Ding Chen-Hong, Deng Long-Fei, Chen Fei, Ding Kai, Chen Wan-Sheng, Xie Wei-Fen, Zhang Xin
Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
Biochem Biophys Res Commun. 2018 Jan 1;495(1):86-91. doi: 10.1016/j.bbrc.2017.10.174. Epub 2017 Nov 1.
Hepatocyte nuclear factor 1α (HNF1α) is a liver-enriched transcription factor that regulates many aspects of hepatocyte functions. Our previous studies have demonstrated that HNF1α has potent therapeutic effects on hepatocellular carcinoma (HCC). Mutations in HNF1α gene are frequently associated with maturity-onset diabetes of the young type 3 (MODY3) and hepatocellular adenomas. However, the association of HNF1α mutation and HCC remains elusive. In this study, the point mutation of HNF1α gene with c.A1532 > T/p.Q511L was identified in an HCC patient by exon-capture high-throughput sequencing. Mutation of c.A1532 > T/p.Q511L in HNF1α gene was only detected in the tumor tissue but not in the adjacent non-tumorous liver tissue of the patient. Luciferase reporter assay and real-time PCR revealed that mutation of p.Q511L reduced the transcriptional activity of HNF1α. Immunofluorescence staining and subcellular fraction analysis revealed that mutation of p.Q511L disturbed the intracellular localization of HNF1α in HCC cells. Moreover, the inhibitory effect of HNF1α on the proliferation, migration and invasion in HCC cells was also partially abolished by the mutation of p.Q511L. Our data suggested that the missense mutation of HNF1α (p.Q511L) may associate with the progression of HCC.
肝细胞核因子1α（HNF1α）是一种肝脏富集转录因子，可调节肝细胞功能的多个方面。我们之前的研究表明，HNF1α对肝细胞癌（HCC）具有强大的治疗作用。HNF1α基因突变常与青少年发病的成年型糖尿病3型（MODY3）和肝细胞腺瘤相关。然而，HNF1α突变与HCC的关联仍不明确。在本研究中，通过外显子捕获高通量测序在一名HCC患者中鉴定出HNF1α基因的c.A1532>T/p.Q511L点突变。仅在该患者的肿瘤组织中检测到HNF1α基因的c.A1532>T/p.Q511L突变，而在相邻的非肿瘤肝组织中未检测到。荧光素酶报告基因检测和实时PCR显示，p.Q511L突变降低了HNF1α的转录活性。免疫荧光染色和亚细胞组分分析显示，p.Q511L突变扰乱了HCC细胞中HNF1α的细胞内定位。此外，p.Q511L突变也部分消除了HNF1α对HCC细胞增殖、迁移和侵袭的抑制作用。我们的数据表明，HNF1α的错义突变（p.Q511L）可能与HCC的进展相关。
