NDRG2 inhibition facilitates angiogenesis of hepatocellular carcinoma.

Jianlong Wang,Jiansheng Kang,Lifeng Ma,Guochao Liu,Guiying Wang,Tao Li

doi:10.1515/med-2021-0268

Abstract

Hepatocellular carcinoma (HCC) is an angiogenesis-dependent tumor, and angiogenesis plays pivotal roles in progression and hematogenous metastasis. Upregulating NDRG2 expression could inhibit endothelial cell proliferation and tumor angiogenesis. However, the development of angiogenesis is a complicated and dynamic process, and the specific mechanisms that NDRG2 influences its progression are largely unknown. Conditioned media (CM) was collected from HCC cells. Cell viability, migration assay, tube formation, and western blot were used to evaluate the effect of NDRG2 on angiogenesis in HCC cells. ELISA assay was used to measure the level of VEGFA in CM. CM from NDRG2 knockdown cells significantly promoted HUVECs proliferation, migration, and tube formation compared with control cells. The level of VEGFA in CM was increased by NDRG2 knockdown relative to the control group. The expression of VEGFA, HIF-1α, and p-Akt was significantly increased in NDRG2 knockdown cells. CM from NDRG2 knockdown cells with VEGFA antibody failed to induce HUVEC proliferation, migration, and tube formation. YC-1 significantly inhibited the level of VEGFA in CM from NDRG2 knockdown cells. YC-1 also inhibited the expression of VEGFA and HIF-1α. Therefore, NDRG2 inhibition promoted the angiogenesis of HCC via VEGFA and may be used to be an anti-angiogenesis target.

Highlights

Hepatocellular carcinoma (HCC) is the fourth cause of cancer-related death and a leading cause of death among patients with cirrhosis [1]
We found that the expression of Hypoxia inducible factor 1α (HIF-1α) and p-Akt was significantly increased in N-Myc downstream-regulated gene 2 (NDRG2) knockdown cells (Figure 2c)
The results indicated that p-Akt/HIF-1α may be involved in the NDRG2-inducing VEGFA upregulation

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fourth cause of cancer-related death and a leading cause of death among patients with cirrhosis [1]. Angiogenesis plays an important role of promoting HCC development, and cancer cells could secret proangiogenic growth factors, which further stimulate the tumor growth [3]. Strategies targeting angiogenesis are efficient for its protective effects against HCC emergence and progression. Upregulating NDRG2 expression could inhibit endothelial cell proliferation and tumor angiogenesis in breast cancer cells [10]. Overexpression of NDRG2 in tumors suppressed the intratumoral and peritumoral angiogenesis in melanoma [11]. The development of angiogenesis is a complicated and dynamic process, and the specific mechanisms by which NDRG2 influences its progression are largely unknown

Methods

Results

Conclusion