Exploring the Role of Wnt/β-Catenin Signaling in Gastric Cancer: Implications for Early Diagnosis and Targeted Therapy

Abstract

Background

Gastric cancer (GC), as one of the main causes of cancer-related death, has relatively few treatment options, and the Wnt/β-catenin signaling pathway plays a crucial role in the course of this disease; this study investigates the pathway’s role and evaluates the therapeutic potential of its inhibition using a rat model.

Materials and Methods

Fifty Sprague Dawley rats were divided into control, model, Wnt/β-catenin inhibition, IWR-1 treatment, and combined treatment groups, with GC induced by methyl-N′-nitro-N-nitrosoguanidine (MNNG) administration. Protein and mRNA expression levels of Wnt, β-catenin, and P-β-catenin were evaluated using Western blotting, hematoxylin–eosin (HE) staining, immunohistochemistry, and RT-PCR.

Results

The tumor proliferation of experimental rats can be significantly inhibited by suppressing the Wnt/β-catenin signaling pathway, and the expression levels of related molecules in this pathway also show obvious downregulation, with combined IWR-1 treatment further enhancing these therapeutic effects compared with the model group.

Conclusion

Targeting the Wnt/β-catenin signaling pathway shows good prospects as a potential strategy for the treatment of GC, with findings suggesting that its inhibition could limit tumor progression and warrant further investigation for clinical applications.

Keywords

gastric cancer Wnt/β-catenin signaling IWR-1 therapeutic inhibition

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References

Ashrafizadeh

Rafiei

Mohammadinejad

Farkhondeh

Samarghandian

(2020). Wnt-regulating microRNAs role in gastric cancer malignancy. Life Sciences, 250, 117547. https://doi.org/10.1016/j.lfs.2020.117547

Zhang

Song

Sun

Mulholland

M. W.

Yin

Zhang

(2024). Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/β-catenin signaling pathway. Gastroenterología y Hepatología, 47(4), 352–365. https://doi.org/10.1016/j.gastrohep.2023.05.016

Bugter

J. M.

Fenderico

Maurice

M. M.

(2021). Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nature Reviews Cancer, 21(1), 5–21. https://doi.org/10.1038/s41568-020-00307-z

Chu

P. Y.

Chen

Y. F.

C. Y.

Yang

J. S.

King

Y. A.

Chiu

Y. J.

(2021). Factors influencing locoregional recurrence and distant metastasis in Asian patients with cutaneous melanoma after surgery: A retrospective analysis in a tertiary hospital in Taiwan. Journal of the Chinese Medical Association, 84(9), 870–876. https://doi.org/10.1097/jcma.0000000000000586

Guan

W. L.

R. H.

(2023). Gastric cancer treatment: Recent progress and future perspectives. Journal of Hematology & Oncology, 16(1), 57. https://doi.org/10.1186/s13045-023-01451-3

Guo

Huang

Yao

Chen

Liu

Zhang

Lin

(2021). ADMA mediates gastric cancer cell migration and invasion via Wnt/β-catenin signaling pathway. Clinical and Translational Oncology, 23(2), 325–334. https://doi.org/10.1007/s12094-020-02422-7

Y. J.

Liao

L. L.

Liu

Tang

Wang

Peng

Q. H.

(2022). Sijunzi decoction inhibits stemness by suppressing β-catenin transcriptional activity in gastric cancer cells. Chinese Journal of Integrative Medicine, 28(8), 702–710. https://doi.org/10.1007/s11655-021-3314-9

López

M. J.

Carbajal

Alfaro

A. L.

Saravia

L. G.

Zanabria

Araujo

J. M.

Quispe

Zevallos

Buleje

J. L.

Cho

C. E.

Sarmiento

Pinto

J. A.

Fajardo

(2023). Characteristics of gastric cancer around the world. Critical Reviews in Oncology/Hematology, 181, 103841. https://doi.org/10.1016/j.critrevonc.2022.103841

Nair

Davis

Campagne

Schuetz

J. D.

Stewart

C. F.

(2022). Development and validation of a sensitive and specific LC-MS/MS method for IWR-1-endo, a Wnt signaling inhibitor: Application to a cerebral microdialysis study. Molecules, 27(17), 5448. https://doi.org/10.3390/molecules27175448

10.

Pakhomova

E. E.

Smirnova

I. O.

(2020). Comparative evaluation of the clinical efficacy of PRP-therapy, minoxidil, and their combination with immunohistochemical study of the dynamics of cell proliferation in the treatment of men with androgenetic alopecia. International Journal of Molecular Sciences, 21(18), 6516. https://doi.org/10.3390/ijms21186516

11.

Shah

Panchal

Patel

(2021). Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacological Research, 167, 105532. https://doi.org/10.1016/j.phrs.2021.105532

12.

Smyth

E. C.

Nilsson

Grabsch

H. I.

van Grieken

N. C.

Lordick

(2020). Gastric cancer. The Lancet, 396(10251), 635–648. https://doi.org/10.1016/s0140-6736(20)31288-5

13.

Tanton

Sewastianik

Seo

H. S.

Remillard

Pierre

R. S.

Bala

Aitymbayev

Dennis

Adler

Geffken

Yeoh

Vangos

Garbicz

Scott

Sethi

Bradner

Dhe-Paganon

Carrasco

R. D.

(2022). A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer. Science Advances, 8(17), eabm3108. https://doi.org/10.1126/sciadv.abm3108

14.

Tian

Peng

Deng

Zhan

Zeng

Dong

(2020). SERPINH1 regulates EMT and gastric cancer metastasis via the Wnt/β-catenin signaling pathway. Aging (Albany NY), 12(4), 3574–3593. https://doi.org/10.18632/aging.102831

15.

Togasaki

Sugimoto

Ohta

Nanki

Matano

Takahashi

Fujii

Kanai

Sato

(2021). Wnt signaling shapes the histologic variation in diffuse gastric cancer. Gastroenterology, 160(3), 823–830. https://doi.org/10.1053/j.gastro.2020.10.047

16.

Wang

W. M.

Gao

Y. M.

Zheng

X. F.

Jin

H. Z.

(2024). IWR-1 attenuates the promotional effect of IL-36γ in a mouse model of psoriasis. BMC Immunology, 25(1), 78–https://doi.org/10.1186/s12865-024-00669-1.

17.

Wang

Zheng

Shang

Yang

Liu

Shao

Chai

Liang

Zeng

Jia

(2022). Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer. Cell Death & Differentiation, 29(11), 2190–2202. https://doi.org/10.1038/s41418-022-01008-w

18.

Wei

Meng

Wang

Shi

(2021). lncRNA SNHG11 promotes gastric cancer progression by activating the Wnt/β-catenin pathway and oncogenic autophagy. Molecular Therapy, 29(3), 1258–1278. https://doi.org/10.1016/j.ymthe.2020.10.011

19.

Zang

Jiang

Chen

Wang

Zhang

Shi

Cai

Qian

Zhang

(2022). Circular RNA EIF4G3 suppresses gastric cancer progression through inhibition of β-catenin by promoting δ-catenin ubiquitin degradation and upregulating SIK1. Molecular Cancer, 21(1), 141. https://doi.org/10.1186/s12943-022-01606-9

20.

Zhang

Yan

Zhang

Zhuang

Zhou

Deng

Zhang

(2022). Effect of VD3 on cell proliferation and the Wnt signaling pathway in bovine endometrial epithelial cells treated with lipopolysaccharide. Theriogenology, 193, 68–76. https://doi.org/10.1016/j.theriogenology.2022.09.002