Sanguinarine inhibits epithelial\u2013mesenchymal transition via targeting HIF-1\u03b1/TGF-\u03b2 feed-forward loop in hepatocellular carcinoma

Qi Su,Yingzhuan Zhan,Yanmin Zhang,Bingling Dai,Dongdong Zhang,Mengying Fan,Jingjing Wang,Asmat Ullah,Mohsin Ahmad Ghauri

doi:10.1038/s41419-019-2173-1

Abstract

Epithelial–mesenchymal transition (EMT) plays a crucial role in hepatocellular carcinoma (HCC) progression. Hypoxia and excessive transforming growth factor-β (TGF-β) have been identified as inducers and target for EMT in HCC. Here, we show hypoxia inducible factor-1α (HIF-1α) and TGF-β form a feed-forward loop to induce EMT in HCC cells. Further mechanistic study indicates under both hypoxia and TGF-β stimulation, Smad and PI3K-AKT pathways are activated. We show sanguinarine, a natural benzophenanthridine alkaloid, impairs the proliferation of nine kinds of HCC cell lines and the colony formation of HCC cells. In hypoxic and TGF-β cell models, sanguinarine inhibits HIF-1α signaling and the expression of EMT markers, translocation of Snail and activation of both Smad and PI3K-AKT pathways. Sanguinarine could also inhibit TGF-β-induced cell migration in HCC cells. In vivo studies reveal that the administration of sanguinarine inhibits tumor growth and HIF-1α signaling, inhibits the expression changes of EMT markers as well as Smad and PI3K-AKT pathway proteins. Our findings suggest that sanguinarine is a promising candidate targeting HIF-1α/TGF-β signaling to improve the treatment for HCC patients.

Highlights

Hepatocellular carcinoma (HCC), the primary liver malignancy, is the fourth leading cause of cancer-related death, and the incidence rate of hepatocellular carcinoma (HCC) has substantially increased worldwide[1]
This study aims to investigate the formation of hypoxia inducible factor-1α (HIF-1α)/ transforming growth factor-β (TGF-β) feed-forward loop that can contribute to the induction and development of epithelial–mesenchymal transition (EMT) in HCC cells
HIF-1α/TGF-β feed-forward signaling in HCC cells To test whether hypoxia affects the TGF-β expression, MHCC-97H and SMMC-7721 cells were cultured with 100 μM CoCl2 or under hypoxic conditions (1% O2) for

Summary

Introduction

Hepatocellular carcinoma (HCC), the primary liver malignancy, is the fourth leading cause of cancer-related death, and the incidence rate of HCC has substantially increased worldwide[1]. Despite advances in the diagnosis and treatment of HCC, the 5-year survival rate remains only 18%, the second lowest among all cancer[2,3]. Official journal of the Cell Death Differentiation Association. Su et al Cell Death and Disease (2019)10:939. TGF-β, one of the most potent EMT inducers, has been identified as a therapeutic target in advanced HCC11,12. Heteromeric Smad complexes translocate into the nucleus, where they regulate the transcription of target genes[13]. Smadindependent signaling pathways, such as PI3K-AKT and MAP kinase pathways, have been implicated in TGFβ-induced EMT non-Smad pathways in TGF-β signaling[14]

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