Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma‐associated oncogene homolog 1 and chemokine CCL2
Yiming Luo,
Zhi Li,
He Zhu,
Junli Lu,
Zhen Lei,
Chen Su,
Furong Liu,
Hongwei Zhang,
Qibo Huang,
Shenqi Han,
Dean Rao,
Tiantian Wang,
Xiaoping Chen,
Hong Cao,
Zhiwei Zhang,
Wenjie Huang,
Huifang Liang
Affiliations
Yiming Luo
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Zhi Li
State Key Laboratory of Biocatalysis and Enzyme Engineering School of Life Sciences Hubei University Wuhan China
He Zhu
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Junli Lu
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Zhen Lei
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Chen Su
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Furong Liu
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Hongwei Zhang
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Qibo Huang
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Shenqi Han
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Dean Rao
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Tiantian Wang
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Xiaoping Chen
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Hong Cao
Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture Institute of Hydrobiology Chinese Academy of Sciences Wuhan China
Zhiwei Zhang
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Wenjie Huang
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Huifang Liang
Hepatic Surgery Centre Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Abstract Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation‐specific homologous factor (EHF), a member of the E26 transformation‐specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma‐associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor‐associated macrophages (TAMs) through the C‐C motif chemokine 2/C‐C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co‐expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF‐mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2‐TAMs to inhibit EHF‐driven CCA development.
