CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Commun Biol. 2020 May 5;3(1):210. doi: 10.1038/s42003-020-0893-5.
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.
剪接因子 SRSF2 在人类癌症中经常发生突变或上调。在这里，我们观察到 Srsf2 特异性缺失会导致小鼠发生肝细胞癌 (HCC)，这也涉及炎症和纤维化。重要的是，我们发现，当补偿性肝细胞增殖受损时，肝祖细胞 (HPC) 的激活在肝脏再生和肿瘤形成中起着重要作用。此外，患有 HCC 的肝脏细胞显示出 HPC 和肝细胞标记物，基因表达谱提示 HPC 起源和胚胎起源。从机制上讲，我们证明肿瘤中胰岛素样生长因子 2 (Igf2) 和 H19 等癌胚基因的水平显著增加，这可能是由于 Igf2/H19 基因座的 DNA 甲基化减少所致。因此，Igf2 通路的信号转导在肿瘤中高度激活。因此，我们的数据表明，Srsf2 的缺失会触发 HPC 介导的再生和癌胚基因的激活，这共同促进了小鼠 HCC 的发生和发展。
