Hepatectomy promotes recurrence of liver cancer by enhancing IL-11-STAT3 signaling

Abstract

Background Patients undergoing surgical resection of hepatocellular carcinoma (HCC) are at risk of recurrence; however, the underlying mechanism remains poorly understood. Methods Through the analysis of gene expression profiles in tumour and matched normal tissues from patients with hepatocellular carcinoma (HCC), we identified differences in interleukin-11 ( IL-11 ) expression. Further, we used genetic mouse, orthotopic tumour, chemically induced, and orthotopic allograft models to study the correlation between IL-11 and postsurgical recurrence. Additionally, we conducted a series of experiments, including histology and immunohistochemistry analysis, three-dimensional culture, immunofluorescence, western blotting, enzyme-linked immunosorbent assay (ELISA) and flow cytometry to investigate the role of IL-11-signal transducer and activator of transcription 3 (STAT3) signaling in HCC recurrence. Findings We demonstrate that IL-11 levels increase after surgery, triggering HCC outgrowth. Accordingly, pharmacological blocking of IL-11-STAT3 signaling in model systems significantly alleviates tumour cell proliferation and suppresses postsurgical recurrence of HCC tumours. Interpretation These data demonstrate 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. Fund Natural Science Foundation of China.

JAK/STAT signaling in hepatocellular carcinoma

“…Collectively, this study demonstrates that drug combinations with napabucasin are a viable treatment approach with potential survival benefits and hence a Phase III trial is ongoing for this combination in gastric and gastroesophageal junction cancers (NCT02178956) [98]. In preclinical studies of HCC, napabucasin promoted apoptosis in vitro and suppressed tumor growth in orthotopic mouse models [104]. Using another orthotopic HCC resection mouse model, napabucasin treatment was also observed to decrease the incidence of recurrence after surgery (hepatectomy), which is likely mediated by inhibition of the IL-11/STAT3 signaling axis [104].…”

“…In preclinical studies of HCC, napabucasin promoted apoptosis in vitro and suppressed tumor growth in orthotopic mouse models [104]. Using another orthotopic HCC resection mouse model, napabucasin treatment was also observed to decrease the incidence of recurrence after surgery (hepatectomy), which is likely mediated by inhibition of the IL-11/STAT3 signaling axis [104]. In addition, AFP and proliferating cell nuclear antigen levels were also reduced after treatment with napabucasin.…”

Establishment of a Prognostic Model Using Immune-Related Genes in Patients With Hepatocellular Carcinoma

“…Hu et al indicated that IL-17 promotes the proliferation of liver cancer cells (HBV + ) by activating the IL-6/STAT3 signaling pathway (Hu et al, 2017), and Tian et al found that IL-17 expression and promoter methylation were closely related to the progression of chronic HBV infection, particularly in patients with HCC (Tian et al, 2019). Moreover, Wang et al revealed that the IL-11 has a chief role in postsurgical HCC recurrence; they also found that the IL-11/STAT3 signaling pathway promotes the proliferation of tumor cells and that the inhibition of IL-11/STAT3 signaling could reduce the postsurgical recurrence of HCC (Wang et al, 2019). IL-11 regulates a variety of immune cells to participate in the immune response.…”

Multivariate gene expression‐based survival predictor model in esophageal adenocarcinoma

“…organs. 38,39 Recent studies have also suggested its role in osteosarcoma deterioration, 40 postoperative recurrence of liver cancer 41,42 and migration and survival of gastric cancer cells. 43 Based on the current knowledge of the biological properties of IL-11 and its role in cancer, IL-11 signaling inhibition might be a new therapeutic approach for cancer treatment.…”