Evaluation of P38 MAPK Pathway as a Molecular Signature in Ulcerative Colitis

Abstract

Early diagnosis and treatment of ulcerative colitis (UC) is clinically challenging. To overcome this problem, we explored the interrelated multiplex signaling pathway to identify molecular signatures in UC by using integrated strategy in proteomics. Intestinal mucosa of 12 UC cases and 12 normal controls underwent comparative proteomic analysis. A total of 26 unique differential proteins were identified, including 12 up-regulated and 14 down-regulated in UC group. A differential protein cluster, consisting of 11 proteins involved in p38 mitogen-activated protein kinase (MAPK) pathway, was deduced and validated by Western blot. Furthermore, three proteins elicited from the protein cluster, phosphorylated p38, MAWBP and galectin-3, as a molecular signature, were analyzed by immunohistochemistry on 118 UC and normal samples. Increased expression of P-p38 and down-regulated MAWBP and/or galectin-3 were detected in UC compared to normal samples (p < 0.001). This signature correlated with disease progression of UC (p < 0.01), and classified UC risk with high sensitivity (94.83 ± 2.91%) and specificity (98.33 ± 1.65%). In addition, P38 MAPK pathway modulated the expression of the protein clusters in macrophage cell line as evidenced by the alteration with specific inhibitor SB203580. These results indicate that molecular signature of P38 MAPK pathway might be a potential biomarker for evaluating UC risk.

Pro-Oncogenic Role of Alternative p38 Mitogen-Activated Protein Kinases p38γ and p38δ, Linking Inflammation and Cancer in Colitis-Associated Colon Cancer

“…Studies using tissue-specific conditional knockouts of p38a mice showed the importance of this isoform in the inflammatory response, both in cultured macrophages in vitro (8) and for development of skin and gut inflammation in vivo (9,10). p38a also mediates inflammation in IBD; it is highly phosphorylated and active in the inflamed intestinal mucosa of patients with IBD (11,12). The role of p38a in colitis was confirmed in experimental mouse models, and p38a/bMAPK inhibitors have been tested in clinical trials (10,(13)(14)(15)(16).…”

Effect of curcumin on p38MAPK expression in DSS-induced murine ulcerative colitis

“…Therefore, the p38 MAPK signal transduction pathway plays an important role in the inflammatory response. Rafiee et al (2002) found that p-p38MAPK was higher in IBD patients than in normal people, and positively correlated with the degree of intestinal inflammation (Zhao et al, 2011). Waetzig et al (2002) found that during IBD intestinal epithelial injury, the activity of p38MAPK was significantly increased, and revealed that by tissue immunohistochemistry high p38MAPK expression in macrophages and neutrophils of the intestinal lamina propria.…”

Identification of Gene Signatures Used to Recognize Biological Characteristics of Gastric Cancer upon Gene Expression Data

“…Commercial antibodies are used in our study: anti-COL1A2 (ab72637), anti-ATP4B (ab2866), and anti-HADSHC (ab54477). Proper validation of the ATP4B, COL1A2, and HADSHC antibodies used the same procedure as was described previously 24. The ICH was semi-quantitatively scaled in a range from “−” to “+++” by evaluating the representative tumor with intensity and percentage of cells showing significantly higher immune staining than normal matched-adjacent tissues.…”