Unlocking ESCC Progression: CCL15-CCR1 Axis Activates AKT/ERK1/2/c-Jun/CDK2 Pathway

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Esophageal squamous cell carcinoma (ESCC) is a significant global health concern.
• Tumor-secreted CCL15 recruits macrophages via CCR1, aiding immune evasion and tumor growth.
• The direct role of tumor-expressed CCL15 and CCR1 in ESCC progression was previously unclear.

Purpose of the Study:

• To investigate the direct functional role of the CCL15-CCR1 axis in ESCC.
• To elucidate the underlying molecular mechanisms driving ESCC progression.
• To identify potential therapeutic targets within the CCL15-CCR1 pathway.

Main Methods:

• Analysis of CCL15 and CCR1 expression in ESCC tissues and cell lines.
• In vitro functional assays (proliferation, migration, invasion) with recombinant CCL15 and gene knockdown.
• Immunofluorescence, co-immunoprecipitation, PCR array, and ChIP-qPCR assays to confirm interactions and signaling pathways.
• Drug screening for CCR1 inhibitors/degraders.

Main Results:

• CCL15 and CCR1 are overexpressed in ESCC tissues and cell lines.
• Recombinant CCL15 enhances ESCC cell proliferation, migration, and invasion.
• Knockdown of CCL15 or CCR1 inhibits ESCC progression, and CCR1 knockdown reverses CCL15 effects.
• The CCL15-CCR1 axis activates CDK2 transcription via c-Jun phosphorylation through the AKT/ERK1/2 pathway.
• Jervine identified as a potential CCR1 degrader.

Conclusions:

• The CCL15-CCR1 axis directly promotes ESCC progression.
• The pathway involves CDK2 activation mediated by c-Jun phosphorylation.
• Targeting the CCL15-CCR1 axis, potentially with Jervine, represents a promising therapeutic strategy for ESCC.