Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma.

Lei Zhan,Xiacheng Sun,Yinghua Lyu,Qichao Huang,Zhenbiao Wu,Jiaze An,Bingrong Liu,Gang Wang,Haiyan Cao,Jinliang Xing

doi:10.18632/oncotarget.11339

Abstract

Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Recently, we have reported that increased mitochondrial fission promotes autophagy and apoptosis resistance in hepatocellular carcinoma (HCC) cell through ROS-mediated coordinated regulation of NF-κB and p53 pathways. However, little is known about the roles of mitochondrial dynamics in HCC cell proliferation, another key feature of cancer cells. In this study, we systematically investigated the functional role of mitochondrial fission in the regulation of HCC cell proliferation. Furthermore, the underlying molecular mechanisms were deeply explored. We found that, increased mitochondrial fission by forced expression of Drp1 promoted the proliferation of HCC cells both in vitro and in vivo mainly by facilitating G1/S phase transition of cell cycle. Whereas, Drp1 knockdown or treatment with mitochondrial division inhibitor-1 induced significant G1 phase arrest in HCC cells and reduced tumor growth in the xenotransplantation model. We further demonstrated that the proliferation-promoting role of Drp1-mediated mitochondrial fission was mediated via p53/p21 and NF-κB/cyclins pathways. Moreover, the crosstalk between p53 and NF-κB pathways was proved to be involved in the regulation of mitochondrial fission-mediated cell proliferation. In conclusion, our findings demonstrate that Drp1-mediated mitochondrial fission plays a critical role in the regulation of cell cycle progression and HCC cell proliferation. Thus, targeting Drp1-dependent mitochondrial fission may provide a novel strategy for suppressing tumor growth of HCC.

Highlights

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is the fifth most common malignant tumor worldwide and the third leading cause of cancer death [1]
Our results showed that dynamin related protein 1 (Drp1) was remarkably upregulated at mRNA level in hepatocellular carcinoma (HCC) tissues when compared with non-tumor tissues across three independent datasets
Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that genes which were significantly correlated to Drp1 in mRNA expression were notably involved in cell cycle progression in all three datasets (Figure 1B, 1C, Figure S1C, S1D and Tables S4–S6)

Summary

Introduction

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is the fifth most common malignant tumor worldwide and the third leading cause of cancer death [1]. There have been continued interest and active research to find a novel strategy for suppressing tumor growth of HCC. Cancer cells are characterized by excessive proliferation and tumor growth due to dysregulation of multiple cellular signaling pathway [3]. One such abnormality in cancer is p53 pathway, which is inactivated in the majority of human cancers due to downregulation or mutation. The key role of p53 as a tumor suppressor is to block cell cycle progression by activating the expression of downstream target genes, such as p21, which directly inhibits the activity of cyclin E/CDK2 complex and Rb and delay G1/S phase transition [4].

Methods

Results

Conclusion