Cancer-Associated Fibroblasts Promote Vascular Invasion of Hepatocellular Carcinoma via Downregulating Decorin-integrin β1 Signaling.

Xiaobo Zheng,Chune Yu,Ming Zhang,Lei Feng,Li Li,Jing Yu,Xiaobo Chen,Peng Wang,Liangliang Xu,Mingqing Xu,Hong Zou,Lian Li,Fuzhen Dai

doi:10.3389/fcell.2021.678670

Abstract

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the high ratio of recurrence and metastasis remains the main cause of its poor prognosis. Vascular invasion of HCC includes microvascular invasion (MVI) and portal vein tumor thrombosis (PVTT) and is regarded as a common roadmap of intrahepatic metastasis in HCC. However, the molecular mechanism underlying vascular invasion of HCC is largely unknown. Here, we analyzed the transcriptomes of primary tumors, PVTT tissues, and tumor tissues with or without MVI. We found that extracellular matrix-related pathways were involved in vascular invasion of HCC and that decorin secreted by cancer-associated fibroblasts was gradually downregulated from normal to tumor tissues and more so in PVTT tissues. We also established that low-level decorin expression is an independent risk factor for MVI and it is associated with a poor prognosis. Decorin downregulated integrin β1 and consequently inhibited HCC cell invasion and migration in vitro. Co-staining DCN and integrin β1 revealed that DCN dynamically regulated integrin β1 protein expression. Integrin β1 knockdown significantly inhibited HCC invasion and migration, and decorin combined with such knockdown synergistically augmented the anti-metastatic effects. Co-IP assay confirmed the direct interaction of decorin with integrin β1. Our findings showed that targeting cancer-associated fibroblast-related decorin is not only a promising strategy for inhibiting HCC vascular invasion and metastasis but also provides insight into the clinical treatment of patients with PVTT.

Highlights

Hepatocellular carcinoma (HCC) is a common malignancy worldwide and the fourth leading cause of cancer-related death (Bray et al, 2018)
We found that DCN expression in tumor tissues was associated with microvascular invasion (MVI), and that low DCN expression was associated with a poor prognosis
The extracellular matrix (ECM)-related genes, DCN, COL11A1, LAMC3, and COL25A1, were significantly downregulated in portal vein tumor thrombosis (PVTT), compared with primary tumor tissues (Figure 1C), indicating that the ECM is involved in macrovascular invasion by HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is a common malignancy worldwide and the fourth leading cause of cancer-related death (Bray et al, 2018). Vascular invasion is a common phenomenon in HCC, and microvascular invasion (MVI) and portal vein tumor thrombosis (PVTT) are found in 44.0–62.2% of patients with HCC at autopsy (Lu J. et al, 2019). Because the mechanism of VI in HCC is not well understood, clinical treatment remains challenging. Biomarkers such as circular RNA (Fransvea et al, 2009) and imaging methods (Huang et al, 2020) have recently been applied to predict MVI, and VI in HCC has been analyzed by multi-omics (Zhang et al, 2015; Yang et al, 2017; Sulaiman et al, 2019). The fundamental molecular mechanism underlying VI in HCC remains largely unknown

Methods

Results

Conclusion