State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
Department of Pathology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
Cell Death Differ. 2019 Nov;26(11):2268-2283. doi: 10.1038/s41418-019-0301-1. Epub 2019 Feb 18.
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies and lacks targeted therapies. Here, we reported a novel potential therapeutic target hematological and neurological expressed 1 like (HN1L) in HCC. First, HCC tissue microarray analysis showed that HN1L was frequently up-regulated in cancer tissues than that in normal liver tissues, which significantly associated with tumor size, local invasion, distant metastases, and poor prognosis for HCC patients. Functional studies demonstrated that ectopic expression of HN1L could increase cell growth, foci formation in monolayer culture, colony formation in soft agar and tumorigenesis in nude mice. In addition, HN1L could also promote HCC metastasis by inducing epithelial-mesenchymal transition. Inversely, silencing HN1L expression with shRNA could effectively attenuate its oncogenic function. We further showed that HN1L transcriptionally up-regulated methyltransferase like 13 (METTL13) gene in an AP-2γ dependent manner, which promoted cell proliferation and metastasis by up-regulating TCF3 and ZEB1. Importantly, administration of lentivirus-mediated shRNA interfering HN1L expression could inhibit tumorigenesis and metastasis in mice. Collectively, HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 promotes HCC growth and metastasis representing a promising therapeutic target in HCC treatment.
肝细胞癌 (HCC) 是最具侵袭性的恶性肿瘤之一，缺乏靶向治疗方法。在这里，我们报道了 HCC 中一种新的潜在治疗靶点——血液和神经系统表达 1 样蛋白 (HN1L)。首先，HCC 组织微阵列分析表明，HN1L 在癌症组织中的表达频率高于正常肝组织，与肿瘤大小、局部浸润、远处转移和 HCC 患者的预后显著相关。功能研究表明，HN1L 的异位表达可增加细胞生长、单层培养中的焦点形成、软琼脂中的集落形成以及裸鼠中的肿瘤生成。此外，HN1L 还可以通过诱导上皮-间充质转化促进 HCC 转移。相反，用 shRNA 沉默 HN1L 表达可有效减弱其致癌功能。我们进一步表明，HN1L 以依赖 AP-2γ 的方式转录上调甲基转移酶样 13 (METTL13) 基因，通过上调 TCF3 和 ZEB1 促进细胞增殖和转移。重要的是，用慢病毒介导的 shRNA 干扰 HN1L 表达的给药可抑制小鼠的肿瘤发生和转移。总之，HN1L 介导的转录轴 AP-2γ/METTL13/TCF3-ZEB1 促进 HCC 的生长和转移，代表 HCC 治疗中有希望的治疗靶点。
