RUNX1-MUC13相互作用激活Wnt/β-连环蛋白信号通路及其对结直肠癌转移的影响

RUNX1-MUC13 Interaction Activates Wnt/β-Catenin Signaling Implications for Colorectal Cancer Metastasis

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International Journal of Biological Sciences

影响因子:10

分区:生物学1区 Top / 生化与分子生物学2区

发表日期:2024

作者: Xinyi Chen, Jingyao Tu, Mu Yang, Yuan Wang, Bo Liu, Hong Qiu, Xianglin Yuan

DOI: 10.7150/ijbs.98396

摘要

背景：结直肠癌（CRC）仍然是全球范围内的重要公共卫生挑战，常表现为晚期转移和预后差。Runt相关转录因子1（RUNX1）在多种癌症中扮演双重角色，既是肿瘤基因又是肿瘤抑制基因，包括CRC。然而，RUNX1在CRC中的具体调控机制，尤其是其直接作用尚未完全阐明。目的：本研究旨在探究RUNX1在CRC进展中的作用及其与Mucin 13（MUC13）的潜在调控关系。方法：比较CRC组织和细胞系中RUNX1的表达水平与对照组的差异。采用体内外实验评估RUNX1过表达和敲除对细胞行为的影响。通过ChIP-seq和RNA-seq分析鉴定RUNX1的靶基因，重点关注MUC13。结果：CRC组织和细胞中RUNX1表达显著上调，并与更高级别的病理特征及患者预后不良相关。RUNX1过表达促进CRC细胞的增殖、迁移、侵袭及G2/M期阻滞，敲除则表现出相反的效应。MUC13被鉴定为RUNX1的直接转录靶基因，其表达水平促使Wnt/β-连环蛋白信号通路的激活。干扰MUC13部分逆转RUNX1诱导的恶性表型。结论：RUNX1通过上调MUC13并激活Wnt/β-连环蛋白通路促进CRC进展。该RUNX1-MUC13轴是潜在的治疗靶点，为CRC的治疗提供新的思路。

Abstract

Background: Colorectal cancer (CRC) remains a significant global health challenge, often characterized by late-stage metastasis and poor prognosis. The Runt-related transcription factor 1 (RUNX1) plays a dual role as both an oncogene and a tumor suppressor in various cancers, including CRC. However, the specific regulatory mechanisms of RUNX1 in CRC, particularly its direct roles, are not fully understood. Objective: This study aimed to investigate the role of RUNX1 in CRC progression and its interaction with Mucin 13 (MUC13) as a potential regulatory target. Methods: RUNX1 expression was analyzed in CRC tissues and cell lines compared to controls. In vitro and in vivo assays were conducted to assess the effects of RUNX1 overexpression and knockdown on cell behavior. ChIP-seq and RNA-seq analyses were performed to identify RUNX1 targets, with a focus on MUC13. Results: RUNX1 expression was significantly upregulated in CRC tissues and cells, correlating with advanced pathological characteristics and poor patient outcomes. RUNX1 overexpression enhanced CRC cell proliferation, migration, invasion, and G2/M phase arrest, while its knockdown had the opposite effects. MUC13 was identified as a direct transcriptional target of RUNX1, with its expression contributing to the activation of the Wnt/β-catenin signaling pathway. Disruption of MUC13 partially reversed the malignant phenotypes induced by RUNX1. Conclusion: RUNX1 promotes CRC progression by upregulating MUC13 and activating the Wnt/β-catenin pathway. This RUNX1-MUC13 axis represents a potential therapeutic target for managing CRC.