An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma.

Meng Li,Hong Li,Taoyang Chen,Tao Fang,Haiyang Xie,Ming Yao,Junxi Liu,Guoping Jiang,Lixing Zhang,Jinjun Li,Chao Ge,Ying Cui,Hua Tian,Lijuan Chen

doi:10.18632/oncotarget.4438

Abstract

In our previous studies, we reported that CD133(+) cancer stem cells (CSCs) were chemoresistant in hepatocellular carcinoma (HCC) and that isocorydine treatment decreased the percentage of CD133(+) CSCs. Here, we found that a derivative of isocorydine (d-ICD) inhibited HCC cell growth, particularly among the CD133(+) subpopulation, and rendered HCC cells more sensitive to sorafenib treatment. d-ICD inhibited IGF2BP3 expression in a time-dependent manner, and IGF2BP3 expression negatively correlated with d-ICD-induced growth suppression. IGF2BP3 overexpression enriched the CD133(+) CSC subpopulation in HCC, enhanced tumor sphere formation and suppressed the cytotoxic effects of sorafenib and doxorubicin. The expression of drug resistance-related genes, including ABCB1 and ABCG2, and the CSC marker CD133 expression was increased after IGF2BP3 overexpression. The significance of these observations was underscored by our findings that high IGF2BP3 expression predicted poor survival in a cohort of 236 patients with HCC and positively correlated with ABCG2 and CD133 expression in vivo. These results suggested that the d-ICD may inhibit HCC cells growth by IGF2BP3 decrease and that IGF2BP3 may serve as a therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common forms of cancer worldwide, and the prognosis of hepatocellular carcinoma (HCC) patients is startling low unless the disease is diagnosed early [1]
We reported that CD133+ cancer stem cells (CSCs) were chemoresistant in hepatocellular carcinoma (HCC) and that isocorydine treatment decreased the percentage of CD133+ CSCs
We found that a derivative of isocorydine (d-ICD) inhibited HCC cell growth, among the CD133+ subpopulation, and rendered HCC cells more sensitive to sorafenib treatment. d-ICD inhibited IGF2BP3 expression in a time-dependent manner, and IGF2BP3 expression negatively correlated with d-ICD-induced growth suppression

Summary

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most common forms of cancer worldwide, and the prognosis of HCC patients is startling low unless the disease is diagnosed early [1]. Cancer stem cells (CSCs) contribute to drug resistance during the treatment of HCC [2]. A positive correlation between ABCG2 expression and the drug resistance of HCC cell lines has been confirmed. Targeting CD133+ CSCs displaying high tumorigenicity and chemoresistance is definitely necessary for the development of efficient anti-cancer strategies for HCC. Its expression in triple-negative breast cancer cells, which are resistant to many chemotherapeutics, increased their sensitivity to doxorubicin and mitoxantrone significantly by directly binding to ABCG2 mRNA and regulating ABCG2 expression [10]. Our research here showed that d-ICD treatment inhibited HCC cell growth and sensitized cancer cells to sorafenib. Further investigation indicated that d-ICD diminished the CD133+ CSC subpopulation in HCC and downregulated ABCB1, ABCG2 and CD133 expression via IGF2BP3 suppression

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS