Abstract
Colorectal cancer (CRC)-associated mortality is primarily caused by lymph node (LN) and distant metastasis, highlighting the need for biomarkers that predict LN metastasis and facilitate better therapeutic strategies. We used an Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-based comparative proteomics approach to identify novel biomarkers for predicting LN metastasis in CRC patients. We analyzed five paired samples of CRC with or without LN metastasis, adjacent normal mucosa, and normal colon mucosa, and differentially expressed proteins were identified and subsequently validated at the protein and/or mRNA levels by immunohistochemistry and qRT-PCR, respectively. We identified 55 proteins specifically associated with LN metastasis, from which we selected ezrin for further analysis and functional assessment. Expression of ezrin at both the protein and mRNA levels was significantly higher in CRC tissues than in adjacent normal colonic mucosa. In univariate analysis, high ezrin expression was significantly associated with tumor progression and poor prognosis, which was consistent with our in vitro findings that ezrin promotes the metastatic capacity of CRC cells by enabling cell invasion and migration. In multivariate analysis, high levels of ezrin protein and mRNA in CRC samples were independent predictors of LN metastasis. Our data thus identify ezrin as a novel protein and mRNA biomarker for predicting LN metastasis in CRC patients.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies worldwide and is a major cause of cancerrelated deaths [1]
We performed Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-based proteomic analysis to identify a novel biomarker for CRC with lymph node (LN) metastasis
Of the 55 proteins differentially expressed in CRC specimens, we selected ezrin as the most promising candidate biomarker for predicting CRCs with LN metastasis
Summary
Colorectal cancer (CRC) is one of the most common malignancies worldwide and is a major cause of cancerrelated deaths [1]. Noninvasive imaging modalities frequently used for the preoperative diagnosis of LN metastasis in CRC patients include computed tomography (CT), magnetic resonance imaging (MRI), endorectal ultrasonography, and positron emission tomography/CT [3, 4] These imaging approaches are generally unreliable and inadequate at identifying LN metastasis (accuracy rates: CT 22–73%, MRI 39–95%, EUS 62–83%) [4]. Several preoperative biomarkers have the potential to act as complementary tools to improve LN metastasis classification in CRC patients, which include tumor markers such as CA199, c-reactive protein, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio [6,7,8,9,10] None of these markers are currently recommended as routine screening tools because of their inherently low sensitivity and specificity
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