Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma

Chenwei Wang,Dinglan Zuo,Wenwu Liu,Zhiwen Yang,Yichuan Yuan,Yongjin Wang,Yuxiong Qiu,Jiliang Qiu,Wei He,Yuanping Zhang,Kai Li,Yunxing Shi,Yadi Liao,Song Gao,Hong Zhang,Yunfei Yuan,Binkui Li

doi:10.1186/s13046-021-01904-y

Abstract

BackgroundElafin is a serine protease inhibitor critical for host defence. We previously reported that Elafin was associated with the recurrence of early-stage hepatocellular carcinoma (HCC) after surgery. However, the exact role of Elafin in HCC remains obscure.MethodsHCC tissue microarrays were used to investigate the correlation between Elafin expression and the prognosis of HCC patients. In vitro migration, invasion and wound healing assays and in vivo lung metastasis models were used to determine the role of Elafin in HCC metastasis. Mass spectrometry, co-immunoprecipitation, western blotting, and immunofluorescence staining assays were performed to uncover the mechanism of Elafin in HCC. Dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the transcriptional regulation of Elafin.ResultsElafin expression was frequently increased in HCC tissues compared to normal tissues, and high Elafin expression in HCC tissues was correlated with aggressive tumour phenotypes and a poor prognosis in HCC patients. Elafin dramatically enhanced the metastasis of HCC cells both in vitro and in vivo by interacting with EGFR and activating EGFR/AKT signalling. Moreover, Elafin attenuated the suppressive effects of erlotinib on HCC metastasis. Besides, Elafin was transcriptionally regulated by Sp1 in HCC cells. Clinically, Elafin expression was positively correlated with Sp1, Vimentin, and EGFR signalling in both our HCC tissue microarrays and TCGA database analysis.ConclusionsUpregulation of Elafin by Sp1 enhanced HCC metastasis via EGFR/AKT pathway, and overexpression of Elafin attenuated the anti-metastatic effects of erlotinib, suggesting a valuable prognostic biomarker and therapeutic target for HCC.

Highlights

Elafin is a serine protease inhibitor critical for host defence
Elafin is upregulated in hepatocellular carcinoma (HCC) tissues and is closely related to the prognosis of HCC patients We previously reported that Elafin was associated with the recurrence of early-stage HCC after surgery [10]
The analysis of the the Cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets verified our above findings (Fig. 1f, g, and h). These results suggest that elevated Elafin expression might correlate with aggressive clinicopathological characteristics and a poor prognosis in HCC patients

Summary

Introduction

We previously reported that Elafin was associated with the recurrence of early-stage hepatocellular carcinoma (HCC) after surgery. The high rates of recurrence and metastasis are the main factors contributing to death in hepatocellular carcinoma (HCC) patients, making HCC the fourth leading cause of cancer-associated death worldwide [1, 2]. Great efforts have been made to investigate the metastasis of HCC, the detailed molecular mechanisms are still obscure. Epidermal growth factor receptor (EGFR) has been reported to be frequently overexpressed in HCC, thereby promoting the tumorigenesis and progression of HCC [4]. It is important to further understand the regulatory mechanisms of EGFR in HCC progression and to explore the application prospects of EGFR antagonists in HCC treatments

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Discussion

Conclusion