Slattery Martha L, Pellatt Andrew J, Lee Frances Y, Herrick Jennifer S, Samowitz Wade S, Stevens John R, Wolff Roger K, Mullany Lila E
Department of Medicine, University of Utah, Salt Lake City, Utah, USA.
Tulane Medical School, New Orleans, Louisiana, USA.
Oncotarget. 2017 Aug 3;8(48):83845-83859. doi: 10.18632/oncotarget.19863. eCollection 2017 Oct 13.
Half of miRNAs expressed in colorectal tissue are expressed < 50% of the population. Many infrequently expressed miRNAs have low levels of expression. We hypothesize that less frequently expressed miRNAs, when expressed at higher levels, influence both disease stage and survival after diagnosis with colorectal cancer (CRC); low levels of expression may be background noise. We examine 304 infrequently expressed miRNAs in 1893 population-based cases of CRC with paired carcinoma and normal mucosa miRNA profiles. We evaluate miRNAs with disease stage and survival after adjusting for age, study center, sex, MSI status, and AJCC stage. These miRNAs were further evaluated with RNA-Seq data to identify miRNA::mRNA associations that may provide insight into the functionality of miRNAs. Eleven miRNAs were associated with advanced disease stage among colon cancer patients ( value = 0.10). Eight infrequently expressed miRNAs influenced survival if highly expressed in overall CRC. Of these, five increased likelihood of dying if they were highly expressed, i.e. miR-124-3p, miR-143-5p, miR-145-3p, miR31-5p, and miR-99b-5p, while three were associated with better survival if highly expressed, i.e. miR-362-5p, miR-374a-5p, and miR-590-5p. Thirteen miRNAs infrequently expressed in colon-specific carcinoma tissue were associated with CRC survival if highly expressed. Evaluation of miRNAs::mRNA associations showed that mRNA expression influenced by infrequently expressed miRNA contributed to networks and pathways shown to influence disease progression and prognosis. Our large study enabled us to examine the implications of infrequently expressed miRNAs after removal of background noise. These results require replication in other studies. Confirmation of our findings in other studies could lead to important markers for prognosis.
在结直肠组织中表达的miRNA有一半在不到50%的人群中表达。许多不常表达的miRNA表达水平较低。我们推测，较少频繁表达的miRNA，当其表达水平较高时，会影响结直肠癌（CRC）诊断后的疾病分期和生存；低表达水平可能是背景噪声。我们在1893例基于人群的CRC病例中检测了304种不常表达的miRNA，并配对了癌组织和正常黏膜的miRNA谱。我们在调整年龄、研究中心、性别、微卫星不稳定性（MSI）状态和美国癌症联合委员会（AJCC）分期后，评估miRNA与疾病分期和生存的关系。这些miRNA通过RNA测序数据进一步评估，以确定miRNA与mRNA的关联，这可能有助于深入了解miRNA的功能。在结肠癌患者中，11种miRNA与晚期疾病分期相关（P值=0.10）。在总体CRC中，如果8种不常表达的miRNA高表达，则会影响生存。其中，5种miRNA高表达时会增加死亡可能性，即miR-124-3p、miR-143-5p、miR-145-3p、miR31-5p和miR-99b-5p，而3种miRNA高表达时与更好的生存相关，即miR-362-5p、miR-374a-5p和miR-590-5p。在结肠特异性癌组织中不常表达的13种miRNA高表达时与CRC生存相关。对miRNA与mRNA关联的评估表明，受不常表达的miRNA影响的mRNA表达参与了显示会影响疾病进展和预后的网络及通路。我们的大型研究使我们能够在去除背景噪声后研究不常表达的miRNA的影响。这些结果需要在其他研究中进行重复验证。在其他研究中证实我们的发现可能会产生重要的预后标志物。
