DMBT1 is a novel gene induced by IL-22 in ulcerative colitis.

BACKGROUND: Interleukin (IL)-22 is a recently identified cytokine that is suggested to play pivotal roles in various inflammatory diseases. Although the IL-22 receptor 1 (IL-22R1) is restrictively expressed in epithelial cells in the colon, the role of IL-22 in colonic diseases still remains unclear. In this study microarray analyses revealed that deleted in malignant brain tumors 1 (DMBT1) is a novel upregulated gene in IL-22-stimulated colon cancer cells. Therefore, we investigated the involvement of DMBT1 and IL-22 in ulcerative colitis (UC) tissues and examined the mechanism regulating the expression of DMBT1 in response to IL-22 stimulation. METHODS: Changes of gene expression in IL-22-stimulated SW403 cells were investigated by microarray analyses. The effects of IL-22 on DMBT1 expression were examined in SW403 cells using a small interfering RNA (si)RNA for STAT3 or inhibitors for MEK, PI3K, and nuclear factor kappa B (NF-κB). The element responsible for IL-22-induced DMBT1 promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay (EMSA). Expression of IL-22, IL-22R1, and DMBT1 in UC tissues was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: IL-22 treatment enhanced the expression of DMBT1 through STAT3 tyrosine phosphorylation and NF-κB activation in colon cancer cells. The IL-22-responsive element was located between -187 and -179 in the DMBT1 promoter region. In the UC mucosa the levels of DMBT1 and IL-22 mRNA expression were significantly enhanced and positively correlated, the numbers of IL-22-positive lymphocytes were increased, and the expression of IL-22R1 and DMBT1 was enhanced in the inflamed epithelium. CONCLUSIONS: The IL-22/DMBT1 axis may play a pivotal role in the pathophysiology of UC.

Detection of desmoplastic reaction in biopsy specimens is useful for predicting the depth of invasion of early colorectal cancer: a Japanese collaborative study.

BACKGROUND: We have previously demonstrated a relationship between the depth of submucosal invasion (SM depth) and the frequency of lymph node metastasis in resected submucosal invasive colorectal cancers (SICRCs). Here, we assessed the desmoplastic reaction (DR) in pretreatment biopsy specimens of SICRC to predict the SM depth. METHODS: A total of 359 patients with SICRCs, who had undergone surgical or endoscopic mucosal resection, were enrolled. The SM depth of the SICRC lesions was evaluated according to the procedure established by the Japanese Society for Cancer of the Colon and Rectum, and the patients' corresponding pretreatment biopsy specimens were examined histologically to evaluate the prevalence of DR. RESULTS: For pedunculated SICRCs, the prevalence of DR in pretreatment biopsy specimens was significantly higher in moderately differentiated than in well-differentiated adenocarcinomas, but was not significantly related to SM depth. For nonpedunculated SICRCs, the prevalence of DR in pretreatment biopsy specimens was significantly related to histological type, tumor size, and SM depth. When non-pedunculated SICRCs were further divided using a specific cutoff value of 1000 µm for SM depth, the DR positivity rate in pretreatment biopsy specimens was significantly higher in SICRCs with an SM depth of ≥1000 µm (termed "SM massive CRCs") than in cases where the SM depth was <1000 µm (termed "SM slight CRCs"). CONCLUSIONS: Detection of DR in pretreatment biopsy specimens is useful for the prediction of SM depth in nonpedunculated SICRCs, and may be useful for the selection of such cases that would be treatable by endoscopic mucosal resection and endoscopic submucosal dissection (EMR/ESD).