The ZIC2-Claudin-18.2 Axis Stimulates Pancreatic Cancer Progression and Metastasis via Activation of the ERK1/2 Signaling Pathway

The ZIC2-Claudin-18.2 Axis Stimulates Pancreatic Cancer Progression and Metastasis via Activation of the ERK1/2 Signaling Pathway

Xiaoping Zhou,¹ Lanying Zou,¹ Jun Xu¹ and Huichuan Zhao¹

¹Department of Pathology, The First Affiliated Hospital of Yangtze University, Jingzhou, China

Claudin-18.2 is considered a promising target in cancer treatment. However, studies on the role of Claudin-18.2 in pancreatic cancer are scarce, and a systematic exploration of its mechanisms of action in disease progression is missing. This research sought to reveal the detailed mechanisms by Claudin-18.2 impacts pancreatic cancer development and metastasis. Claudin-18.2 expression levels in pancreatic cancer were investigated through The Cancer Genome Atlas (TCGA) database, with subsequent validation by immunohistochemistry and quantitative reverse transcription polymerase chain reaction analysis. The potential regulatory transcription factors (TFs) for Claudin-18 were forecasted by the KnockTF database. Pearson’s correlation was applied to ascertain the correlation between Claudin-18 and ZIC2, and the Molotool was utilized to analyze their potential binding sites. The TCGA database facilitated our analysis of ZIC2 expression levels within pancreatic cancer. Activation of the ERK signaling pathway was validated by western blot (WB). The colony formation assay evaluated cell proliferation, while the cell scratch and Transwell assays were used to determine cell migration and invasion abilities. WB was used to detect the expression of E-cadherin, N-cadherin and Vimentin associated with epithelial-mesenchymal transition. The ZIC2-Claudin-18.2 regulatory axis, via ERK1/2 signaling pathway activation, enhanced the malignant behaviors of pancreatic cancer. Claudin-18.2, when highly expressed in pancreatic cancer, facilitated tumor malignancy, primarily through activating the ERK1/2 signaling pathway. Additionally, ZIC2 was identified as an upstream regulatory molecule for Claudin-18.2. Our findings reveal that ZIC2, a TF, can upregulate Claudin-18.2, and initiate the ERK1/2 signaling pathway, eventually facilitating the malignant progression of pancreatic cancer.

Key words —— Claudin-18.2; ERK1/2; pancreatic cancer; ZIC2

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Tohoku J. Exp. Med., 2025 May, 266(3), 247-256.

Correspondence: Huichuan Zhao, Department of Pathology, The First Affiliated Hospital of Yangtze University, No. 8, Hanghang Road, Shashi District, Jingzhou 434000, China.

e-mail: Zhaohuichuann@163.com