is a central hub in Wnt pathway, aberrant activation of Wnt/β-catenin signaling pathway promotes the tumorigenesis/progression of CRC. Methods and Results: Here we found a β-catenin interactor, UXT-V1, could modulate Wnt signaling. The expression of UXT-V1 mRNA was increased in CRC tissues. Overexpression of UXT-V1 increased the canonical Wnt signaling, as evidenced by Wnt reporter systems and the up-regulation of marker genes including Axin, CyclinD1 and c-Myc. While, knockdown of UXT-V1 impaired the expression of these genes and attenuated Wnt signaling. Mechanistically, overexpression of UXT-V1 could inhibit GSK3β mediated β-catenin phosphorylation and degradation. Knockout of UXT-V1 increased β-catenin phosphorylation, prevented CRC cell growth, and inhibited tumorigenesis in NOD-SCID mice. Conclusions: Taken together, our findings revealed that UXT-V1 could control Wnt signaling through targeting GSK3β mediated β-catenin phosphorylation and degradation, providing a molecular basis for CRC treatment.

Regulation of epithelial cell differentiation by the Ubiquitous expressed transcript isoform 1 in ulcerative colitis

“…Furthermore, UXT‐V1 upregulated the colonocyte differentiation markers in human IECs, whereas the lack of UXT‐V1 led to the downregulation of MUC2 and VIL1, the differentiation markers for enterocytic lineages. Contradictory to our findings, a recent study showed that UXT‐V1 expression in CRC tissues is higher than that in the corresponding para‐cancerous tissues and promotes CRC cell growth 21 . Thus, the exact function of UXT‐V1 may depend on the cell type.…”

“…Contradictory to our findings, a recent study showed that UXT-V1 expression in CRC tissues is higher than that in the corresponding para-cancerous tissues and promotes CRC cell growth. 21 Thus, the exact function of UXT-V1 may depend on the cell type. .…”

“…UXT contains two mRNA splicing variants that generate two UXT isoforms, UXT‐V1 and UXT‐V2, respectively. Previous studies have demonstrated that UXT is highly expressed in colorectal tumor tissues and is involved in cell proliferation or differentiation 20,21 . In addition, UXT can act as an essential part of the NF‐κB enhancer in response to TNF‐α stimulation 22,23 .…”

“…Previous studies have demonstrated that UXT is highly expressed in colorectal tumor tissues and is involved in cell proliferation or differentiation. 20,21 In addition, UXT can act as an essential part of the NF-κB enhancer in response to TNF-α stimulation. 22,23 As the activated TNF-α/NF-κB pathway is a major factor in colitis processes, 24 and UC is an important risk factor for subsequent development of colorectal cancer, 25 it suggests that UXT seem to play acritical role in UC.…”