Pei-Wen Yang1, Pei-Ming Huang1, Luo-Sheng Yong1, Ya-Han Chang1, Chia-Wei Wu1, Kuo-Tai Hua2, Min-Shu Hsieh3,4, Jang-Ming Lee5. 1. Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 2. Graduate Institute of Toxicology, National Taiwan University Hospital, Taipei, Taiwan. 3. Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan. mshsieh065@gmail.com. 4. Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. mshsieh065@gmail.com. 5. Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. jmlee@ntu.edu.tw.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The results of this study provide a novel direction for a biomarker-based targeted therapy for ESCC.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The results of this study provide a novel direction for a biomarker-based targeted therapy for ESCC.
Authors: Paul Beinhoff; Lavannya Sabharwal; Vindhya Udhane; Cristina Maranto; Peter S LaViolette; Kenneth M Jacobsohn; Susan Tsai; Kenneth A Iczkowski; Liang Wang; William A Hall; Scott M Dehm; Deepak Kilari; Marja T Nevalainen Journal: Cancers (Basel) Date: 2021-10-17 Impact factor: 6.575