Abstract
Caudal-related homeobox transcription factor 2 (CDX2), an intestine-specific nuclear transcription factor, has been strongly implicated in the tumourigenesis of various human cancers. However, the functional role of CDX2 in the development and progression of colorectal cancer (CRC) is not well known. In this study, CDX2 knockdown in colon cancer cells promoted cell proliferation in vitro, accelerated tumor formation in vivo, and induced a cell cycle transition from G0/G1 to S phase, whereas CDX2 overexpression inhibited cell proliferation. TOP/FOP-Flash reporter assay showed that CDX2 knockdown or CDX2 overexpression significantly increased or decreased Wnt signaling activity. Western blot assay showed that downstream targets of Wnt signaling, including β-catenin, cyclin D1 and c-myc, were up-regulated or down-regulated in CDX2-knockdown or CDX2-overexpressing colon cancer cells. In addition, suppression of Wnt signaling by XAV-939 led to a marked suppression of the cell proliferation enhanced by CDX2 knockdown, whereas activation of this signaling by CHIR-99021 significantly enhanced the cell proliferation inhibited by CDX2 overexpression. Dual-luciferase reporter and quantitative chromatin immunoprecipitation (qChIP) assays further confirmed that CDX2 transcriptionally activates glycogen synthase kinase-3β (GSK-3β) and axis inhibition protein 2 (Axin2) expression by directly binding to the promoter of GSK-3β and the upstream enhancer of Axin2. In conclusion, these results indicated that CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling.
Highlights
Colorectal cancer (CRC) is the third most common cancer and ranks as the fourth leading cause of cancer death[1]
To investigate whether the tumor suppression potential of Caudal-related homeobox transcription factor 2 (CDX2) in vivo could be due to its cell proliferation inhibition, the expression levels of the universal proliferation biomarker Ki67 were determined by IHC
The results showed the xenograft tumor tissues formed by CDX2-knockdown cells demonstrated a much stronger Ki67-staining score than those formed by the control cells (Fig. 2a, b), whereas the xenograft tumor tissues formed by CDX2-overexpressing cells had the opposite effect (Fig. 2a, b)
Summary
Colorectal cancer (CRC) is the third most common cancer and ranks as the fourth leading cause of cancer death[1]. Canonical Wnt signaling performs a crucial role in maintaining intestinal homeostasis by regulating proliferation, differentiation, and cell-fate decisions[6,7,8]. Aberrant activation of Wnt signaling is associated with human carcinogenesis, including CRC9,10. An elevated nuclear β-catenin level is considered a hallmark of invasive CRC, leading to the activation of Wnt-related targets, including c-myc, cyclin D1, MMP2, and MMP9, thereby promoting cell proliferative, invasive, and migratory potential[14,15,16,17]. Increasing evidence supports a potential role of CDX2 as an oncogene or suppressor in tumourigenesis of various human malignancies including hepatocellular carcinoma[20], pancreatic cancer[21,22], lung cancer[23,24], and gastric cancer[25,26]. The role of CDX2 in regulating Wnt signaling in human CRC development and progression remain to be elucidated
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