Significant decrease of mucosal cytoglobin+ pericryptal myofibroblasts in longstanding ulcerative colitis with colorectal neoplasia, correlatively with alpha-SMA and HSP47 phenotypic expression

Abstract

Cytoglobin (Cygb) is speculated to supply O2 to mitochondria and act as free radical scavenger to protect cells from oxidative stress. It also relates with organ fibrosis. We showed Cygb expression and characterization in hepatic stellate cells and splanchnic fibroblast-like cells1,2. Recently, we presented that colonic pericryptal (subepithelial) myofibroblasts and interstitial myofibroblasts correspond to colonic stellate cells3. Further, we have demonstrated that early genomic instability, including MSI and LOH, appeared not only in mucosal epithelial cells but also stromal cells in regenerative rectal mucosa of long-standing ulcerative colitis (UC) cases, suggesting the alteration of epithelial and mesenchymal interaction in UC-tumorigenesis4,5. Following the above described results, we tried to see Cygb expression and phenotypic alteration of pericryptal myofibroblasts and interstitial cells in the rectal mucosa in long-standing UC cases with or without colorectal neoplasia. Immunoreactive Cygb +, alpha-smooth muscle actin (alpha -SMA) +, heat shock protein (HSP)47+ pericryptal cells (/crypt) and interstitial cells (/lower half of mucosa propria, 250μm in length), respectively, were counted on frozen histologic sections of non-cancerous rectal mucosa of sporadic colorectal cancer (controls, 16; male 9, female 7; 64.6±14.6 y/o) and long-standing UC cases (total duration of illness >5 years) with (14; m 8, f 6; 53.1 ± 14.4 y/o) or without neoplasia (20; m 10, f 10; 46.8 ± 14.0 y/o), and results were compared each other. Cygb expression was demonstrated in pericryptal myofibroblasts and interstitial cells, similar to hepatic stellate cells by immunohistochemistry and immunoelectron microscopy. Coexpression of Cygb and alpha-SMA or HSP47 was also confirmed in some of pericryptal myofibroblasts and interstitial cells by double immunofluorescence method. Significant decrease of Cygb+ pericryptal myofibroblasts in long-standing UC cases without neoplasia was shown, correlatively with alpha-SMA+ or HSP47+ pericryptal cells, compared to controls. Further, Cygb+ pericryptal myofibroblasts were significantly decreased in long-standing UC cases with neoplasia, compared to without neoplasia, suggesting a suppressive role of Cygb in tumorigenesis. In contrast, Cygb+ or alpha-SMA + or HSP47+ interstitial cells increased in long-standing UC with and without neoplasia. Significant inverse correlations were also revealed between Cygb+ or alpha-SMA + or HSP47+ pericryptal myofibroblasts and interstitial cells, respectively, in relation with the progression of mucosal remodeling due to UC. Taken together, alterations of pericryptal myofibroblasts and interstitial cells may play an important role on colorectal tumorigenesis in UC.