Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, 3410 Worth Street, Suite 610, Dallas, TX, 75246, USA.
Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
Mol Cancer. 2018 Jan 30;17(1):16. doi: 10.1186/s12943-018-0767-3.
Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may be important epigenetic regulators of gene expression in human cancers; however, their functional and clinical significance in colorectal cancer (CRC) remains unknown.
We performed piRNA expression profiling in paired cancer and normal tissues through small RNA-sequencing. The clinical significance of candidate piRNAs was investigated, and independently validated in 771 CRC patients from three independent cohorts. The biological function of piRNAs was characterized in cell lines, followed by identification and validation of downstream target genes in CRC tissues.
We identified piR-1245 as a novel and frequently overexpressed noncoding RNA in CRC, and its expression significantly correlated with advanced and metastatic disease. Patients with high piR-1245 expression experienced significantly shorter overall survival, and multivariate analysis identified its expression to serve as an independent prognostic biomarker in CRC. Functionally, piR-1245 acts as an oncogene and promotes tumor progression, and gene expression profiling results identified a panel of downstream target-genes involved in regulating cell survival pathway. Based upon piRNA:mRNA sequence complementarity, we identified a panel of tumor suppressor genes (ATF3, BTG1, DUSP1, FAS,NFKBIA, UPP1, SESN2, TP53INP1 and MDX1) as direct targets of piR-1245, and successfully validated an inverse correlation between their expression and piR-1245 in CRC.
We for the first time have identified the role for a PIWI-interacting noncoding RNA, piR-1245, as a novel oncogene and a potential prognostic biomarker in colorectal cancer.
新出现的证据表明，PIWI 相互作用 RNA（piRNAs）可能是人类癌症中基因表达的重要表观遗传调节剂；然而，它们在结直肠癌（CRC）中的功能和临床意义尚不清楚。
我们通过小 RNA-seq 对配对的癌症和正常组织进行 piRNA 表达谱分析。研究了候选 piRNA 的临床意义，并在来自三个独立队列的 771 名 CRC 患者中进行了独立验证。在细胞系中对 piRNA 的生物学功能进行了表征，随后在 CRC 组织中鉴定和验证了下游靶基因。
我们确定 piR-1245 是 CRC 中一种新型且经常过表达的非编码 RNA，其表达与晚期和转移性疾病显著相关。高 piR-1245 表达的患者总生存期明显缩短，多变量分析确定其表达是 CRC 的独立预后生物标志物。功能上，piR-1245 作为癌基因促进肿瘤进展，基因表达谱分析结果确定了一组下游靶基因参与调节细胞存活途径。基于 piRNA:mRNA 序列互补性，我们确定了一组肿瘤抑制基因（ATF3、BTG1、DUSP1、FAS、NFKBIA、UPP1、SESN2、TP53INP1 和 MDX1）作为 piR-1245 的直接靶基因，并成功验证了它们在 CRC 中的表达与 piR-1245 呈负相关。
我们首次确定了 PIWI 相互作用的非编码 RNA piR-1245 在结直肠癌中作为一种新型致癌基因和潜在的预后生物标志物的作用。
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