Plasma extracellular cold inducible RNA-binding protein levels are elevated for 1 month post-colectomy which may promote metastases

Abstract

BACKGROUND

Cold-inducible RNA-binding protein (CIRP) is related to a family of stress-induced RNA-binding proteins. It is primarily found in the nucleus, where it regulates transcription. Under stress, CIRP translocates to the cytoplasm where it modulates translation; a subset is secreted as extracellular CIRP (eCIRP) which is a damage-associated molecular pattern (DAMP) molecule that stimulates the production of inflammatory mediators. Elevated blood eCIRP levels may foster immune tolerance and facilitate tumor growth. Increased CIRP levels have been noted in various malignancies including colorectal cancer (CRC). This study’s objective was to determine plasma eCIRP levels before and after minimally invasive colorectal resection (MICR) for CRC.

AIM

To assess plasma eCIRP levels prior to and following minimally invasive colorectal resection in the context of cancer pathology.

METHODS

MICR patients from an IRB-approved data/tissue bank for whom plasma samples were available were eligible. Plasma specimens were obtained preoperatively (preop) and at least 3 time’s postop [between postoperative day (POD) 1-41]; late samples were grouped into 7-day blocks and were considered separate time points. eCIRP levels were assessed via enzyme-linked immunosorbent assay (pg/mL) and results presented as mean ± SD, analysis with Wilcoxon paired t-test).

RESULTS

A total of 83 CRC patients who underwent MICR [colon 66%, rectal 34%; laparoscopic-assisted (LA), 70%; hand-assisted laparoscopic (HAL), 30%] were studied. The mean preop eCIRP level was 896.8 ± 757.0 pg/mL. Elevations in mean plasma levels (P = < 0.001) were noted on POD1 (2549 ± 2632 pg/mL, n = 83), POD3 (1871 ± 1362 pg/mL, n = 77), POD7-13 (1788 ± 1403 pg/mL, n = 57), POD14-20 (1473 ± 738.8 pg/mL, n = 30), and POD21-27 (1681 ± 1375 pg/mL, n = 21). No significant differences were noted at POD 28-41. Higher values were noted in the HAL’s (vs LA) group, however, there were more rectal cancers in the former.

CONCLUSION

Elevated plasma eCIRP levels persist for a month post MICR for CRC (change from baseline, 77%-184%); highest values seen on POD1. The initial surge may be due to the acute inflammatory response while later elevations may be related to wound healing and remodeling. The higher levels noted in the HAL’s group (with greater IL and more rectal cases) suggest the extent of surgical trauma impacts eCIRP levels. Further investigations are needed.

Keywords: Effects of surgery; Plasma extracellular cold-inducible RNA-binding protein levels; Colorectal resection; Colorectal cancer; Angiogenesis

Core Tip: Our findings have substantiated that plasma collected during the second and third weeks post minimally invasive colorectal cancer resection (MICR) possesses the capacity to stimulate endothelial cell proliferation, invasion, and migration, which are essential prerequisites for neovascularization. This study, investigating perioperative plasma extracellular cold-inducible RNA-binding protein (eCIRP) levels in the context of MICR, evaluated six postoperative time points and unveiled that blood levels remain significantly elevated above preoperative baseline for a month after surgery. eCIRP and acts as a damage-associated molecular pattern molecule that promotes an inflammatory response (including TNF-α, IL-6 and HMGB production in macrophages, neutrophils, lymphocytes and dendritic cells. Elevated levels of eCIRP together with other elevated angiogenic proteins including T cell immunoglobulin and mucin domain-3 and monocyte chemo-attractant protein-1 may enhance macrophage activity and promote immune tolerance, potentially facilitating tumor growth and progression.