LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity

作者：Chenchen Liu, Aiwen Shen, Junquan Song, Lei Cheng, Meng Zhang, Yanong Wang, Xiaowen Liu · 发表于：癌症：英文版 · 年份：2023 · DOI：10.1002/cac2.12507 · 被引用次数：62 · 研究领域：Wnt/β-catenin signaling in development and cancer、Cancer-related molecular mechanisms research、Ferroptosis and cancer prognosis

Abstract Background Although the constitutively activated Wnt/β‐catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non‐coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt‐transactivated lncRNA, colon cancer‐associated transcript 5 (CCAT5), in GC metastasis. Methods LncRNA‐sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation‐resistant β‐catenin (S33Y mutated) in ascites‐derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)‐re‐ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain‐ and loss‐of‐function studies. The molecular mechanism was explored through RNA‐sequencing, mass spectrometry, and CRISPR/Cas9‐knocknout system. The therapeutic potential of CCAT5 was examined through RNAi‐based cell xenograft model and patient‐derived xenograft (PDX) model of IPD. Results We identified a novel Wnt‐regulated lncRNA, CCAT5, which was transactivated by the β‐catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirm...