Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Department of Surgical Oncology, The Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing, China.
Exp Cell Res. 2020 May 1;390(1):111955. doi: 10.1016/j.yexcr.2020.111955. Epub 2020 Mar 9.
Tumor-initiating cells (T-ICs) are involved in the tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Herein, we find that miR-454 is upregulated in liver T-ICs and has an important function in liver T-ICs. Functional studies have revealed that knockdown of miR-454 inhibits liver T-IC self-renewal and tumorigenesis. Conversely, forced miR-454 expression promotes liver T-IC self-renewal and tumorigenesis. Mechanistically, we found that miR-454 downregulates SOCS6 expression in liver T-ICs. The correlation between miR-454 and SOCS6 is validated in human HCC tissues. Furthermore, HCC cells that overexpress miR-454 are resistant to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrates that miR-454 may predict sorafenib benefits in HCC patients. In conclusion, our findings reveal the crucial role of miR-454 in liver T-IC expansion and sorafenib response.
肿瘤起始细胞（T-ICs）参与肝癌（HCC）的发生、发展、耐药和复发。然而，肝 T-IC 增殖的潜在机制尚不清楚。在此，我们发现 miR-454 在肝 T-IC 中上调，并在肝 T-IC 中具有重要功能。功能研究表明，miR-454 的敲低抑制肝 T-IC 的自我更新和致瘤性。相反，强制表达 miR-454 促进肝 T-IC 的自我更新和致瘤性。在机制上，我们发现 miR-454 下调肝 T-IC 中的 SOCS6 表达。miR-454 和 SOCS6 之间的相关性在人 HCC 组织中得到验证。此外，过表达 miR-454 的 HCC 细胞对索拉非尼治疗有耐药性。对患者来源的异种移植（PDXs）的分析进一步表明，miR-454 可能预测 HCC 患者对索拉非尼的获益。总之，我们的研究结果揭示了 miR-454 在肝 T-IC 扩增和索拉非尼反应中的关键作用。
