Self-enforcing HMGB1/NF-κB/HIF-1α Feedback Loop Promotes Cisplatin Resistance in Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) is ranked the sixth most common cancer and the fourth leading cause of cancer-related death worldwide, and its incidence is expected to increase in the future. Cisplatin has been widely used in chemotherapy and transarterial chemoembolization in treatment for HCC. However, the main obstacle to the clinical use of cisplatin is the development of resistance, the mechanisms of which are poorly defined. Therefore, it is imperative to investigate the cellular mechanisms mediating cisplatin resistance in HCC. Here, we demonstrated that high mobility group box 1 (HMGB1) is upregulated in patients with cancer, and implicated in a tumor-supportive role. Further, we showed that HMGB1 has an important role in mediating cisplatin resistance via an HMGB1/ nuclear factor kappa-B (NF-kappaB)/ hypoxia inducible factor-1alpha (HIF-1alpha) feedback loop. The study findings reveal an unappreciated molecular mechanism of HMGB1-mediated cisplatin resistance and may provide a new clue in cancer therapy.