Circulating Interleukin-6 is Associated with Prognosis and Genetic Polymorphisms of MIR608 in Patients with Esophageal Squamous Cell Carcinoma
No effective targeted therapy exists for esophageal squamous cell carcinoma (ESCC), the major cell type of esophageal cancer. The pleiotropic cytokine interleukin (IL)-6 is associated with adverse prognosis of some cancers, and the open reading frame of IL-6 contains an miR-608 microRNA-targeted site. We investigated the correlation of circulating IL-6 levels with prognosis and with the mir608:rs4919510 genetic polymorphism in ESCC.
A total of 213 patients with primary ESCC were enrolled. Plasma IL-6 levels of ESCC patients were analyzed by enzyme-linked immunosorbent assay (ELISA). The patients’ genotypes of mir608:rs4919510 were analyzed using the MassARRAY system, and functional assays were performed by transient overexpression in cells. The cytotoxicity of IL-6 signaling blockers in ESCC cells was analyzed by MTT assay.
We found that plasma IL-6 levels significantly correlated with overall survival (p = 0.019), disease recurrence (p = 0.003), and postoperative complications (p =0.002). Patients with the GG genotype of mir608:rs4919510 had a 4.56-fold increased risk of high expression of IL-6 compared with patients with the CC genotype (odds ratio 4.56, 95% confidence interval 1.87–11.09; p =0.001). Transient overexpression of the miR-608 C (miR-608_C) and G variants (miR-608_G) in cancer cells revealed that the miR-608_G variant was less efficient in regulating the expression of IL-6 compared with miR-608_C. Finally, the IL-6 signaling blocker ruxolitinib exhibited effective cytotoxicity in ESCC cells.
The results of this study provide a novel direction for a biomarker-based targeted therapy for ESCC.
The authors thank the staff of the Second Core Laboratory, Department of Medical Research, NTUH, for technical support.
This study was supported by the NTUH (NTUH.105-S3005, NTUH.106-S3439, and NTUH.107-S3867), the Ministry of Science and Technology (MOST 104-2314-B-002-182- MY3 and MOST 106-2320-B-002-029-MY3), and the Taiwan Health Foundation of the Republic of China.
Pei-Wen Yang, Pei-Ming Huang, Luo-Sheng Yong, Ya-Han Chang, Chia-Wei Wu, Kuo-Tai Hua, Min-Shu Hsieh, and Jang-Ming Lee have no conflicts of interest regarding the publication of this study.
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