CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma

Shuai Lu,Qing Shao,Runqiu Jiang,Chao Zhou,Yao Yao,Jie Sun,Yuan Zhang,Yun Chen,Guolong Xu

doi:10.1038/s41419-018-0681-z

Abstract

Hepatocellular carcinoma is one of most common solid cancers worldwide. Sorafenib is indicated as a treatment for advanced hepatocellular carcinoma (HCC). However, the clinical efficacy of sorafenib has been severely compromised by the development of drug resistance, and the precise mechanisms of drug resistance remain largely unknown. Here we found that a cell surface molecule, CD24, is overexpressed in tumor tissues and sorafenib-resistant hepatocellular carcinoma cell lines. Moreover, there is a positive correlation between CD24 expression levels and sorafenib resistance. In sorafenib-resistant HCC cell lines, depletion of CD24 caused a notable increase of sorafenib sensitivity. In addition, we found that CD24-related sorafenib resistance was accompanied by the activation of autophagy and can be blocked by the inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown. In further research, we found that CD24 overexpression also leads to an increase in PP2A protein production and induces the deactivation of the mTOR/AKT pathway, which enhances the level of autophagy. These results demonstrate that CD24 regulates sorafenib resistance via activating autophagy in HCC. This is the first report to describe the relationships among CD24, autophagy, and sorafenib resistance. In conclusion, the combination of autophagy modulation and CD24 targeted therapy is a promising therapeutic strategy in the treatment of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in the world[1]
We found that the tumor cells of HCC patients have significantly higher ATP-binding cassette sub-family G member 2 (ABCG2) than the adjacent normal liver tissues, while the cells of sorafenib-resistant HCC patients expressed the highest ABCG2 (Fig. 1b)
The protein expression of CD24 was verified by both western blot and IHC staining, and the results indicated that CD24 was highly expressed in human HCC tissues especially in tumor cells, and that sorafenib-resistant cells expressed significantly higher levels of CD24 (Fig. 1c, d)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in the world[1]. As with any other cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor pathology, size and the overall health of the patient[2]. Most HCC patients are diagnosed in advanced stages, and there is an urgent need for novel treatments for advanced HCC3,4. Official journal of the Cell Death Differentiation Association. Lu et al Cell Death and Disease (2018)9:646. Resistance[11]; and third, activation of autophagy, which may enhance sorafenib resistance in hepatocellular carcinoma[12]. There are still many other mechanisms which may contribute to sorafenib resistance. We elucidated a new mechanism of resistance

Methods

Results

Conclusion