Caudal type homeobox 2 expression induced by leukocytapheresis might be associated with mucosal healing in ulcerative colitis.

BACKGROUND AND AIM: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. Although the goal of UC therapy has recently been to target mucosal healing, the molecular mechanism of mucosal healing remains unknown. In this study, we aimed to elucidate the molecular dynamics related to the proliferation and differentiation of intestinal epithelial cells during cytapheresis therapy in a short duration. METHODS: Endoscopy was performed in 26 patients with UC in multicentre hospitals, and biopsy specimens were collected from the rectum before and within two weeks after leukocytapheresis (LCAP). The expression of representative proteins in intestinal epithelial cells and pathological findings was compared before and after LCAP. RESULTS: The expression of caudal type homeobox 2 (CDX2) and a hes family bHLH transcription factor 1(HES1) markedly increased after LCAP. Patients with endoscopic improvement after LCAP showed the expression of CDX2 before LCAP. Moreover, the number of goblet cells significantly increased after LCAP. Patients without endoscopic improvement after LCAP did not show the expression of CDX2 before LCAP. However, the expression of CDX2 markedly increased after LCAP. CONCLUSION: This study suggests that cytapheresis might induce CDX2 expression without affecting the cell proliferation, thus resulting in mucosal healing with goblet cell restoration.

Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line.

Patients with inflammatory bowel disease (IBD) have an increased risk of developing colitis-associated colorectal cancer (CAC). CAC cells often develop chemoresistance, resulting in a poorer prognosis than that of sporadic colorectal cancer (CRC). The mechanism by which CAC enhances malignant potential remains unknown. We have previously reported that the proteasomal degradation of the transcription factor Atonal homolog 1 (Atoh1) protein results in the non-mucinous form of CRC. It also remains unknown whether Atoh1 protein is expressed in CAC. Therefore, in the present study, we investigated whether Atoh1 protein stabilizes in CAC. Consequently, the treatment with TNF-α stabilized Atoh1 protein through the inactivation of GSK-3ß via Akt, resulting in the mucinous form of CRC cell lines. Atoh1 protein also enriched cancer stem cells with upregulated Lgr5 expression and cells in G0/G1 cell cycle phase, resulting in both the chemoresistance to 5-fluorouracil and oxaliplatin and the promotion of cell migration. Immunofluorescence of the human mucinous CAC specimens showed the accumulation of NF-κB p65 at nuclei with the expression of Atoh1 in mucinous cancer. In conclusion, the inflammation associated with carcinogenesis may preserve the differentiation system of intestinal epithelial cell (IEC), resulting in the acquisition of both the mucinous phenotype and high malignant potential associated with the enrichment of cancer stem cell.

Reduced Human α-defensin 6 in Noninflamed Jejunal Tissue of Patients with Crohn's Disease.

BACKGROUND: Mucosal barrier dysfunction is considered a critical component of Crohn's disease (CD) pathogenesis after the identification of susceptibility genes. However, the precise mechanism underlying mucosal barrier dysfunction has not yet been elucidated. We therefore aimed to elucidate the molecular mechanism underlying the expression of human α-defensin 6 (HD6) in patients with CD. METHODS: HD6 expression was induced by the transfection of an atonal homolog 1 (Atoh1) transgene and was assessed by reverse transcription polymerase chain reaction. The HD6 promoter region targeted by Atoh1 and ß-catenin was determined by reporter analysis and chromatin immunoprecipitation assay. HD5/HD6/Atoh1/ß-catenin expression in noninflamed jejunal samples collected by balloon endoscopy from 15 patients with CD and 9 non-inflammatory bowel disease patients were assessed by immunofluorescence. RESULTS: Both promoter activity and gene expression of HD6 was significantly upregulated by the Atoh1 transgene in human colonic cancer cell line. We identified a TCF4 binding site and an E-box site, critical for the regulation of HD6 transcriptional activity by directly binding of Atoh1 in the 200-bp HD6 promoter region. The treatment with ß-catenin inhibitor also decreases HD6 promoter activity and gene expression. Moreover, HD6 expression, but not HD5 expression, was found to be decreased in noninflamed jejunal regions from patients with CD. In HD6-negative crypts, nuclear accumulation of ß-catenin was impaired. CONCLUSIONS: HD6 expression was found to be regulated by cooperation between Atoh1 and ß-catenin within the HD6 promoter region. Downregulation of HD6 in noninflamed mucosa may contribute to mucosal barrier dysfunction of patients with CD.

Hyalinizing spindle cell tumor with giant rosettes of the omentum.

We report the first case of a hyalinizing spindle cell tumor with giant rosettes of the omentum. The mesenchymal tumor arises from a multiplication of fibroblastic cells containing large rosette-like structures composed of a central collagen core surrounded by plump oval to spindle tumor cells. A 38-year-old woman exhibited the symptom of abdominal pain in the right side, with a correlated sensation of a mass in the same area. A tumor consisting of both solid and cystic cytologic features was subsequently diagnosed, on the right side of the uterus. Her serum level of CA-125 was only slightly elevated. Surgical intervention indicated that the tumor originated from lower pole of the omentum and the histological diagnosis was hyalinizing spindle cell tumor with giant rosettes. The metastatic potential of this type of tumor is considered similar to that of the metastatic low-grade fibromyxoid sarcoma, which indicated the need for careful clinical follow up of this case.

Differentiation between completely hyalinized uterine leiomyomas and ordinary leiomyomas: three-phase dynamic magnetic resonance imaging (MRI) vs. diffusion-weighted MRI with very small b-factors.

PURPOSE: To assess the possibility of differentiating between completely hyalinized leiomyomas and ordinary leiomyomas by using diffusion-weighted (DW) magnetic resonance imaging (MRI) (DWI) employing very small b-factors (b = 1.51 and 55.3 seconds/mm(2)) in comparison with three-phase dynamic MRI. MATERIALS AND METHODS: The subjects were 25 patients with 52 histopathologically confirmed uterine leiomyomas. All leiomyomas were divided into two histopathologic subtypes (5 completely hyalinized leiomyomas and 47 ordinary leiomyomas). For each leiomyoma, the enhancement index (EI) at three-phase dynamic MRI and apparent diffusion coefficient (ADC) were obtained and then compared. RESULTS: The EIs at second and third dynamic phases clearly differentiated the two types of leiomyomas without overlap of values. ADCs also clearly differentiated the two types of leiomyomas without overlap of values. Moreover, there were significant positive correlations between ADCs and EIs at all dynamic phases (r = 0.41-0.50, P < 0.01). CONCLUSION: Not only three-phase dynamic MRI but also DWI with very small b-factors could be useful for differentiating completely hyalinized leiomyomas from ordinary leiomyomas.