Recent studies have displayed that circular RNA plays a key regulatory role in tumorigenesis and development. However, evidence supporting the critical role of circular RNA in the prognosis of colorectal cancer (CRC) is still limited. This study was designed to screen and identify novel circular RNA biomarkers in CRC. The microarray analysis of circular RNA expression profile was performed in three matched CRC and normal tissues. Compared with normal mucosa, a total of 208 differentially expressed circular RNAs were found in CRC, of which 95 were upregulated and 113 were downregulated. Then, the top 10 circular RNAs with the most significant differential expression were selected for verification by quantitative polymerase chain reaction (qPCR) in the above samples. The results of qPCR basically coincided with the findings of microarray analysis. The hsa_circ_022382 expression was the most significant upregulation in CRC among the 10 circular RNAs validated by qPCR. Because hsa_circ_022382 is derived from the human FADS2 gene, we named it circFADS2. Next, the increased expression of circFADS2 was further confirmed by qPCR, and its correlation with clinicopathologic parameters was analyzed in 200 CRC tissues. Herein, the expression of circFADS2 was shown to increase in 187 cases and decrease in 13 cases of CRC, and the elevated circFADS2 expression was closely related to the size, differentiation, infiltration depth, lymphatic and distant metastasis, and tumor/node/metastasis (TNM) stage of CRC. The survival analyses by Kaplan–Meier method demonstrated that patients with higher circFADS2 expression levels had shorter overall survival time and vice versa. Cox regression and area under ROC curve analyses revealed that the circFADS2 expression may be a promised biomarker for prognosis of CRC patients and had better prediction value when combined with TNM stage. In conclusion, our study identifies circFADS2 as an oncogenic biomarker and a potential prognostic factor in CRC.

Impact statement

Colorectal cancer (CRC) is the third most common malignancy worldwide with the second highest mortality rate. Although multidisciplinary cooperative therapies are helpful for improving the survival of CRC patients, the prognosis remains poor. Therefore, it is imperative to seek new biomarkers for the development of individualized treatment for each CRC patient. Circular RNA, an endogenous transcript with specific covalent closed loop, exhibits higher stability, conservation and expression abundance than the corresponding linear component and thus may be utilized as a promised biomarker. Although the majority of studies have focused on circular RNA expression profiling in various types of cancers, evidence supporting their critical role in the diagnosis and prognosis of CRC is limited. This study aimed to screen and identify novel circular RNA biomarkers of CRC by chip analysis and qPCR verification, and to highlight their potential as targets for CRC prognosis, and therapy.

中文翻译：

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CircFADS2：结直肠癌的潜在预后生物标志物。

最近的研究表明，环状 RNA 在肿瘤发生和发展中起着关键的调节作用。然而，支持环状 RNA 在结直肠癌 (CRC) 预后中起关键作用的证据仍然有限。本研究旨在筛选和鉴定 CRC 中的新型环状 RNA 生物标志物。在三个匹配的 CRC 和正常组织中进行了环状 RNA 表达谱的微阵列分析。与正常黏膜相比，CRC共发现208个差异表达的环状RNA，其中95个上调，113个下调。然后，选择上述样本中差异表达最显着的前 10 个环状 RNA 进行定量聚合酶链反应 (qPCR) 验证。qPCR的结果与微阵列分析的结果基本一致。hsa_circ_022382表达是通过 qPCR 验证的 10 种环状 RNA 中 CRC 中最显着的上调。由于hsa_circ_022382源自人类FADS2基因，我们将其命名为circFADS2。接下来，通过 qPCR 进一步证实了circFADS2表达的增加，并在 200 个 CRC 组织中分析了其与临床病理参数的相关性。在此，circFADS2的表达在 187 例 CRC 中增加，13 例在 CRC 中减少，并且circFADS2的升高表达与CRC的大小、分化、浸润深度、淋巴和远处转移以及肿瘤/淋巴结/转移（TNM）分期密切相关。Kaplan-Meier 方法的生存分析表明，circFADS2表达水平较高的患者总体生存时间较短，反之亦然。Cox回归和ROC曲线下面积分析表明，circFADS2表达可能是CRC患者预后的一个有希望的生物标志物，与TNM分期结合具有更好的预测价值。总之，我们的研究将circFADS2确定为 CRC 的致癌生物​​标志物和潜在的预后因素。

影响陈述

结直肠癌 (CRC) 是全球第三大常见恶性肿瘤，死亡率位居第二。尽管多学科合作治疗有助于提高 CRC 患者的生存率，但预后仍然很差。因此，迫切需要寻找新的生物标志物来为每个 CRC 患者开发个体化治疗。环状 RNA 是一种具有特定共价闭环的内源性转录物，与相应的线性成分相比，表现出更高的稳定性、保守性和表达丰度，因此可用作有希望的生物标志物。尽管大多数研究都集中在各种类型癌症中的环状 RNA 表达谱，但支持它们在 CRC 诊断和预后中起关键作用的证据是有限的。