Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China.
Oncogene. 2020 Dec;39(50):7279-7295. doi: 10.1038/s41388-020-01500-y. Epub 2020 Oct 12.
Metastasis is the main reason for high mortality in hepatocellular carcinoma (HCC) patients and the molecular mechanism remains unclear. Therefore, it is important to elucidate the mechanism underlying HCC metastasis. Here, we report a novel role of SIX homeobox 4 (SIX4), one of the SIX gene family, in promoting HCC metastasis. The elevated expression of SIX4 was positively correlated with loss of tumor encapsulation, microvascular invasion, higher TNM stage, and poor prognosis in human HCC. SIX4 expression was an independent and significant risk factor for the recurrence and survival in HCC patients. Upregulation of SIX4 promoted HCC invasion and metastasis, whereas downregulation of SIX4 decreased HCC invasion and metastasis. SIX4 transactivated Yes1 associated transcriptional regulator (YAP1) and MET proto-oncogene, receptor tyrosine kinase (MET) expression through directly binding to their promoters. Knockdown of YAP1 and c-MET inhibited SIX4-medicated HCC metastasis, while the stable overexpression of YAP1 and c-MET reversed the decreased metastasis induced by SIX4 knockdown. Hepatocyte growth factor (HGF), the specific ligand of c-MET, upregulated SIX4 expression through ERK/NF-κB pathway. Knockdown of SIX4 significantly decreased HGF-enhanced HCC metastasis. In human HCC tissues, SIX4 expression was positively correlated with nuclear YAP1, c-MET and HGF expression. Patients with positive coexpression of SIX4/ nuclear YAP1, SIX4/c-MET or HGF/SIX4 had the poorest prognosis. Moreover, the combination treatment of YAP1 inhibitor Verteporfin and c-MET inhibitor Capmatinib significantly suppressed SIX4-mediated HCC metastasis. In conclusion, SIX4 is a prognostic biomarker in HCC patients and targeting the HGF-SIX4-c-MET positive feedback loop may provide a promising strategy for the treatment of SIX4-driven HCC metastasis.
转移是肝细胞癌 (HCC) 患者高死亡率的主要原因，其分子机制尚不清楚。因此，阐明 HCC 转移的机制非常重要。在这里，我们报告了 SIX 同源盒 4 (SIX4) 在促进 HCC 转移中的一个新作用，SIX4 是 SIX 基因家族之一。SIX4 的表达升高与肿瘤包膜丢失、微血管侵犯、更高的 TNM 分期和人 HCC 的不良预后呈正相关。SIX4 表达是 HCC 患者复发和生存的独立且显著的危险因素。上调 SIX4 促进 HCC 的侵袭和转移，而下调 SIX4 则降低 HCC 的侵袭和转移。SIX4 通过直接结合其启动子，转录激活 Yes1 相关转录调节剂 (YAP1) 和原癌基因 MET 受体酪氨酸激酶 (MET) 的表达。YAP1 和 c-MET 的敲低抑制了 SIX4 介导的 HCC 转移，而 SIX4 敲低诱导的转移减少被 YAP1 和 c-MET 的稳定过表达所逆转。肝细胞生长因子 (HGF)，c-MET 的特异性配体，通过 ERK/NF-κB 通路上调 SIX4 的表达。SIX4 的敲低显著降低了 HGF 增强的 HCC 转移。在人 HCC 组织中，SIX4 的表达与核 YAP1、c-MET 和 HGF 的表达呈正相关。SIX4/核 YAP1、SIX4/c-MET 或 HGF/SIX4 共表达阳性的患者预后最差。此外，YAP1 抑制剂 Verteporfin 和 c-MET 抑制剂 Capmatinib 的联合治疗显著抑制了 SIX4 介导的 HCC 转移。总之，SIX4 是 HCC 患者的预后标志物，靶向 HGF-SIX4-c-MET 正反馈环可能为治疗 SIX4 驱动的 HCC 转移提供有前途的策略。
