Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan.
Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan.
Cancer Sci. 2018 Jun;109(6):2013-2026. doi: 10.1111/cas.13610. Epub 2018 May 22.
We previously used RNA sequencing to establish the microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC). We found that both strands of pre-miR-148a (miR-148a-5p: the passenger strand and miR-148a-3p: the guide strand) were downregulated in cancer tissues. Ectopic expression of miR-148a-5p and miR-148a-3p significantly inhibited cancer cell migration and invasion, indicating that both strands of pre-miR-148a had tumor-suppressive roles in PDAC cells. In silico database and genome-wide gene expression analyses identified a total of 15 genes that were putative targets regulated by these miRNAs. High expression of miR-148a-5p targets (PHLDA2, LPCAT2 and AP1S3) and miR-148a-3p targets (SMA, ENDOD1 and UHMK1) was associated with poor prognosis of patients with PDAC. Moreover, knockdown of PHLDA2 expression inhibited cancer cell aggressiveness, suggesting PHLDA2 acted as an oncogene in PDAC cells. Involvement of the passenger strand of pre-miR-148a (miR-148-5p) is a new concept in cancer research. Novel approaches that identify tumor-suppressive miRNA regulatory networks in lethal PDAC might provide new prognostic markers and therapeutic targets for this disease.
我们之前使用 RNA 测序建立了胰腺导管腺癌（PDAC）的 microRNA（miRNA）表达特征。我们发现 pre-miR-148a 的两条链（miR-148a-5p：过客链和 miR-148a-3p：引导链）在癌症组织中均下调。miR-148a-5p 和 miR-148a-3p 的异位表达显著抑制癌细胞迁移和侵袭，表明 pre-miR-148a 的两条链在 PDAC 细胞中均具有肿瘤抑制作用。计算机数据库和全基因组基因表达分析总共鉴定出 15 个可能受这些 miRNA 调控的靶基因。miR-148a-5p 靶基因（PHLDA2、LPCAT2 和 AP1S3）和 miR-148a-3p 靶基因（SMA、ENDOD1 和 UHMK1）的高表达与 PDAC 患者的预后不良相关。此外，PHLDA2 表达的敲低抑制了癌细胞的侵袭性，表明 PHLDA2 在 PDAC 细胞中作为癌基因发挥作用。pre-miR-148a 过客链（miR-148-5p）的参与是癌症研究中的一个新概念。识别致命性 PDAC 中肿瘤抑制 miRNA 调控网络的新方法可能为该疾病提供新的预后标志物和治疗靶点。
