WDR5 drives the development of cervical squamous cell carcinoma by inducing epithelial-mesenchymal transition and cancer-associated fibroblasts formation

Fangli Sun; Linmei Mo; Ying Lan; Qiuping Lu; Nengxian Wu; Honglin Song

doi:10.1016/j.prp.2022.154076

WDR5 drives the development of cervical squamous cell carcinoma by inducing epithelial-mesenchymal transition and cancer-associated fibroblasts formation

Pathol Res Pract. 2022 Oct:238:154076. doi: 10.1016/j.prp.2022.154076. Epub 2022 Aug 17.

Authors

Fangli Sun¹, Linmei Mo¹, Ying Lan¹, Qiuping Lu¹, Nengxian Wu¹, Honglin Song²

Affiliations

¹ Department of Gynecologic Oncology, Guangxi Medical University Cancer Hospital, Nanning City, Guangxi Province, China.
² Department of Gynecologic Oncology, Guangxi Medical University Cancer Hospital, Nanning City, Guangxi Province, China. Electronic address: song123honglin123@163.com.

PMID: 36055087
DOI: 10.1016/j.prp.2022.154076

Abstract

Background: WD repeat domain 5 (WDR5) has been indicated to be involved in tumor progression, however, its role in cervical cancer (CC) has not been investigated yet.

Methods: A total of 350 pairs of CC tissues and para-carcinoma tissues (PCT) were collected. Primary human cervical epithelial cells (hCECs) and cancer-associated fibroblasts (CAFs) were isolated from cervical cancer tissues. MM102 was used to block the interaction between WDR5 and mixed lineage leukemia protein-1 (MLL1), and it was used in vivo to investigate its therapeutic value.

Results: WDR5 was up-regulated in cervical squamous cell carcinoma (CSCC) tissues compared to that in PCT. C-X-C motif chemokine ligand 8 (CXCL8) was indicated to be the target gene of WDR5. Highly expressed CXCL8 promoted epithelial-mesenchymal transition (EMT) to form CAFs, and enhanced the cytokine secretions in CAFs to promote CSCC progression. CXCL8 expression was regulated by the interaction between WDR5 and MLL1, and blocking the interaction between these two proteins using MM102 significantly suppressed tumor growth in mice models.

Conclusions: WDR5 plays a key role in CSCC progression by inducing CXCL8 expression and promoting the transformation of CAFs from epithelial cells.

Keywords: C-X-C motif chemokine ligand 8; Cancer-associated fibroblasts; Cervical squamous cell carcinoma; Epithelial-mesenchymal transition; WD repeat domain 5.