Inactivation of EGFR/ERK/NF‐κB signalling associates with radiosensitizing effect of 18β‐glycyrrhetinic acid on progression of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is recognized as the fifth most common cancer and the third most common cause of death in Asian population. Studies reported that HCC is relatively insensitive to radiotherapy (RT); thus, considering how to sensitize HCC to RT is worth to be elucidated. Epidermal growth factor receptor (EGFR)‐mediated signalling transduction plays the important role in regulating treatment efficacy of HCC. An active compound, 18beta‐glycyrrhetinic acid (18β‐GA), has been reported to own anti‐tumour effect. However, whether 18β‐GA possess RT sensitization ability in HCC remains unclear. Here, we used RNA data from TCGA‐LIHC (Liver hepatocellular carcinoma) to identify the role between EGFR/ERK/nuclear factor kappa B (NF‐κB) signalling and RT by radiosensitivity index (RSI) analysis. We suggested that patients with activated NF‐κB signalling may show resistance to RT treatment, whereas combining 18β‐GA may reinforce RT efficacy in a Hep3B‐bearing animal model. 18β‐GA combined with RT showed superior tumour inhibition capacity as compared to monotherapy and even reached similar efficacy as erlotinib combined with RT. Treatment promotion of RT by 18β‐GA in HCC is not only through diminishing RT‐induced EGFR/ERK/NF‐κB signalling but also promoting RT‐induced apoptosis pathways. 18β‐GA may act as radiosensitizer through inactivating EGFR‐mediated HCC progression and inducing caspase‐dependent apoptosis signalling.

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“…The statistical analysis of each protein between different treatment group was presented in Table VIII and Table IX. Furthermore, our earlier studies demonstrated an increased RSI value in HCC patients with high expression of EGFR, ERK, and NF-ĸB (24). In Figure 3C, we also showed that HCC samples with high expression of PKC-δ, P38 and VEGF-A exhibit resistance to radiotherapy.…”

“…High expression of both EGFR and NF-ĸB correlated with a diminished survival advantage of radiotherapy in HCC patients (24). The information retrieved from the TCGA databank revealed that heightened levels of both PKC-δ and P38 were linked to a reduced effectiveness of radiotherapy in improving survival outcomes for HCC patients (Figure 3C).…”

“…All experiments were repeated twice. Subsequently, a 10 days period was allowed for the progression and development of HCC tumors in the experimental subjects (24). Upon reaching a tumor volume of 80 to 100 mm 3 , mice were randomly allocated into four groups.…”