Silencing CXCR6 promotes epithelial-mesenchymal transition and invasion in colorectal cancer by activating the VEGFA/PI3K/AKT/mTOR pathway

Zhuo Liu; Jinhua Tao; Yuping Zhu; Dechuan Li; Lisong Teng

doi:10.1016/j.intimp.2024.113529

Silencing CXCR6 promotes epithelial-mesenchymal transition and invasion in colorectal cancer by activating the VEGFA/PI3K/AKT/mTOR pathway

Int Immunopharmacol. 2024 Nov 4;143(Pt 3):113529. doi: 10.1016/j.intimp.2024.113529. Online ahead of print.

Authors

Zhuo Liu¹, Jinhua Tao², Yuping Zhu², Dechuan Li², Lisong Teng³

Affiliations

¹ Zhejiang University, Hangzhou 310058, China; Department of Colorectal Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
² Department of Colorectal Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
³ Department of Surgery, First Affiliated Hospital of Zhejiang University, Hangzhou 310003, China. Electronic address: lsteng@zju.edu.cn.

PMID: 39500082
DOI: 10.1016/j.intimp.2024.113529

Abstract

This study investigated the role of C-X-C motif chemokine receptor 6 (CXCR6) in colorectal cancer (CRC). It was found that lower CXCR6 expression is correlates with poorer prognostic outcomes, suggesting that CXCR6 may inhibit tumor progression and thus improve patient outcomes. Silencing CXCR6 in CRC cell lines SW620 and CT-26 resulted in significantly enhanced migration and invasion, as demonstrated by wound healing and transwell assays. Further analysis revealed that CXCR6 activity is associated with activation of the VEGFA/PI3K/AKT/mTOR signaling pathway. Inhibition of this pathway through VEGFA siRNA and pathway-specific inhibitors reversed the effects of CXCR6 silencing on cell migration and invasion. Moreover, xenograft experiments showed that silencing CXCR6 led to increased tumor growth and upregulated proteins associated with the extracellular matrix and epithelial-mesenchymal transition. These findings were validated through immunohistochemical, immunofluorescence, and Western blot analyses. This study highlights CXCR6's critical role in CRC and its potential as a therapeutic target to manage cancer progression.

Keywords: CXCR6; Colorectal cancer; Epithelial-to-mesenchymal transition; High-throughput sequencing; Prognosis; VEGFA.