TBX19 is overexpressed in colorectal cancer and associated with lymph node metastasis.

The T-box 19 (TBX19) gene encodes a transcription factor characterized by a highly conserved DNA-binding motif (T-box). Recent studies have revealed that TBX19 has been identified as one of the genes activated by KRAS mutations, and is upregulated in colon adenoma. These results indicate that TBX19 may work as an oncogene in colorectal cancer (CRC). However, the expression and role of TBX19 have yet to be investigated. Here, we investigated TBX19 mRNA and protein expressions in colon cancer cells or surgically resected CRC. We found that TBX19 mRNA expression was significantly increased in tumorous tissues compared to that in non-tumorous tissues, and increased TBX19 mRNA expression was associated with positive lymph node metastasis in our cohort. The expression of TBX19 mRNA was not correlated with that of TBX19 protein in tissue sample taken from the CRC patients. Moreover, TBX19 showed positive staining even in the normal colonic tissues and the adjacent non-tumorous tissues. These results suggest that the expression of TBX19 protein is not correlated with the expression of TBX19 mRNA. In addition, our results promote further investigations into the impact of TBX19 upregulation on colorectal carcinogenesis, as well as the underlying mechanisms.

CDX2 is involved in microRNA-associated inflammatory carcinogenesis in gastric cancer.

The development of gastric cancer is significantly associated with chronic inflammation, such as caused by Helicobacter pylori (H. pylori) infection. Caudal-type homeobox 2 (CDX2) is a homeobox protein involved in intestinal differentiation in normal and in aberrant locations, and is associated with inflammation. The authors of the present study have previously reported that CDX2 may have a suppressive role in the progression and carcinogenesis of gastric carcinoma. In the present study, the authors initially confirmed that a decreased expression of CDX2, as detected by immunohistochemistry, is associated with poor cancer-specific survival in 210 gastric cancer cases, which is consistent with several previously published studies. To elucidate the potential mechanisms underlying this association, the authors investigated the mechanism of CDX2 suppression, which included interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) and p53 signaling pathways. The present study confirmed that CDX2 was suppressed by activation of the IL-6/STAT3 signaling pathway via miR-181b in vitro. It was further revealed that gastric cancer with negative CDX2 expression is associated with negative p53 staining, and this association was particularly significant in undifferentiated gastric cancer. The activation of the IL-6/STAT3 signaling pathway suppressed miR-34a, which is induced by p53. This suggests that the activation of the IL-6/STAT3 signaling pathway inflammation signaling pathway suppresses the p53 signaling pathway in tumors without TP53 mutation, which results in poor prognostic outcomes. In conclusion, CDX2 may be a useful prognostic biomarker for gastric cancer and is associated with p53 inactivation.

Clinicopathological examination of dipeptidase 1 expression in colorectal cancer.

Dipeptidase 1 (DPEP1) is a zinc-dependent metalloproteinase that is fundamental in glutathione and leukotriene metabolism. DPEP1 was initially considered as a tumor suppressor gene in Wilms' tumor and breast cancer. However, it has been reported that DPEP1 is upregulated in colorectal cancers (CRCs) and high DPEP1 expression levels are associated with poorer patient survival. The role of DPEP1 genes in CRC, as well as their expression, requires investigation. Therefore, the present study investigated DPEP1 expression using reverse transcription-quantitative polymerase chain reaction or immunohistochemistry on surgically resected samples from CRC cases, and further examined the biological significance of DPEP1 by comparing the expression of the epithelial to mesenchymal transition (EMT) markers, including epithelial cadherin and Vimentin to clarify the function of DPEP1 in CRC, particularly in metastasis. The level of DPEP1 expression was identified to be significantly increased in tumorous tissue samples compared with that in non-tumorous tissue samples. In addition, increased DPEP1 mRNA expression levels were associated with positive lymph node metastasis in the included cohort. However, no positive correlations were observed between DPEP1 and EMT markers in the cohort. The results indiciates that further investigations into the upregulation of DPEP1 in colorectal carcinogenesis and the role of therapeutic or prognostic biomarkers are required.

Concomitant existence of pheochromocytoma in a patient with multiple endocrine neoplasia type 1.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant inherited disorder that is classically characterized by the presence of neoplastic lesions of the parathyroid glands, the anterior pituitary gland, and the pancreas. However, MEN1 with concomitant pheochromocytoma is extremely rare. CASE REPORT: We report a case of MEN1 concomitant with pheochromocytoma. A 44-year-old Japanese man, who had undergone total parathyroidectomy due to primary hyperparathyroidism at the age of 18, was referred to our hospital with a complaint of a large abdominal tumor. He was diagnosed as having a giant insulinoma (maximum diameter 18 cm) in the pancreatic tail, five other non-functional neuroendocrine tumors in the pancreatic body and tail, multiple liver metastases of pancreatic neuroendocrine tumors, a pituitary prolactinoma, non-functional adrenal cortical adenomas, a pheochromocytoma in addition to a subcutaneous neurofibroma, and a cutaneous fibroma. The genetic screening revealed a deletion mutation at codons 83-84 in exon 2 of the MEN1 gene. He underwent distal pancreatectomy, splenectomy, cholecystectomy, right adrenalectomy, abdominal subcutaneous tumor excision, and cutaneous tumor biopsy for the purpose of tumor volume reduction. Extended right posterior segmentectomy with partial hepatectomy of S2, S3, and S8 was performed to resect residual tumors 9 months after the initial surgery. Although a newly formed liver metastasis was found 19 months after the hepatectomy, he is still alive 4 years and 4 months after the initial surgery. CONCLUSIONS: We reported an extremely rare case of giant insulinoma and simultaneous occurrence of pheochromocytoma and adrenal cortical adenoma in the ipsilateral adrenal gland in a patient clinically and genetically diagnosed as having MEN1.

[An inflammatory pseudotumor of the liver mimicking a metastatic lesion of gallbladder cancer - a case report].

An inflammatory pseudotumor (IPT) of the liver is a rare benign disorder.As its characteristics based on computer tomography and magnetic resonance imaging findings are still unclear, it is difficult to distinguish IPT from malignant diseases of the liver.Herein, we report a case of IPT of the liver concurrent with advanced gallbladder cancer, which we could not diagnose preoperatively.First, we performed lateral segmentectomy of the liver.Second, a radical operation for gallbladder cancer was performed after confirming that the hepatic tumor was IPT via intraoperative pathological diagnosis.Therefore, modalities less invasive than surgical resection should be innovated, even though surgical resection is accurate.

[Myeloid-derived suppressor cells in patients with breast cancer].

Myeloid-derived suppressor cells (MDSC) are one of the major cell populations responsible for regulating immune responses. These cells have been reported to accumulate in the blood, lymph nodes, and tumor sites in most patients during tumor progression and in chronic infection. They are also reported to potently suppress T-cell functions. We studied MDSC in the peripheral blood mononuclear cells(PBMC)by flow cytometry using blood samples from 29 patients with breast cancer, and from 11 healthy donors. The cell level was significantly high for patients compared to the 11 healthy donors (5. 68±6. 09% vs. 0. 91±0. 54%). MDSC was significantly higher in all of the breast cancer patients (5. 68±6. 09%), preoperative patients (5. 79±4. 92%) and recurrent disease patients (5. 59±7. 28%), compared to healthy donors, but not for postoperative patients (1. 50±0. 95%). Thus, MDSC was elevated in patients with breast cancer, but decreased to the range of healthy individuals after the removal of the tumor mass. However, MDSC increased again with recurrence. We also report that in 2 cases, MDSC in the peripheral blood and pleural effusion of patients with metastatic breast cancer decreased after chemotherapy with gemcitabine.

[Simultaneous relapse of Basedow's disease in a patient with adult-onset Still's disease].

This report describes a 50-year-old woman with coexisting Basedow's disease and adult-onset Still's disease (AOSD) that relapsed simultaneously. She was diagnosed with Basedow's disease in 1999, and treatment with antithyroid agents was started. However, the treatment was soon stopped because of severe side effects. A partial thyroidectomy was performed and the thyroid function stayed well-controlled after the surgery. In August 2007, she was admitted to our hospital with fever, a sore throat, skin rashes, arthritis and leukocytosis, and was diagnosed with AOSD. At the same time, her laboratory data revealed decreased serum TSH and elevated serum free T4, suggesting a relapse of Basedow's disease. After initiation of steroid pulse therapy accompanied by oral prednisolone, both diseases improved significantly. Prednisolone was gradually reduced, and the disease activity remained in remission. Immediately after prednisolone reached 3 mg/day in November 2009, both diseases relapsed. Prednisolone was increased to 30 mg/day, and the diseases became well-controlled again. In this case, Basedow's disease was aggravated when AOSD was in the active stage. Literature searches revealed five previously reported cases with coexisting Basedow's disease and AOSD. In four of the six cases, including our case, both diseases were activated simultaneously. AOSD in the active stage is known to cause hypercytokinemia and immunological derangement. Our case indicated that the pathogenesis of AOSD might lead to relapse of coexisting Basedow's disease.

[A case of carcinoma associated with anal fistula resected after preoperative chemoradiotherapy].

A 66-year-old man with a 39-year history of anal fistula was admitted to our hospital for anal pain and bleeding. Fistulectomy was carried out for anal fistula. Histological examination of the specimen revealed carcinoma associated with anal fistula. A computed tomography showed that the tumor had invaded the prostate. Therefore, preoperative chemoradiotherapy(S-1 plus radiation 40 Gy/body)for locally advanced cancer was performed. Magnetic resonance imaging showed that the boundary between the tumor and the prostate was unclear, but we performed an abdominoperineal resection and the prostate was fully preserved. Histopathologically, no cancer cell existed on the surgical margin. The histological effect of chemoradiotherapy was judged as grade 2. This case suggested that surgical treatment combined with preoperative chemoradiotherapy may be effective for locally advanced carcinoma associated with anal fistula, in which preservation of adjacent organs is considered to be difficult.

Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.

Suppression of autophagy is always accompanied by marked accumulation of p62, a selective autophagy substrate. Because p62 interacts with the Nrf2-binding site on Keap1, which is a Cullin 3-based ubiquitin ligase adapter protein, autophagy deficiency causes competitive inhibition of the Nrf2-Keap1 interaction, resulting in stabilization of Nrf2 followed by transcriptional activation of Nrf2 target genes. Herein, we show that liver-specific autophagy-deficient mice harbor adenomas linked to both the formation of p62- and Keap1-positive cellular aggregates and induction of Nrf2 targets. Importantly, similar aggregates were identified in more than 25% of human hepatocellular carcinomas (HCC), and induction of Nrf2 target genes was recognized in most of these tumors. Gene targeting of p62 in an HCC cell line markedly abrogates the anchorage-independent growth, whereas forced expression of p62, but not a Keap1 interaction-defective mutant, resulted in recovery of the growth defect. These results indicate the involvement of persistent activation of Nrf2 through the accumulation of p62 in hepatoma development.

Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N'-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism.

Indole-3-carbinol (I3C), found in cruciferous vegetables, has been shown to suppress or promote carcinogenesis depending on various animal models. Regarding its preventive effects, I3C acts as an anti-estrogen and can induce apoptosis, but precise mechanisms remain to be determined. Since I3C induces cytochrome P450 enzymes in the liver, it affects hydroxylation of estrogens and might therefore be expected to influence endometrial adenocarcinoma development. The present study was performed to clarify the effects of I3C using a rat two-stage endometrial carcinogenesis model, focusing on induction of cytochrome P450s and other estrogen-metabolic enzymes in the liver. First, to determine the estrogenic or anti-estrogenic activity, an uterotropic assay was conducted using ovariectomized Donryu rats (experiment 1). Second, to elucidate the effects on endometrial carcinogenicity, female Donryu rats initiated with a single dose of N-ethyl-N'-nitro-N-nitrosoguanidine into a uterine horn were fed 0 or 500 p.p.m. I3C in diets for 12 months (experiment 2). In experiment 3, similarly initiated animals received 0 or 2000 p.p.m. I3C in their diet, or 1 microg/kg 17beta-estradiol (E2) or 5 microg/kg 4-hydroxyestradiol (4HE) subcutaneously twice a week for 12 months. In the uterotrophic assay, neither 500 nor 2000 p.p.m. of I3C showed any estrogenic or anti-estrogenic activity. In the two uterine carcinogenicity studies, I3C and 4HE increased incidences of uterine adenocarcinomas and/or multiplicities of uterine proliferative lesions, E2-treatment being associated with a tendency for promotion. In the liver, I3C treatment consistently elevated estradiol 2- and 4-hydroxylase activities, in particular the latter, but without effects on estradiol 16alpha-hydoxylase activity. mRNAs for CYP 1A1, 1A2 and 1B1 were increased by I3C treatment, with translation confirmed immunohistochemically. These results suggest that induction of the CYP 1 family in the liver and sequential modulation of estrogen metabolism to increase 4HE might play a crucial role in promoting the effects of dietary I3C on endometrial adenocarcinoma development.

Uterine adenocarcinoma in N-ethyl-N'-nitro-N-nitrosoguanidine-treated rats with high-dose exposure to p-tert-octylphenol during adulthood.

Since many risk factors are associated with the development of uterine adenocarcinomas in humans, the etiology is unclear in most cases, although it has been pointed out that estrogen may play essential roles. To clarify the effects of exposure to p-tert-octylphenol (OP), an environmental xenoestrogen, on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and exposed thereafter to 100 mg / kg OP by s.c. injection until 15 months of age. Adult ovariectomized (OVX) rats were also treated in a similar way. OP had no effect on occurrence of persistent estrus in middle age, although uterotrophic effects were obvious in OVX rats. At the termination, development of uterine adenocarcinomas was significantly increased in animals exposed to OP during adulthood. No tumors, but a few focal hyperplasias, developed in OVX rats. These findings suggest that OP has tumor-promoting effects on ENNG-treated endometrium of rats, possibly due to direct action on the uterus, as indicated by the uterotrophic effect when a high dose of OP was given. The results provide clues to the mechanisms of influence of hormonal disrupters on uterine carcinogenesis.