Open Access
Issue
Vis Cancer Med
Volume 4, 2023
Article Number 2
Number of page(s) 2
DOI https://doi.org/10.1051/vcm/2022006
Published online 06 January 2023

© The Authors, published by EDP Sciences, 2023

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gastric cancer (GC) is the fifth most common cancer incidence and the third most common cause of cancer death worldwide. About half of the GC patients come from China, most of whom were in the late stages with lymph node or distal metastasis at the time of diagnosis, resulting in only 16.35% of the diseases at stages I and II [13]. It is, therefore, critical to elucidate the underlying mechanisms for GC promotion and progression by which novel therapeutics could be developed.

Initially found in Wilms tumor, WTX (Wilms tumor gene on the X chromosome, also called AMER1) is an X-linked tumor suppressor located on chromosome Xq11.2. This gene has 1 transcript (splice variant), 189 orthologues, 2 paralogues and is associated with phenotypes. The full-length WTX protein resides at the plasma membrane and cytoplasm and possesses three adenomatous polyposis coli (APC) binding domains [4, 5]. The short isoform localizes primarily to the nucleus. Nuclear WTX forms a complex with β-catenin and the destruction complex (AXIn1, β-transducin repeat-containing protein 2, and APC) and promotes ubiquitylation and degradation of β-catenin. The short isoform negatively regulates the Wnt/β-catenin signaling pathway [6].

The inactivation of the WTX gene just needs a monoallelic “single-hit” that targets the single X chromosome in tumors from males and the active X chromosome in tumors from females [7]. The loss of WTX is also linked to a predisposition for nephroblastoma [8]. Mechanistic research has revealed that WTX can inhibit Wnt/β-catenin signaling pathway activation by binding β-catenin and promoting β-catenin ubiquitination and degradation [9, 10]. The interaction between WTX and p53 affects nuclear proteins. The loss of WTX accelerates CBP/p300 protein turnover and attenuates this modification of p53. In p53-reconstitution experiments, cell-cycle arrest, apoptosis, and p53 target-gene expression are suppressed by the depletion of WTX. Together, these results suggest that WTX modulates the p53 function partly by regulating its activator CBP/p300 [11].

According to previous studies, WTX was generally lost in GC, and the stomach was identified as another important target organ of the WTX gene [12]. Different from the high mutation rate (16.3%–30%) and high loss rate in Wilms tumor [13], WTX mutations and high methylation levels of WTX promoters are rare among GC, which suggests that there may be other mechanisms leading to the silencing of WTX gene. Li and colleagues report in the Journal of Experimental & Clinical Cancer Research that using three published target prediction databases, they selected miR-20a-5p as the top candidate regulator of WTX expression in GC. The following luciferase assay experiments confirmed that miR-20a-5p could directly bind to the WTX 3’UTR. After that, the authors established gastric tumor mouse models to determine the effect of WTX on tumor formation and growth in vivo. Additional cellular functional tests in GC cell lines showed that WTX significantly inhibited the proliferation, migration, and invasion abilities of GC cells. Over-expression of WTX in AGS cells significantly inhibited the activity of PI3K/AKT signaling. Mechanistically, WTX expression suppresses PI3K/AKT/mTOR pathway activity by inhibiting PI3K phosphorylation (Video 1). Finally, miR-20a-5p was found to positively regulate PI3K/AKT pathway activation by inhibiting WTX expression, thereby promoting GC progression [14].

Video 1

WTX inhibits PI3K/AKT/mTOR pathway.

It has been reported that WTX plays a major role in organ development and tumor suppression, but its functions have not been well elucidated. The clinical significance and specific mechanism of the WTX gene in different tumor types still need further study. Li’ s article first reveals the clinical significance of the WTX gene in GC, and the clinicopathological consequences showed that WTX loss is associated with poorer GC differentiation, more invasion, increased tumor cell proliferation, increased lymph node metastasis, and poorer GC patient prognosis. These findings suggest that WTX loss could be used as a prognostic marker for GC patients.

The mechanism of inhibiting PI3K phosphorylation by WTX to suppress PI3K/AKT/mTOR signaling in GC might also work in other type of malignancies. Further explorations are warranted to identify the specific protein binding sites of miR-20a-5p on the promoter regions of WTX and the phosphorylation sites of PI3K.

Conflict of interest

The authors have nothing to disclose.

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Cite this article as: Zhang Q, Hu Q, Li J & Lin Z. WTX beyond WNT signaling pathway. Visualized Cancer Medicine. 2023. 4, 2.

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Video 1

WTX inhibits PI3K/AKT/mTOR pathway.

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