Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Yonago, Japan.
Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago, Japan.
Cancer Sci. 2019 Feb;110(2):550-560. doi: 10.1111/cas.13884. Epub 2019 Jan 4.
Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We undertook a genome-wide shRNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55- and C7orf43-responsive sites exist between base pairs -58 and +36 and -169 and -59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression through Yes-associated protein 1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non-tumor tissues, compared to normal liver tissues from non-HCC patients. Analysis of 377 HCC patients in The Cancer Genome Atlas dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment.
端粒酶逆转录酶（TERT）通过保护癌细胞中的端粒来促进永生化。TERT 启动子的突变是肝细胞癌（HCC）中最常见的遗传改变之一，这表明 TERT 的上调是肝癌发生的关键事件。因此，TERT 转录的调节剂被预测为 HCC 治疗的合理靶点。我们进行了全基因组 shRNA 文库筛选，鉴定出 C15orf55 和 C7orf43 是 HepG2 细胞中 TERT 表达的调节剂。启动子分析表明，C15orf55 和 C7orf43 响应位点分别存在于 TERT 启动子的碱基对-58 和+36 之间以及-169 和-59 之间。C15orf55 通过结合 TERT 启动子 SP1 结合位点中的两个 GC 基序上调 TERT 表达。C7orf43 通过 Yes 相关蛋白 1 上调 TERT 表达。C15orf55 和 C7orf43 的表达水平也与 TERT 相关，与非 HCC 患者的正常肝组织相比，在 HCC 组织及其相邻非肿瘤组织中均显著升高。对 377 例 HCC 患者的分析表明，在肿瘤组织中 C15orf55 和 C7orf43 表达水平低的患者的总生存率明显高于 C15orf55 和/或 C7orf43 表达水平高的患者。这些结果表明，C15orf55 和 C7orf43 通过上调 TERT 参与 HCC 的发生和进展。总之，我们鉴定出 C15orf55 和 C7orf43 是 HCC 组织中 TERT 表达的正调节剂。这些基因是 HCC 治疗的有前途的靶点。
