PLASMA LEVELS OF EXTRACELLULAR COLD-INDUCIBLE RNA-BINDING PROTEIN (ECIRP) IS SIGNIFICANTLY INCREASED IN PATIENTS WITH COLORECTAL CANCER
Hmc Shantha Kumara*1, Xiaohong Yan1, Neil Mitra1, Doaa F. Morrar1, Hiromichi Miyagaki2, Hansani N. Angammana1, Yanni Hedjar1, Vesna Cekic1, Jennifer L. Agnew1, Richard L. Whelan1
1Surgery, Lenox Hill Hospital, Northwell Health, New York, NY; 2Department of Surgery, Osaka Rousai Hospital, Osaka-fu, Sakai-shi, Japan
Introduction: Cold-Inducible RNA-Binding Protein is (CIRP) is usually found in the nucleus where it regulates transcription. In response to stress CIRP relocates to the cytoplasm where it regulates translation; a fraction is released into the extracellular space (eCIRP) where it has other effects. Under stress, macrophages, neutrophils and lymphocytes generate eCIRP. eCIRP promotes inflammatory responses including TNF-alpha, IL-6, and HMGB production. CIRP overexpression has been noted in colorectal cancer (CRC). Elevated eCIRP blood levels may impact macrophage function and induce immune tolerance that may promote tumor progression. It was earlier shown that blood levels of MCP-1, CHI3L1 and IL8 are increased preoperatively (preop); these changes may promote macrophage recruitment/function in CRC patients (pts). Plasma levels of eCIRP in CRC pts have not been well studied. This study's purpose was to compare PreOp plasma eCIRP levels in CRC and benign colonic pathology (BCP) pts.
Method: PreOp plasma samples from CRC and BCP pts who underwent elective colon resection were obtained from an IRB approved data/plasma bank. Clinical/pathologic data were collected. Plasma eCIRP levels were measured via ELISA in duplicate and reported as median +95%CI (ng/ml). CIRP expression levels were determined in paired tumor/normal tissue samples for a pt subset by QRT-PCR. Immunohistochemistry (IHC) was performed on formalin preserved CRC and normal tissue samples. The candidacy of eCIRP as CRC diagnostic marker was evaluated by assessing the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) results. The Mann-Whitney test was used for statistical analysis (sig. p<0.05).
Results: 147 CRC (75%colon, 25%rectal) and 132 BCP pts (adenoma 46%, diverticulitis 52%) were studied. The Stage (S) breakdown was: S 1, 25%; S 2, 27%; S 3, 30%; and S 4, 19%. The median CRC plasma eCIRP levels were significantly higher (962.0, CI: 825.2, 1043.3) vs. the BCP pts (719.1,CI: 672.5, 772.5; P=< 0.0001). Plasma eCIRP levels were significantly higher in S II and S IV pts vs. Stage I pts (p<0.05). Increased expression of eCIRP was noted in 81% (26/30) of the CRC tissue samples tested vs. paired normal tissues. As regards intracellular CIRP distribution, less was found in the nucleus of cancer cells (72%) vs normal cells (97%). The AUC value for the ROC curve was 0.662 (sensitivity 33%, specificity 92%).
Conclusion: The CRC median plasma eCIRP level was 38% higher than the BCP level. In general, plasma eCIRP levels increased with advancing cancer stage. Expression data suggests the tumor is the source of the added eCIRP in the blood. Intracellularly, more CIRP was found in the cytoplasm of CRC vs normal cells suggesting tumor cells are stressed. CIRP does not appear to have value as a diagnostic/prognostic factor. Further studies are warranted.
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