Cingulin is an RNA-binding protein promoting pancreatic cancer through enhancing importin 7-mediated phospho-ERK nuclear translocation

Yuling Su; Fang Wei; Shu Li; Jiaming Qi; Guohuan Lin; Guantuo Li; Ping Liang; Zhenwei Yang; You Long; Xiaojia Li; Tingting Jiang; Jie He; Weiye Liang; Keping Xie

doi:10.1016/j.celrep.2025.115925

Cingulin is an RNA-binding protein promoting pancreatic cancer through enhancing importin 7-mediated phospho-ERK nuclear translocation

Cell Rep. 2025 Jun 27;44(7):115925. doi: 10.1016/j.celrep.2025.115925. Online ahead of print.

Authors

Yuling Su¹, Fang Wei², Shu Li¹, Jiaming Qi¹, Guohuan Lin¹, Guantuo Li¹, Ping Liang¹, Zhenwei Yang¹, You Long¹, Xiaojia Li¹, Tingting Jiang¹, Jie He², Weiye Liang¹, Keping Xie³

Affiliations

¹ Center for Pancreatic Cancer Research, South China University of Technology School of Medicine, Guangzhou, Guangdong 500106, China.
² The Second Affiliated Hospital and Guangzhou First People's Hospital, South China University of Technology School of Medicine, Guangzhou, Guangdong 510180, China.
³ Center for Pancreatic Cancer Research, South China University of Technology School of Medicine, Guangzhou, Guangdong 500106, China; The Second Affiliated Hospital and Guangzhou First People's Hospital, South China University of Technology School of Medicine, Guangzhou, Guangdong 510180, China. Electronic address: mcxiekeping@scut.edu.cn.

PMID: 40580477
DOI: 10.1016/j.celrep.2025.115925

Abstract

Pancreatic ductal adenocarcinoma (PDAC), a lethal malignancy with difficult early diagnosis and poor prognosis, urgently requires elucidation of the molecular determinants dictating pancreatic cancer initiation and progression. Little is known about cingulin (CGN) in carcinogenesis. In this study, we demonstrated the critical oncogenic role of CGN in PDAC pathogenesis. Increased expression of CGN promoted pancreatic acinar-to-ductal metaplasia (ADM), and CGN is progressively upregulated during PDAC initiation and progression. CGN was required for PDAC cell proliferation, gemcitabine (GEM) resistance, tumorigenesis, and metastasis, and its overexpression predicted a poor patient prognosis. Mechanistically, CGN, as an RNA-binding protein, stabilizes the mRNAs of AXL and importin-7 (IPO7), activating the mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinase (ERK) signaling and promoting the nuclear translocation of phosphorylated ERK (pERK), which facilitates the malignant behavior of PDAC cells. Therefore, our study has demonstrated that CGN forms an oncogenic signaling axis, which could be an effective therapeutic target for PDAC treatment.

Keywords: CP: Cancer; ERK; RNA-binding protein; cingulin; importin; molecular biomarkers; nuclearcytoplasmic transport; pancreatic cancer; tight junction.