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Chemerin promotes invasion of oral squamous cell carcinoma by stimulating IL-6 and TNF-α production via STAT3 activation

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Abstract

Aims

Elevated levels of adipokine chemerin have been identified in oral squamous cell carcinoma (OSCC) and found to be associated with metastasis to the cervical lymph nodes. The underlying mechanism through which chemerin affects OSCC progression is unclear. The aims of this study were firstly to determine chemerin levels and cytokine concentrations in serum from patients with OSCC and in OSCC cell cultures, and secondly to observe chemerin effects on OSCC cell cytokine secretion, migration, and invasion in vitro.

Methods

Serum samples were collected from 20 patients diagnosed with OSCC, including groups with (LN+) and without (LN-) cervical lymph node metastasis. A Luminex liquid suspension assay was used to quantify serum concentrations of 27 types of cytokines. Correlations between chemerin and cytokines (i.e., IL-6, IL-15, GM-CSF, RANTES, TNF-α, and VEGF) were analyzed. ELISAs (enzyme-linked immunosorbent assays) were used to determine concentrations of chemerin and selected cytokines in serum and in supernatants of OSCC cell cultures (SCC9 and SCC25 cell lines). OSCC cells were stimulated with human recombinant chemerin, STAT3 inhibitor, or IL-6 together with TNF-α neutralizing antibodies. Phosphorylated STAT3 protein levels were measured with western blot analysis. OSCC cell migration and invasion were investigated with Transwell assays.

Results

Compared to the LN- group, OSCC patients with cervical lymph node metastasis had higher levels of IL-6 (P = 0.006), IL-15 (P = 0.020), GM-CSF (P = 0.036), RANTES (P = 0.032), TNF-α (P = 0.005), VEGF (P = 0.006), and chemerin (P = 0.001). Patients’ serum chemerin levels correlated directly with IL-6, GM-CSF, TNF-α, and VEGF levels in OSCC patients. Exogenous recombinant chemerin treatment promoted secretion of IL-6 and TNF-α via activation of STAT3 in OSCC cells. Chemerin induced OSCC-cell migration and invasion, and these effects were reduced by IL-6 and TNF-α neutralizing antibodies.

Conclusion

Our findings indicate that chemerin may play a role in advancing OSCC progression by increasing production of IL-6 and TNF-α, perhaps via a mechanism involving STAT3 signaling.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by Basic and Applied Basic Research Foundation of Guangdong Province (Grant No. 2020A1515111039, 2022A1515220112), Basic and Applied Basic Research Foundation of Guangzhou (Grant No. 202102021209), Science and Technology Projects in Guangzhou (Grant No.202102010304) and Research foundation of Guangzhou Women and Children’s Medical Center for Clinical Doctor (Grant No. 2019BS018).

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China

    Zhiyuan Lu, Jiayu Liu, Quan Wan, Yu Wu, Wanqiu Wu & Yiyang Chen

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  1. Zhiyuan Lu
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  2. Jiayu Liu
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  3. Quan Wan
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  4. Yu Wu
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  5. Wanqiu Wu
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Contributions

Z.L. designed the studies, performed experiments, acquired data and analyzed the data. J.L.and Q.W. conducted experiments, acquired data and assisted analysis of data. Y.W. and W.W. contributed to experimental design and manuscript drafting. Y.C. guided conception of the study design, wrote the manuscript and finalization of the manuscript. All authors reviewed the manuscript and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Yiyang Chen.

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Ethical approval

The ethical committee of the First Affiliated Hospital of Sun Yat-sen University approved this study (No. 2017173).

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Written informed consent was obtained from all subjects included in the study or from patients’ family member.

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All participants provide informed consent for the publication of the study.

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No potential conflict of interest was reported by the authors.

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Lu, Z., Liu, J., Wan, Q. et al. Chemerin promotes invasion of oral squamous cell carcinoma by stimulating IL-6 and TNF-α production via STAT3 activation. Mol Biol Rep 51, 436 (2024). https://doi.org/10.1007/s11033-024-09359-y

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