Toshimichi Tanaka

Homeobox-Only Protein Expression Is a Critical Prognostic Indicator of Pancreatic Neuroendocrine Tumor and Is Regulated by Promoter DNA Hypermethylation.

Objectives We have identified homeobox-only protein (HOPX) as a tumor suppressor gene in various human cancer, and its expression was reduced by promoter DNA hypermethylation. Homeobox-only protein is strongly expressed on pancreatic islet cells; however, clinical relevance of HOPX expression has remained elusive in pancreatic neuroendocrine tumor (pNET). Methods We investigated 36 patients with pNET who undertook surgical resection between 1988 and 2012 for HOPX expression and DNA methylation to reveal its clinical significance. Results (1) Homeobox-only protein is strongly expressed on pancreatic islet cells by immunohistochemistry (IHC). Homeobox-only protein expression was recognized on pNET tumor cells for 1+ in 15, for 2+ in 16, and for 3+ in 5. (2) Homeobox-only protein IHC expression was significantly associated with prognosis (P = 0.03), and survival rate was 37.5%, 70.3%, and 100% in HOPX 1+, 2+, and 3+, respectively. (3) Promoter DNA methylation was quantitatively assessed, and HOPX hypermethylation is found in 6.3%, 11.8%, and 66.7% of G1/G2/G3 pNET, respectively (P = 0.02). (4) Multivariate Cox proportional hazards model identified HOPX IHC expression and HOPX promoter DNA hypermethylation as independent prognostic factors in pNET. Conclusions Homeobox-only protein expression is a critical prognostic indicator of pNET, and its regulation may be made through promoter DNA methylation.

The H19-PEG10/IGF2BP3 axis promotes gastric cancer progression in patients with high lymph node ratios

We previously demonstrated that the lymph node ratio (LNR) is a prognostic factor associated with EGFR expression, among first priority genes amplified or overexpressed in cancer. Here, we investigated the associations between high LNR and second, third, and fourth priority genes. We performed mRNA expression microarray analysis of tumor tissue from patients with stage III gastric cancer and high or low LNRs. Candidate high LNR-associated genes were further evaluated in 39 patients with stage III gastric cancer. The functional relevance of these genes was evaluated in gastric cancer cell lines. We focused on five genes: H19,PEG10, IGF2BP3, CD177, and PGA3. H19 and PEG10 were confirmed as high LNR-associated genes. H19, PEG10, and IGF2BP3 were found to promote each other’s expression. Knocking down H19 or PEG10 using RNAi decreased cell proliferation, invasion, anchorage-independent growth, and chemoresistance. These genes had a mutual relationship in MKN7 cells. H19 knockdown decreased expression of epithelial-mesenchymal transition-associated genes in MKN74 cells to suppress transformation. Thus, H19 promotes epithelial-mesenchymal transition in gastric cancer and is a potential therapeutic target.

The clinical significance of cysteine dioxygenase type 1 methylation in Barrett esophagus adenocarcinoma

Methylation of cysteine dioxygenase type 1 (CDO1) gene, a tumor suppressor gene, has been studied in various cancers; however, there is no information regarding Barrett esophagus cancer. In this study, the clinical significance of CDO1 methylation in Barrett esophagus adenocarcinoma (BEA) was clarified. CDO1 gene promoter methylation was analyzed for DNA from the patients specimens using quantitative methylation-specific polymerase chain reaction. Thirty-eight BEA patients who underwent resection were identified between 2000 and 2014. Hypermethylation of CDO1 gene was demonstrated to be frequently recognized even at early stage in BEA by quantitative methylation-specific polymerase chain reaction. In BEA, there is a robust prognostic difference between stage I and stage II/III/IV with regard to 5-year relapse-free survival (P = 0.0016) and 5-year overall survival (P = 0.0024), and the tumor size separated by 7 cm was also a prognostic factor. There was significant difference in CDO1 gene methylation according to the tumor size (P = 0.036). BEA patients with CDO1 gene methylation were shown marginally significantly poorer prognosis (P = 0.054) than otherwise patients. In conclusion, higher CDO1 gene methylation was seen in BEA at earlier stage than in squamous cell carcinoma, and it may account for aggressive phenotype of BEA.

Cysteine dioxygenase type 1 (CDO1) gene promoter methylation during the adenoma-carcinoma sequence in colorectal cancer

Background Progression of colorectal cancer (CRC) has been explained by genomic abnormalities along with the adenoma-carcinoma sequence theory (ACS). The aim of our study is to elucidate whether the promoter DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in CRC. Methods The study group comprised 107 patients with CRC who underwent surgical resection and 90 adenomas treated with endoscopic resection in the Kitasato University Hospital in 2000. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. Results The methylation level increased along with the ACS process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and low-grade adenoma (p < 0.0001), and between low-grade adenoma and high-grade adenoma (p = 0.01), but not between high-grade adenoma and cancer with no liver metastasis. Furthermore, primary CRC cancers with liver metastasis harbored significantly higher methylation of CDO1 than those without liver metastasis (p = 0.02). As a result, the area under the curve by CDO1 promoter methylation was 0.96, 0.80, and 0.67 to discriminate cancer from NAM, low-grade adenoma from NAM, and low-grade adenoma from high-grade adenoma, respectively. Conclusions CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.

Potential therapeutic targets of TP53 gene in the context of its classically canonical functions and its latest non-canonical functions in human cancer

In normal tissue, p53 protein has a wide range of functions involving cell homeostasis; its mutation, however, permits a carcinogenic acquisition of function. TP53 gene mutation is a major genomic aberration in various human cancers and is a critical event in the multi-step carcinogenesis process. TP53 mutation is clinically relevant for the molecular classification of carcinogenesis, as most recently described rigorously by the Cancer Genome Atlas Research Network. TP53 gene mutation has been considered to work as a tumor suppressor gene through the loss of its transcriptional activity, which is designated as a canonical function. However, in cancer patients with mutant TP53, mutated p53 protein is frequently overexpressed, suggesting the activation of an oncogenic process through a gain of function (GOF). As part of this GOF, molecular mechanisms explaining the non-canonical function of TP53 gene abnormality have been reported, in which mutant p53 unconventionally binds with various critical molecules suppressing oncogenic properties, such as p63 and p73. Moreover, mutant TP53 gene-targeted therapy has been rigorously developed, and promising clinical trials have been started. In this study, we summarize the novel aspects of mutant p53 and describe its prominent therapeutic potentials in human cancer.

Patients’ preoperative background causes gastric stasis after laparoscopy-assisted pylorus-preserving gastrectomy: Cause of stasis in LAPPG

Despite technical improvements in laparoscopic gastrectomy, gastric stasis is still a serious problem in laparoscopy‐assisted pylorus‐preserving gastrectomy (LAPPG). The aim of this study was to investigate the factors that might cause gastric stasis in LAPPG.

Epigenetic Status of CDO1 Gene May Reflect Chemosensitivity in Colon Cancer with Postoperative Adjuvant Chemotherapy

BackgroundCysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor gene, and its expression is regulated by promoter DNA methylation in human cancer. The metabolic product mediated by CDO1 enzyme increases mitochondrial membrane potential (MMP), putatively representing chemoresistance. The aim of this study is to investigate the functional relevance of CDO1 gene in colon cancer with chemotherapy.Patients and MethodsWe investigated 170 stage III colon cancer patients for CDO1 methylation by using quantitative methylation-specific polymerase chain reaction (PCR). To elucidate the functional role of CDO1 gene in colorectal cancer (CRC) biology, we established cell lines that stably express CDO1 gene and evaluated chemosensitivity, MMP, and tolerability assay including anaerobic environment.ResultsHypermethylation of CDO1 gene was an independent prognostic factor for stage III colon cancer on multivariate prognostic analysis. Surprisingly, patients with CDO1 hypermethylation exhibited better prognosis than those with CDO1 hypomethylation in stage III colon cancer with postoperative chemotherapy (P = 0.03); however, a similar finding was not seen in those without postoperative chemotherapy. In some CRC cell lines, forced expression of CDO1 gene increased MMP accompanied by chemoresistance and/or tolerance under hypoxia.ConclusionCDO1 methylation may be a useful biomarker to increase the number of stage III colon cancer patients who can be saved by adjuvant therapy. Such clinical relevance may represent the functionally oncogenic property of CDO1 gene through MMP activity.

Effect of Preoperative Nutritional Status on Surgical Site Infection in Colorectal Cancer Resection

Background/Aims: Postoperative complications of colorectal cancer (CRC) can sometimes be life threatening. Prevention of morbidity is therefore the most important issue, and among such complications, surgical site infections (SSIs) are the most critical. Predictive factors for SSI were evaluated. Patients and Methods: This was a retrospective study of 432 patients with CRC. SSIs were classified into incisional SSIs (iSSIs) and organ/space SSIs (o/sSSIs). Results: Preoperative serum albumin (relative risk (RR) 2.51, p = 0.01) and body mass index (BMI: RR 2.36, p = 0.02) were the independent risk factors for iSSIs, while rectal cancer (RR 6.34, p < 0.0001), preoperative serum albumin (RR 7.03, p = 0.004), age (RR 2.71, p = 0.02), and male sex (RR 2.41, p = 0.05) were the independent risk factors for o/sSSIs. Patients with both low serum albumin and high BMI had the highest incidence of iSSIs (34.2%), and the group with rectal cancer and low serum albumin had the highest incidence of o/sSSIs (57.1%). Conclusions: Preoperative nutritional status is a risk factor for SSIs in CRC, and its proper preoperative management may reduce the risk of SSIs.