Monocyte chemotactic protein 1 (MCP-1) modulates pro-survival signaling to promote progression of head and neck squamous cell carcinoma

Wen-Tsai Ji; Hau-Ren Chen; Chun-Hsuan Lin; Jeng-Woei Lee; Ching-Chih Lee

doi:10.1371/journal.pone.0088952

Monocyte chemotactic protein 1 (MCP-1) modulates pro-survival signaling to promote progression of head and neck squamous cell carcinoma

PLoS One. 2014 Feb 19;9(2):e88952. doi: 10.1371/journal.pone.0088952. eCollection 2014.

Authors

Wen-Tsai Ji¹, Hau-Ren Chen¹, Chun-Hsuan Lin², Jeng-Woei Lee³, Ching-Chih Lee⁴

Affiliations

¹ Department of Life Science, Institute of Molecular Biology and Institute of Biomedical Science, College of Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
² Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.
³ Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan ; Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan.
⁴ Department of Otolaryngology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan ; School of Medicine, Tzu Chi University, Hualian, Taiwan.

Abstract

Background: Monocyte chemotactic protein-1 (MCP-1) recruits monocytes and macrophages to inflammation sites, and inflammatory infiltration correlates with the progression of head and neck squamous cell carcinoma (HNSCC). This study aims to determine whether MCP-1 expression is related to HNSCC malignancy and patient survival. We also investigated the relationship between MCP-1 expression and the phosphorylation state of the pro-survival pathway factors Akt, ERK, and STAT3.

Methods: Expression of MCP-1 and related proteins in HNSCC cell lines was investigated using western blotting. HNSCC patients (34) without distant metastasis at diagnosis were recruited for tissue specimen evaluation of MCP-1 expression and clinical outcomes. The relationship between MCP-1 expression and survival was evaluated using the Cox proportional hazard model with stepwise selection.

Results: High-grade HNSCC cell lines were found to have higher levels of active Akt, ERK, and/or STAT3 than did lower grade cell lines under serum-free condition. OCSL, the most malignant cell line, had the highest level of endogenous MCP-1. Administration of exogenous recombinant MCP-1 increased phosphorylation of Akt, ERK, and STAT3 in a dose- and time-dependent manner and increased cellular resistance to serum starvation. Inhibition of Akt, ERK, or STAT3 reduced cell growth and caused cell death. Long-term survival of HNSCC patients was negatively associated with the histological intensity of MCP-1, implicating MCP-1 as a potential prognostic marker for HNSCC.

Conclusions: These results suggest that overexpressed MCP-1 in cancer cells may promote HNSCC progression through upregulating pro-survival signaling pathways. High cellular MCP-1 expression is related to poor overall survival rate in HNSCC patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Apoptosis / drug effects*
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / mortality
Carcinoma, Squamous Cell / pathology*
Cell Survival / drug effects
Chemokine CCL2 / metabolism
Chemokine CCL2 / pharmacology*
Disease Progression
Dose-Response Relationship, Drug
Female
Head and Neck Neoplasms / metabolism
Head and Neck Neoplasms / mortality
Head and Neck Neoplasms / pathology*
Humans
MAP Kinase Signaling System / drug effects
Male
Middle Aged
Proto-Oncogene Proteins c-akt / metabolism
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects
Squamous Cell Carcinoma of Head and Neck
Survival Analysis
Tumor Cells, Cultured

Substances

CCL2 protein, human
Chemokine CCL2
STAT3 Transcription Factor
Proto-Oncogene Proteins c-akt

Grants and funding

This study was supported partly by the National Science Council (101-2314-B-303-011-MY2 and 100-2314-B-303-002-) and Buddhist Dalin Tzu Chi General Hospital (DTCRD101(2)-E-06). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.