Loss of SRSF2 triggers hepatic progenitor cell activation and tumor development in mice

Chang Zhang,Zhiqin Xie,Zheng Zhan,Ruochen Guo,Yuguo Liu,Lei Shen,Ying Feng,Wei Yuan,Wenwu Wu,Yangjun Luo,Guohao Wu

doi:10.1038/s42003-020-0893-5

Abstract

Splicing factor SRSF2 is frequently mutated or up-regulated in human cancers. Here, we observe that hepatocyte-specific deletion of Srsf2 trigger development of hepatocellular carcinoma (HCC) in mice, which also involves inflammation and fibrosis. Importantly, we find that, when compensatory hepatocyte proliferation is impaired, activation of hepatic progenitor cells (HPCs) play an important role in liver regeneration and tumor formation. Moreover, the cells of HCC- bearing livers display both HPC and hepatocyte markers, with gene expression profiling suggesting HPC origin and embryonic origin. Mechanically, we demonstrate that levels of oncofetal genes insulin-like growth factor 2 (Igf2) and H19 are significantly increased in the tumors, likely due to decreased DNA methylation of the Igf2/H19 locus. Consequently, signaling via the Igf2 pathway is highly activated in the tumors. Thus, our data demonstrate that loss of Srsf2 triggers HPC-mediated regeneration and activation of oncofetal genes, which altogether promote HCC development and progression in mice.

Highlights

Splicing factor SRSF2 is frequently mutated or up-regulated in human cancers
Our results suggested that hepatic progenitor cells (HPCs) activation, proliferation and expansion could be responsible for hepatocellular carcinoma (HCC) development
Inactivation of Srsf[2] either in hepatocytes by Alb-Cre or in adult hepatocytes by Mx1-Cre triggered substantial P21 acceleration, which impaired hepatocyte replication that in turn could induce the activation of HPCs

Summary

Introduction

Splicing factor SRSF2 is frequently mutated or up-regulated in human cancers. Here, we observe that hepatocyte-specific deletion of Srsf[2] trigger development of hepatocellular carcinoma (HCC) in mice, which involves inflammation and fibrosis. We find that, when compensatory hepatocyte proliferation is impaired, activation of hepatic progenitor cells (HPCs) play an important role in liver regeneration and tumor formation. The cells of HCC- bearing livers display both HPC and hepatocyte markers, with gene expression profiling suggesting HPC origin and embryonic origin. Our data demonstrate that loss of Srsf[2] triggers HPC-mediated regeneration and activation of oncofetal genes, which altogether promote HCC development and progression in mice. Mutations at proline 95 substituted with histidine (Srsf2P95H) were sufficient to induce in myelodysplastic syndromes (MDS) in inducible Mx1-Cre Srsf2P95H/WT knock-in mice[15,16] This was consistent with the fact that SRSF2 mutations played a major role in the pathogenesis of MDS17. High levels of SRSF2 contributed to HCC progression and were associated with poor prognosis in patients[18]

Methods

Results

Conclusion