HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, UK.
HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S37. doi: 10.1016/S0140-6736(15)60352-X.
MicroRNAs (miRNAs) are small non-coding RNAs involved in the post-transcriptional regulation of mRNAs and are aberrantly expressed in cancer with important roles in tumorigenesis. A broad analysis of the combined effects of altered activities of miRNAs in pancreatic ductal adenocarcinoma (PDAC) has not been done, and how miRNAs might affect tumour progression or patient outcomes is unclear.
We combined data from miRNA and mRNA expression profiles from PDAC and normal pancreas samples (each n=9) and used bioinformatic analyses to identify a miRNA-mRNA regulatory network in PDAC. We validated our findings in PDAC cell-lines (PANC-1, MIA PaCa-2, LPc006, and LPc167), subcutaneous PDAC xenografts in mice, and laser capture microdissected PDACs from patients (n=91). We used this information to identify miRNAs that contributed most to tumorigenesis.
We identified three miRNAs (miR-21, miR-23a, and miR-27a) that acted as cooperative repressors of a network of tumour suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of miR-21, miR-23a, and miR-27a had synergistic effects in reducing proliferation of PDAC cells in culture and the growth of xenograft tumours. The level of inhibition was greater than that of silencing oncomiR-21 alone. In PDACs from patients, high levels of the combination of miR-21, miR-23a, and miR-27a was a strong independent predictor of short overall survival after surgical resection (hazard ratio 3·21, 95% CI 1·78-5·78). High expression of this combination was also associated with a more aggressive tumour phenotype: more microscopic tumour infiltration at resection margin and increased perineural invasion.
In an integrated data analysis, we identified functional miRNA-mRNA interactions that contribute to PDAC growth. These findings indicate that miRNAs act together to promote tumour progression and that future therapeutic strategies might require inhibition of several miRNAs. Furthermore, high tumour expression of the miR-21, miR-23a, and miR-27a combination could have potential use in the future as a prognostic signature for patients with PDAC.
Peel Medical Research Trust, Alliance Family Foundation, Action Against Cancer, National Institute for Health Research, Association for International Cancer Research, Jason Boas Fellowship, Imperial Biomedical Research Centre, Rosetrees Trust, Joseph Ettedgui Charitable Foundation.
微小 RNA（miRNAs）是参与 mRNA 转录后调控的小非编码 RNA，在癌症中表达异常，在肿瘤发生中具有重要作用。目前尚未对胰腺导管腺癌（PDAC）中 miRNA 活性改变的综合影响进行广泛分析，miRNA 如何影响肿瘤进展或患者预后尚不清楚。
我们结合了 PDAC 和正常胰腺样本的 miRNA 和 mRNA 表达谱数据（每组 n=9），并使用生物信息学分析方法在 PDAC 中鉴定 miRNA-mRNA 调控网络。我们在 PDAC 细胞系（PANC-1、MIA PaCa-2、LPc006 和 LPc167）、小鼠皮下 PDAC 异种移植瘤和激光捕获显微解剖的 PDAC 患者（n=91）中验证了我们的发现。我们利用这些信息来鉴定对肿瘤发生贡献最大的 miRNAs。
我们鉴定出三个 miRNA（miR-21、miR-23a 和 miR-27a）作为肿瘤抑制基因网络的协同抑制剂，该网络包括 PDCD4、BTG2 和 NEDD4L。抑制 miR-21、miR-23a 和 miR-27a 可协同减少 PDAC 细胞在培养中的增殖和异种移植瘤的生长。抑制程度大于单独沉默致癌 miRNA-21 的程度。在患者的 PDAC 中，miR-21、miR-23a 和 miR-27a 的组合高水平是手术切除后总生存期短的独立强预测因素（危险比 3.21，95%CI 1.78-5.78）。这种组合的高表达还与更具侵袭性的肿瘤表型相关：在切除边缘有更多的显微镜下肿瘤浸润和增加的神经周围侵犯。
在综合数据分析中，我们鉴定出有助于 PDAC 生长的功能性 miRNA-mRNA 相互作用。这些发现表明，miRNAs 共同作用以促进肿瘤进展，未来的治疗策略可能需要抑制几种 miRNAs。此外，高肿瘤表达 miR-21、miR-23a 和 miR-27a 的组合可能具有作为 PDAC 患者预后标志物的潜在用途。
皮尔医学研究信托基金、联盟家庭基金会、抗癌行动、英国国家卫生研究院、国际癌症研究协会、杰森·博阿斯奖学金、帝国生物医学研究中心、罗塞斯信托基金、约瑟夫·埃特迪吉慈善基金会。
