Abstract
Hypoxia has been particularly associated with poor prognosis in cancer patients. Recent studies have suggested that hypoxia-related miRNAs play a critical role in various cancers, including colorectal cancer (CRC). In the present study, we found 52 differentially expressed miRNAs in HT-29 cells under hypoxic conditions versus normoxic conditions by analyzing the profiles of miRNAs. Using Cox model, we developed a hypoxia-related miRNA signature consisting of four miRNAs, which could successfully discriminate high-risk patients in the Cancer Genome Atlas (TCGA) training cohort (n=381). The prognostic value of this signature was further confirmed in the TCGA testing cohort (n=190) and an independent validation cohort composed of formalin-fixed paraffin-embedded clinical CRC samples (n=220), respectively. Multivariable Cox regression and stratified survival analysis revealed this signature was an independent prognostic factor for CRC patients. Time-dependent receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of this signature was significantly larger than that of any other clinical risk factors or single miRNA alone. A nomogram was constructed for clinical use, which incorporated both the miRNA signature and clinical risk factors and performed well in the calibration plots. Collectively, this novel hypoxia-related miRNA signature was an independent prognostic factor, and it possessed a stronger predictive power in identifying high-risk CRC patients than currently used clinicopathological features.
Highlights
Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide with substantial mortality [1]
To identify hypoxia-induced miRNAs, we cultured CRC cells (HT-29) under normoxic and hypoxic conditions for 48 h, and performed high-throughput sequencing (HTS) on these cells to identify the miRNAs with significantly altered expression
To evaluate the translational potential of our miRNA signature in identifying high-risk patients, we deliberately examined its performance in formalin-fixed paraffin-embedded (FFPE) tissues, which are routinely available in the clinical settings
Summary
Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide with substantial mortality [1]. The most commonly used approach for predicting patient survival remains pathological staging according to the tumor-node-metastasis (TNM) classification system, and it provides only limited information for the clinical prognostication because even patients within the same stage exhibit huge variation in prognosis and treatment response [2,3]. Our group has previously reported that the hypoxia-inducible miR-210 is an independent prognostic factor and contributes to metastasis in CRC [18]. These findings suggest that the hypoxia-induced dysregulation of miRNAs in cancer has potential prognostic implications. To date, there is no comprehensive analysis of prognostic biomarkers based on hypoxia-related miRNA expression profiles in CRC patients
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