Successful identification of a predictive biomarker for lymph node metastasis in colorectal cancer using a proteomic approach
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Koichiro Mori1, Yuji Toiyama1, Kohei Otake1, Shozo Ide1, Hiroki Imaoka1, Masato Okigami1, Yoshinaga Okugawa1, Hiroyuki Fujikawa1, Susumu Saigusa1, Junichiro Hiro1, Minako Kobayashi1, Masaki Ohi1, Koji Tanaka1, Yasuhiro Inoue1, Yuhko Kobayashi2, Yasuhiko Mohri1, Issei Kobayashi2, Ajay Goel3 and Masato Kusunoki1
1Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
2Center for Molecular Biology and Genetics, Mie University, Mie, Japan
3Center for Gastrointestinal Research & Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX USA
Yuji Toiyama, email: [email protected]
Ajay Goel, email: [email protected]
Keywords: iTRAQ-based quantitative proteomic analysis; ezrin; lymph node metastasis; colorectal cancer; biomarker
Received: February 02, 2017 Accepted: June 29, 2017 Published: October 30, 2017
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.
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