Abstract
Liver X receptors (LXRs) are involved in various diseases associated with lipid disorders, and in regulating cancer cell proliferation. However, the underlying molecular mechanisms, especially those in gastric cancer (GC) remain to be clarified. In this study, immunohistochemistry analysis revealed that LXRβ was mainly expressed in GC tissue, with less expression in adjacent normal tissues. The LXRβ agonist T0901317 efficiently suppressed the proliferation and colony formation of various GC cell lines. We further showed that LXRβ translocated from the cytoplasm to the nucleus when activated by T0901317. LXRβ nuclear localization suppressed the activation of Wnt signalling and decreased the expression of target genes such as MYC, BMP4, and MMP7 through binding to their promoters. Moreover, we demonstrated that the LXR agonist efficiently suppressed GC tumour growth in a nude mouse xenograft model. Taken together, these results revealed that LXRβ agonist inhibited GC cells proliferation by suppressing Wnt signalling via LXRβ relocalization. The results strongly suggest that LXRβ could be a promising target in GC therapy.
Highlights
Liver X receptors (LXRs) are important members of the nuclear receptor (NR) superfamily that are involved in a number of diseases, including lipid disorders, cancer, and neurodegenerative diseases.[1]
We demonstrated that LXRβ was strongly expressed in gastric cancer (GC) tissues from clinical samples at both the mRNA and protein levels
LXRβ expression was much weaker in adjacent normal tissue than in GC tissue (Figure 1)
Summary
Liver X receptors (LXRs) are important members of the nuclear receptor (NR) superfamily that are involved in a number of diseases, including lipid disorders, cancer, and neurodegenerative diseases.[1]. One of the main mechanisms by which LXR agonist inhibits tumour growth is through inhibition of cell proliferation and induction of cell death.[3]. LXR agonist treatments inhibit cell proliferation, cell‐cycle progression, and colony formation, regulating multiple gene networks involved in cell cycle arrest and growth factor signalling.[5]. LXR agonists inhibit cell proliferation and cell cycle arrest in breast cancer cells by regulating hepatic expression of the oestrogen deactivation enzyme.[6]. The subcellular localization of LXR is controversial in different cancer cells. LXRβ shows predominant cytoplasmic localization in colon cancer cells but not in normal colon mucosa cells.[8,9]. Both nuclear and cytoplasmic localization was observed in PDAC samples.[5]. The in vivo experiment demonstrated that the LXR agonist suppresses tumour growth in a nude mouse model
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