Chen Yang, Sun Qihui, Zou Qi, Zhu Xiaoqi, Wen Tingting, Li Xiaojia, Li Shu, He Jie, Wei Fang, Xie Keping
Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong, China.
Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, Guangzhou, China.
Mol Carcinog. 2025 Mar;64(3):565-579. doi: 10.1002/mc.23870. Epub 2025 Jan 6.
Pancreatic cancer is a highly lethal malignancy with few effective treatment options. Connexin 31 (Cx31) is a membrane protein capable of forming hexameric channels to facilitate the exchange of metabolites and signaling molecules. Yet, the contribution of Cx31 to the onset and progression of pancreatic cancer remains to be understood. We analyzed Cx31 expression in pancreatic cancer tissues and cell lines using public databases and experimental models. The correlation between Cx31 expression and clinical outcomes was evaluated. The effects of Cx31 on pancreatic cancer cell proliferation, stemness, migration, chemoresistance, and immune infiltration were investigated. Transcriptome analysis and bioinformatics tools were employed to explore the underlying mechanisms. Cx31 was found to be upregulated in pancreatic cancer tissues compared to normal tissues, and its high expression correlated with shorter overall survival and higher mortality risk. Cx31 promoted acinar-to-ductal metaplasia (ADM), stemness, proliferation, migration, metastasis, and chemoresistance in pancreatic cancer cells. Bioinformatics analysis suggested a positive correlation between Cx31 and stemness-related genes. Cx31 knockdown altered the expression of genes involved in stemness and chemoresistance pathways, such as Wnt and Notch. Additionally, Cx31 was identified as a direct target of the transcription factor FOXM1, which upregulated its expression. Cx31 plays a multifaceted role in pancreatic cancer, influencing processes from initiation to metastasis and chemoresistance. It may serve as a potential therapeutic target to combat the aggressive nature of pancreatic cancer. The FOXM1-Cx31 axis could be a promising target for overcoming treatment resistance in pancreatic cancer.
胰腺癌是一种极具致死性的恶性肿瘤，有效的治疗选择极少。连接蛋白31（Cx31）是一种膜蛋白，能够形成六聚体通道以促进代谢产物和信号分子的交换。然而，Cx31对胰腺癌发生和进展的作用仍有待明确。我们使用公共数据库和实验模型分析了胰腺癌组织和细胞系中Cx31的表达情况。评估了Cx31表达与临床结局之间的相关性。研究了Cx31对胰腺癌细胞增殖、干性、迁移、化疗耐药性和免疫浸润的影响。采用转录组分析和生物信息学工具来探究潜在机制。结果发现，与正常组织相比，胰腺癌组织中Cx31表达上调，其高表达与较短的总生存期和较高的死亡风险相关。Cx31促进胰腺癌细胞的腺泡-导管化生（ADM）、干性、增殖、迁移、转移和化疗耐药性。生物信息学分析表明Cx31与干性相关基因之间呈正相关。敲低Cx31可改变参与干性和化疗耐药性途径的基因表达，如Wnt和Notch。此外，Cx31被确定为转录因子FOXM1的直接靶点，FOXM1上调了其表达。Cx31在胰腺癌中发挥多方面作用，影响从起始到转移和化疗耐药性的多个过程。它可能作为一个潜在的治疗靶点来对抗胰腺癌的侵袭性。FOXM1-Cx31轴可能是克服胰腺癌治疗耐药性的一个有前景的靶点。
