Hepatectomy Promotes Recurrence of Liver Cancer by Enhancing IL11-STAT3 Signaling

Abstract

Background: Patients undergoing surgical resection of hepatocellular carcinoma (HCC) are at risk of recurrence, but the mechanism remains poorly understood. Methods: Through the analysis of gene expression profiles in tumor tissues and matched normal tissues from patients with hepatocellular carcinoma (HCC), we identified difference in interlukine-11 (IL-11) expression. Besides, we utilized a genetic mouse model, orthotopic tumor model, chemically induced model, and orthotopic allograft model to study the correlation between IL-11 and postsurgical recurrence. Furthermore, a series of experiments including histology and immunohistochemistry analysis, three-dimensional culture, immunofluorescence, western blotting, enzyme-linked immunosorbent assay (ELISA) and flow cytometry were conducted to investigate the role of IL-11- Signal transducer and activator of transcription 3 (STAT3) signaling in recurrence. Findings: We demonstrate that IL-11 levels increase after surgery and trigger HCC outgrowth. Accordingly, pharmacologically blocking IL-11- STAT3 signaling in these models significantly alleviates tumor cell proliferation and suppresses postsurgical recurrence. Interpretation: These data identify that IL-11 has a central role in postsurgical HCC recurrence and that inhibition of IL-11-STAT3 signaling is a potential therapeutic strategy to prevent recurrence. Funding Statement: This work was supported by the Natural Science Foundation of China (# 81788101). Declaration of Interests: The authors declare no potential conflict of interest. Ethics Approval Statement: The collection of all samples was in accordance with the ethical guidelines of the 1975 Declaration of Helsinki, the Principles of Good Clinical Practice, and the guidelines of China’s regulatory requirements, and was approved by the ethical review board of the University of Science and Technology of China (No. USTCEC201600004). All of the experimental procedures involving animals were conducted in accordance with the National Guidelines for Animal Usage in Research (China) and permission for these animal studies was obtained from the Ethics Committee at the University of Science & Technology of China.