WYC-209 inhibited GC malignant progression by down-regulating WNT4 through RARα.

IF 4.4 4区医学 Q2 ONCOLOGY Cancer Biology & Therapy Pub Date : 2024-12-31 Epub Date: 2024-01-04 DOI:10.1080/15384047.2023.2299288

Zhenyuan Qian, Wenfa Lin, Xufan Cai, Jianzhang Wu, Kun Ke, Zaiyuan Ye, Fang Wu

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Abstract

Gastric cancer (GC) has been a major health burden all over the world but there are fewer promising chemotherapeutic drugs due to its multidrug resistance. It has been reported that WYC-209 suppresses the growth and metastasis of tumor-repopulating cells but the effect on GC was not explored. MTT, colony formation, and transwell assays were performed to examine the effects of WYC-209 on the proliferation, colony growth, and mobility of GC cells. Western blotting and qRT-PCR were used to detect the expression of proteins and mRNA. RNA-seq and enrichment analyses were conducted for the differentially expressed genes and enriched biological processes and pathways. The rescue experiments were carried out for further validation. Besides, we constructed xenograft model to confirm the effect of WYC-209 in vivo. The dual-luciferase reporter and Chromatin immunoprecipitation were implemented to confirm the underlying mechanism. WYC-209 exerted excellent anti-cancer effects both in vitro and in vivo. Based on RNA-seq and enrichment analyses, we found that Wnt family member 4 (WNT4) was significantly down-regulated. More importantly, WNT4 overexpression breached the inhibitory effect of WYC-209 on GC progression. Mechanically, WYC-209 significantly promoted the binding between retinoic acid receptor α (RARα) and WNT4 promoter. WYC-209 exerts anti-tumor effects in GC by down-regulating the expression of WNT4 via RARα.

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WYC-209 通过 RARα 下调 WNT4，从而抑制 GC 的恶性发展。

胃癌（GC）一直是全球主要的健康负担，但由于其多药耐药性，有前景的化疗药物较少。有报道称，WYC-209 可抑制肿瘤繁殖细胞的生长和转移，但对 GC 的影响尚未探究。为了研究 WYC-209 对 GC 细胞的增殖、集落生长和移动性的影响，我们进行了 MTT、集落形成和透孔试验。采用 Western 印迹和 qRT-PCR 检测蛋白质和 mRNA 的表达。对差异表达基因和富集的生物过程和通路进行了 RNA-seq 和富集分析。为了进一步验证，我们还进行了拯救实验。此外，我们还构建了异种移植模型来证实 WYC-209 在体内的作用。我们还利用双荧光素酶报告和染色质免疫沉淀来证实其潜在机制。WYC-209在体外和体内都发挥了很好的抗癌作用。基于 RNA-seq 和富集分析，我们发现 Wnt 家族成员 4（WNT4）被显著下调。更重要的是，WNT4的过表达破坏了WYC-209对GC进展的抑制作用。在机制上，WYC-209 能明显促进视黄酸受体α（RARα）与 WNT4 启动子的结合。WYC-209 通过 RARα 下调 WNT4 的表达，从而在 GC 中发挥抗肿瘤作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Biology & Therapy 医学-肿瘤学

CiteScore

7.00

自引率

0.00%

发文量

审稿时长

2.3 months

期刊介绍： Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.