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Stage-dependent differential expression of microRNAs in colorectal cancer: potential role as markers of metastatic disease

机译：microRNA在结直肠癌中的阶段依赖性差异表达：作为转移性疾病标志物的潜在作用

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MicroRNAs (miRs) are short non-coding RNAs that bind complementary sequences in mRNA resulting in translation repression and/or mRNA degradation. We investigated expression of the reported metastasis-associated miRs-335, 206, 135a, 146a, 146b, 10b, 21, let7a and let7b in normal mucosa, non-metastatic and metastatic colorectal cancer (CRC). Expression of target miRs in micro-dissected paraffin embedded tissues was evaluated in 15 primary tumours with adjacent normal tissue from patients that were disease-free at 4 years (cohort A) and 19 paired primary tumours with corresponding liver metastases (cohort B) by quantitative real-time PCR. Increased expression of miR-21, mir-135a and miR-335 was associated with clinical progression of CRC, while miR-206 demonstrated an opposite trend. The levels of mir-21 did not associate with the expression of PTEN, an important tumour suppressor in CRC and one of many putative targets of miR-21, but interestingly was associated with stage of disease in the PTEN expressing tumours. Surprisingly, let7a, a KRAS-targeting miR, showed elevated expression in metastatic disease compared to normal mucosa or non-metastatic disease, and only in KRAS mutation positive tumors. Finally, a prognostic signature of miR 21,135a, 335, 206 and let-7a for detecting the presence of metastases had a specificity of 87% and sensitivity of 76% for the presence of metastases. In summary, we have shown stage-associated differential expression of five out of nine tested metastasis-associated miRs. We have further found that an analysis of these five miRs expression levels in primary tumors significantly correlates with the presence of metastatic disease, making this a potential clinically useful prognostic tool.
机译：MicroRNA（miR）是短的非编码RNA，与mRNA中的互补序列结合，导致翻译抑制和/或mRNA降解。我们调查了与转移相关的miRs-335、206、135a，146a，146b，10b，21，let7a和let7b在正常黏膜，非转移性和转移性结直肠癌（CRC）中的表达。通过定量分析评估了在4岁时无疾病的患者的15例原发癌和邻近正常组织中的微解剖石蜡包埋组织中的靶标miRs的表达（组A）和19例配对的原发性肝癌伴有相应的肝转移（组B）。实时PCR。 miR-21，mir-135a和miR-335的表达增加与CRC的临床进展有关，而miR-206则显示出相反的趋势。 mir-21的水平与PTEN的表达不相关，PTEN是CRC中重要的肿瘤抑制因子，也是miR-21的许多推定靶标之一，但有趣的是与PTEN表达肿瘤的疾病阶段有关。令人惊讶的是，与正常粘膜或非转移性疾病相比，靶向KRAS的miR let7a在转移性疾病中表达升高，并且仅在KRAS突变阳性肿瘤中表达。最后，miR 21,135a，335、206和let-7a用于检测转移灶的预后特征对转移灶的特异性为87％，敏感性为76％。总而言之，我们已经显示了9个与转移相关的miR中有5个与阶段相关的差异表达。我们进一步发现，对原发肿瘤中这五个miRs表达水平的分析与转移性疾病的存在显着相关，这使其成为潜在的临床有用的预后工具。

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