Vitamin K2 Inhibits Hepatocellular Carcinoma Cell Proliferation by Binding to 17β-Hydroxysteroid Dehydrogenase 4.

Xin Lu,Panpan Ma,Lingling Jiang,Yaqi Wang,Xi Wang,Lingyu Kong

doi:10.3389/fonc.2021.757603

Abstract

Our previous studies have proved that 17β-hydroxysteroid dehydrogenase 4 (HSD17B4) is a novel proliferation-promoting protein. The overexpression of HSD17B4 promotes hepatocellular carcinoma (HCC) cell proliferation. Vitamin K2 (VK2), a fat-soluble vitamin, has the function of promoting coagulation and can inhibit the progression of liver cancer. A previous study demonstrated that VK2 could bind to HSD17B4 in HepG2 cells. However, the mechanism of VK2 in inhibiting HCC cell proliferation is not clear. In this study, we investigate whether VK2 can inhibit the proliferation of HCC cell induced by HSD17B4 and the possible mechanism. We detected the effect of VK2 on HSD17B4-induced HCC cell proliferation, and the activation of STAT3, AKT, and MEK/ERK signaling pathways. We measured the effect of HSD17B4 on the growth of transplanted tumor and the inhibitory effect of VK2. Our results indicated that VK2 directly binds to HSD17B4, but does not affect the expression of HSD17B4, to inhibit the proliferation of HCC cells by inhibiting the activation of Akt and MEK/ERK signaling pathways, leading to decreased STAT3 activation. VK2 also inhibited the growth of HSD17B4-induced transplanted tumors. These findings provide a theoretical and experimental basis for possible future prevention and treatment of HCC using VK2.

Highlights

Vitamin K2 (VK2) is a fat-soluble vitamin; in addition to promoting blood coagulation, it has antitumor effects
To further verify that VK2 can directly inhibit proliferation of hepatocellular carcinoma (HCC) cells with HSD17B4 overexpression, we measured the activation of cells that were transfected with expression plasmid of HSD17B4 or siHSD17B4 to increase or knock down HSD17B4 expression by MTS assay
VK2 showed a dose-dependent inhibition on the proliferation in HSD17B4 overexpressed HepG2 cells (Figure 1B)

Summary

Introduction

VK2 is a fat-soluble vitamin; in addition to promoting blood coagulation, it has antitumor effects. VK2 has been shown to induce cancer cell apoptosis and suppress cancer growth and differentiation in various types of cancer cells. Some studies have shown that VK2 has anticancer effects on hepatocellular cancer, breast cancer, and leukemia [1,2,3,4]. Natural VK2 can inhibit HCC cell growth and induce apoptosis [5,6,7,8]. VK2 has been demonstrated to exert an antiproliferative action toward a variety of cancer cells [9,10,11,12]. The mechanisms of the inhibitory action of VK2 have not been defined

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Results

Conclusion