Oncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy.
SAFU Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy.
Theranostics. 2018 Feb 12;8(7):1850-1868. doi: 10.7150/thno.22167. eCollection 2018.
Over 70% of head & neck squamous cell carcinoma (HNSCC) patients carry oncogenic mutations. Here we studied the role of specific tumor-derived mutant p53 proteins in the aberrant transcription of long non-coding (lnc) gene in head and neck cancer cells. To understand the role of lncMIR205HG, that we showed to be transcriptionally regulated by mutant p53 in HNSCC, we have employed siRNA and shRNA in CAL27 and FaDu HNSCC cell lines to suppress p53 gene expression in ChIP assays and RT-qPCR. We validated our findings in a cohort of 522 HNSCC patients from The Cancer Genome Atlas Data Portal (TCGA). We further evaluated our results in 63 HNSCC tumor samples collected at our institute, 32 of which were characterized by mutated (missense mutations) while 31 were characterized by wild-type . Maturation of pre-MIR205HG transcript produces two non-coding RNAs, lncMIR205HG and hsa-miR-205-5p. Down-regulation of lncMIR205HG expression significantly reduced cell proliferation, cell migration and clonogenic activity of head and neck cancer cells. Expression of MIR205HG was significantly increased in HNSCC with mutated when compared with matched non-tumoral tissues. Furthermore, MIR205HG expression levels were significantly higher in tumoral samples with mutant p53 than in tumoral tissues expressing wild-type p53. Mechanistically, MIR205HG depletes endogenous miR-590-3p leading to increased cyclin B, cdk1, and YAP protein expression. Taken together, these findings identify a transcriptional and post-transcriptional molecular network that includes mutant p53 protein, lncMIR205HG, YAP, and other proliferation-related genes, which are enriched in HNSCC patients with poor prognosis.
超过 70%的头颈部鳞状细胞癌（HNSCC）患者携带致癌突变。在这里，我们研究了特定的肿瘤衍生突变 p53 蛋白在头颈部癌细胞中异常转录长非编码（lnc）基因的作用。为了了解 lncMIR205HG 的作用，我们已经证明它在 HNSCC 中受突变 p53 转录调控，我们在 CAL27 和 FaDu HNSCC 细胞系中使用 siRNA 和 shRNA 来抑制 ChIP 测定和 RT-qPCR 中的 p53 基因表达。我们在来自癌症基因组图谱数据门户（TCGA）的 522 名 HNSCC 患者队列中验证了我们的发现。我们进一步在我们研究所收集的 63 个 HNSCC 肿瘤样本中评估了我们的结果，其中 32 个样本具有突变（错义突变），31 个样本具有野生型。pre-MIR205HG 转录物的成熟产生两种非编码 RNA，lncMIR205HG 和 hsa-miR-205-5p。lncMIR205HG 表达下调显著降低头颈部癌细胞的增殖、细胞迁移和克隆形成活性。与匹配的非肿瘤组织相比，MIR205HG 在具有突变的 HNSCC 中的表达显著增加。此外，与表达野生型 p53 的肿瘤组织相比，突变 p53 肿瘤样本中的 MIR205HG 表达水平显着更高。从机制上讲，MIR205HG 耗尽内源性 miR-590-3p，导致 cyclin B、cdk1 和 YAP 蛋白表达增加。总之，这些发现确定了包括突变 p53 蛋白、lncMIR205HG、YAP 和其他与增殖相关的基因在内的转录和转录后分子网络，这些基因在预后不良的 HNSCC 患者中富集。
Zotero 插件
