1. Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.
2. Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China.
3. Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
4. Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200050, China.
# Contributed equally.
Background: Although sorafenib is adopted as the first-line treatment for unresectable liver cancer, the antitumor efficacy is severely limited by the pro-invasive side effect.
Methods: To explore the underlying mechanisms, various-dosage sorafenib was applied to survey its effect on cell invasion in HCCLM3 and PLC cell models.
Results: Our results revealed that high-dosage sorafenib inhibited liver cancer cell invasion. By contrast, sorafenib with low and median dosages promoted the invasion. In vivo studies showed that sorafenib with a median dosage increased the intrahepatic metastasis (IHM) and lung metastasis (LM) of liver cancer cells, while sorafenib with a high dosage inhibited IHM and LM. Then, bioinformatics analysis indicated that HIF-1α, IL-6, and PFKFB3 were associated with the sorafenib resistance. In vitro models showed that the pro-invasive effect was mediated by IL-6/HIF-1α/PFKFB3 regulation in dosage- and time-dependent manners. PFKFB3 knockdown confirmed that PFKFB3 promoted HCCLM3 cell migration via modulating EMT-related markers. Furthermore, we found that sorafenib upregulated PFKFB3 by IL-6/HIF-1α in a time-dependent manner, without direct effect on PFKFB3 expression.
Conclusions: In summary, these results demonstrated that sorafenib could dose-dependently promote cell invasion, intrahepatic and lung metastasis in hepatocellular carcinoma through IL-6/HIF-1α mediated PFKFB3 activation, providing novel insights to improve the therapeutic efficacy of sorafenib.
Keywords: hepatocellular carcinoma, sorafenib, IL-6, PFKFB3, invasion