Biomarkers of Human Esophageal Cancer

我们已经发现某些microRNA的表达与诊断和生存有关。食管癌患者的悲惨结局凸显了对新型预后生物标志物的需求，如microRNA（miRNAs）。虽然最近的研究已经确定了miRNA在食管癌中的作用，但仍然缺乏一项全面的多中心研究，研究不同的组织学类型，包括鳞状细胞癌（SCC）和腺癌（ADC）伴或不伴Barrett's。在来自美国、加拿大和日本的4个临床中心招募的100名ADC和70名SCC患者的癌组织和邻近非癌组织对中测量miRNA表达。基于微阵列的表达在两个组群中的样品子集中测量，并在所有可用的样品中验证。在ADC患者中，与非癌组织相比，癌组织中miR-21、miR-223、miR-192和miR-194表达升高，而miR-203表达降低。在SCC患者中，我们发现与非癌组织相比，癌组织中miR-21表达水平升高，miR-375表达水平降低。当比较ADC和SCC患者之间的癌组织表达时，miR-194和miR-375在ADC患者中升高。值得注意的是，SCC患者非癌组织中miR-21表达升高和ADC患者Barrett's癌组织中miR-375水平降低与预后不良密切相关。预后与肿瘤分期或淋巴结状态、队列类型和放化疗无关。我们基于多中心的结果突出了参与食管癌主要组织学类型的miRNAs，并揭示了与预后的显著相关性。阐明与食管癌发生相关的miRNA对于开发预后生物标志物和鉴定新的药物靶点和治疗方法具有潜在的临床意义。

We have discovered that expression of certain microRNAs are associated with diagnosis and survival. The dismal outcome of esophageal cancer patients highlights the need for novel prognostic biomarkers, such as microRNAs (miRNAs). While recent studies have established the role of miRNAs in esophageal carcinoma, a comprehensive multi-center study investigating different histological types, including squamous cell carcinoma (SCC) and adenocarcinoma (ADC) with or without Barrett's, is still lacking. miRNA expression was measured in cancerous and adjacent non-cancerous tissue pairs collected from 100 ADC and 70 SCC patients enrolled at 4 clinical centers from the US, Canada, and Japan. Microarray-based expression was measured in a subset of samples in two cohorts and was validated in all available samples. In ADC patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, while miR-203 expression was reduced in cancerous compared to non-cancerous tissue. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared to non-cancerous tissue. When comparing cancerous tissue expression between ADC and SCC patients, miR-194 and miR-375 were elevated in ADC patients. Significantly, elevated miR-21 expression in non-cancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of ADC patients with Barrett's were strongly associated with worse prognosis. Associations with prognosis were independent of tumor stage or nodal status, cohort type, and chemoradiation therapy. Our multi-center-based results highlight miRNAs involved in major histological types of esophageal carcinoma and uncover significant associations with prognosis. Elucidating miRNAs relevant to esophageal carcinogenesis is potentially clinically useful for developing prognostic biomarkers and identifying novel drug targets and therapies.