Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer.

Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the clinical importance of LOX expression and its epigenetic regulation in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Using a database of 284 ESCCs, we examined LOX expression and its prognostic characteristics. The functional role of LOX was assessed by in vitro growth, migration, and invasion assays. The relationship between LOX expression, global DNA hypomethylation (ie, LINE-1 methylation), and LOX promoter methylation was evaluated by using mRNA expression arrays and pyrosequencing technology. High LOX expression cases had a significantly shorter overall survival and cancer-specific survival (log-rank, P < .001). The prognostic effect of LOX expression was not significantly modified by other clinical variables. Silencing and enzymatic inhibition of LOX suppressed growth and reduced the invasion and migration ability of ESCC cell lines along with the downregulation of AKT and MMP2. An integrated gene analysis in tissues and cell lines revealed that LOX was the most highly upregulated gene in LINE-1 hypomethylated tumors. In vitro, LOX expression was upregulated following DNA demethylation. LOX promoter methylation was not associated with LOX expression. Conclusively LOX expression was associated with poor prognosis in ESCC and was regulated epigenetically by genome-wide hypomethylation. It could serve as a prognostic biomarker in ESCC patients, and therapeutically targeting LOX could reverse the progression of esophageal cancer.

[A case of recurrent esophageal cancer with lymph node and lung metastases, successfully treated with systemic chemotherapy and radiofrequency-ablation].

We report a case of recurrent esophageal cancer with lymph node and lung metastases, successfully treated with systemic chemotherapy and radiofrequency-ablation(RFA). A 45-year-old man was diagnosed with thoracic esophageal cancer.Radical esophagectomy with three-field lymphadenectomy was performed.After 6 months, mediastinal lymph node recurrence occurred.Although the size of the recurrent mediastinal lymph nodes were reduced after 10 courses of systemic chemotherapy, two new lung metastatic nodules appeared in the right segments 8 and 9.CT -guided percutaneous RFA was successfully achieved for the 2 lesions.However, 6 months after the RFA, a local recurrence at the RFA site of segment 9 occurred, and an additional RFA was performed for this tumor.Five years and four months after the first operation, the tumor marker level remained within a normal range, and the patient is doing very well without any signs of recurrence. RFA appears to be an effective and minimally invasive technique for controlling local recurrence of esophageal cancer when combined with systemic chemotherapy.

The role of oxysterol binding protein-related protein 5 in pancreatic cancer.

The expression of oxysterol binding protein-related protein (ORP) 5 is related to invasion and a poor prognosis in pancreatic cancer patients. ORP5 induced the expression of sterol response element binding protein (SREBP) 2 and activated the downstream gene of sterol response element. ChIP using SREBP2 antibody revealed that histone deacetylase 5 (HDAC5) was one of the downstream genes of SREBP2. The effect of HMG-CoA reductase inhibitors (statins) were analyzed according to the expression level of ORP5. The invasion rate and growth was suppressed in cells that strongly expressed ORP5 in a time- and dose-dependent manner, but had less effect in cells weakly expressing ORP5, suggesting that when the potential of invasion and growth relies on the cholesterol synthesis pathway, it becomes sensitive to HMG-CoA reductase inhibitor. Furthermore, HDAC inhibitor, tricostatin A, induced the expression of phosphatase and tensin homolog as well when ORP5 was suppressed or the cells were treated with statin. Treatment with both statin and tricostatin A showed a synergistic antitumor effect in cells that highly expressed ORP5. Therefore, in some pancreatic cancers, continuous ORP5 expression enhances the cholesterol synthesis pathway and this signal transduction regulates phosphatase and tensin homolog through HDAC5 expression. This is the first report to detail how the signal transduction of cholesterol synthesis is related to cancer invasion and why statins can suppress invasion and growth.

Adenoviral oncolytic suicide gene therapy for a peritoneal dissemination model of gastric cancer in mice.

BACKGROUND: Peritoneal dissemination of gastric cancer is often refractory to systemic therapies. Although adenoviral gene therapy has been reported to be a potentially useful therapeutic modality, the adenovirus itself has a dose-limiting toxicity. A novel system was constructed using adenoviral oncolytic suicide gene therapy targeting carcinoembryonic antigen (CEA), and its therapeutic effect and the possibility to reduce the total viral dose while still preserving the antitumor effect were assessed. METHODS: Three types of adenoviruses were prepared for this novel system: (A) Ad/CEA-Cre, (B) Ad/lox-CD::UPRT for a Cre/loxP system, and (C) Ad/CEA-E1 for conditionally replicating adenovirus. The antitumor effect of the oncolytic suicide gene therapy (A + B + C) was then evaluated in vitro. Mice bearing peritoneal dissemination of human gastric cancer were treated with either this system (A + B + C) or with a tenfold viral dose of suicide gene therapy (A + B). The adverse effects in terms of hepatotoxicity were then evaluated between the two groups. RESULTS: The current system (A + B + C) demonstrated significantly better cytotoxic effect for CEA-producing cell lines than did suicide gene therapy (A + B) at the same viral dose in vitro. The effect of oncolytic suicide gene therapy was almost equal to that of the tenfold viral dose of suicide gene therapy in vivo. The hepatotoxicity of the two treated groups was also found to be equivalent. CONCLUSION: It was possible to reduce the total adenoviral dose of oncolytic suicide gene therapy while still preserving the antitumor effect.

MicroRNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma.

PURPOSE: MicroRNAs are approximately 22 nucleotide noncoding RNA molecules that posttranscriptionally regulate gene expression. The aim of this study was (a) to determine a role of microRNA-21 in esophageal squamous cell carcinoma and (b) to elucidate the regulation of the programmed cell death 4 (PDCD4) gene by microRNA-21. EXPERIMENTAL DESIGN: MicroRNA-21 expression was investigated in 20 matched normal esophageal epitheliums and esophageal squamous cell carcinomas and seven esophageal squamous cell carcinoma cell lines (TE6, TE8, TE10, TE11, TE12, TE14, KYSE30) by TaqMan quantitative real-time PCR and in situ hybridization. To evaluate the role of microRNA-21, cell proliferation and invasion were analyzed with anti-microRNA-21-transfected cells. In addition, the regulation of PDCD4 by microRNA-21 was elucidated to identify the mechanisms of this regulation. RESULTS: Of 20 paired samples, 18 cancer tissues overexpressed microRNA-21 in comparison with matched normal epitheliums. Specifically, patients with lymph node metastasis or venous invasion showed significantly high expression of microRNA-21. In situ hybridization for microRNA-21 showed strong positive staining in paraffin-embedded esophageal squamous cell carcinoma tissues. All seven esophageal squamous cell carcinoma cell lines also overexpressed microRNA-21, and anti-microRNA-21-transfected cells showed significant reduction in cellular proliferation and invasion. The PDCD4 protein levels in esophageal squamous cell carcinoma cells have an inverse correlation with microRNA-21 expression. Anti-microRNA-21-transfected cells increased PDCD4 protein expression without changing the PDCD4 mRNA level and increased a luciferase-reporter activity containing the PDCD4-3' untranslated region construct. CONCLUSIONS: MicroRNA-21 targets PDCD4 at the posttranscriptional level and regulates cell proliferation and invasion in esophageal squamous cell carcinoma. It may serve as a novel therapeutic target in esophageal squamous cell carcinoma.

Multiple heterochronic gastrointestinal stromal tumors in the stomach detected 6 years after resection: a case report.

BACKGROUND: To date, only a few cases of multiple GISTs with different clones in different organs have been published. However, a case of multiple GISTs with different clones occurring in a single organ has never been reported. CASE PRESENTATION: A 41-year-old patient underwent laparoscopic partial gastrectomy for gastric gastrointestinal stromal tumor (GIST) in 2012. The pathological findings showed high-risk characteristics for recurrence, so he received adjuvant therapy with imatinib for 3 years. In 2018, 3 years after completing the adjuvant therapy, tumor lesions at residual gastric cardia were incidentally identified by follow-up computed tomography (CT). The pathological findings of the tumor biopsy revealed gastric GIST. He underwent secondary laparoscopic partial gastrectomy and was diagnosed with high-risk GIST. Adjuvant therapy with imatinib was restarted immediately. The two gastric GISTs had the same exon 11 mutations in the c-kit gene, but they had different missense mutations. This molecular heterogeneity suggested that they were derived from different origins. CONCLUSION: We reported a multiple heterochronic GIST in the stomach detected 6 years after resection. There may be a possibility that another heterochronic GIST will occur in the remnant stomach in the future, so close follow-up will be needed.

The relationship between the glucose transporter type 1 expression and F-fluorodeoxyglucose uptake in esophageal squamous cell carcinoma.

OBJECTIVE: Glucose transporter type 1 (Glut1) has been reported to be present in several types of carcinomas. The aims of this study are to evaluate Glut1 expression in both primary tumors and metastatic lymph nodes (LNs) of esophageal squamous cell carcinoma (ESCC) and to assess the relationship between Glut1 expression and (18)F-fluorodeoxyglucose (FDG) accumulation. METHODS: We immunohistochemically examined the expression of Glut1 in 60 surgically resected primary lesions and 95 metastatic LNs of ESCC and classified them into 3 groups. The FDG accumulation was assessed with a positron emission tomography (PET). RESULTS: In the primary tumors, a high Glut1 expression was found to be significantly associated with advanced lesions: depth of tumor (p < 0.01), LN metastasis (p < 0.05) and advanced pathological stage (p < 0.01). The Glut1 expression of the metastatic LNs significantly correlated with that of each primary tumor (p < 0.001). The PET-positive lesions had a larger size and higher Glut1 expression than the PET-negative lesions in both the primary tumors and metastatic LNs. CONCLUSIONS: In both the primary tumors and metastatic LNs of ESCC, the Glut1 expression and tumor size correlated with the FDG accumulation and influence the sensitivity of the PET scan.

p12CDK2-AP1 is associated with tumor progression and a poor prognosis in esophageal squamous cell carcinoma.

p12 CDK2-associating protein 1 (p12CDK2-AP1) is a growth suppressor that negatively regulates cyclin-dependent kinase 2 (CDK2) activities. In addition, p12CDK2-AP1 has also been shown to interfere in DNA replication. A reduction of p12CDK2-AP1 expression is known to be a negative prognostic indicator in patients with oral squamous cell carcinoma. To elucidate the role of p12CDK2-AP1 expression in esophageal squamous cell carcinoma (ESCC), we immunohistochemically examined the expression of p12CDK2-AP1 protein in 120 resected ESCC specimens and determined its association with the clinicopathological characteristics and prognosis. Of the 120 ESCCs, 79 (65.8%) showed positive staining (>or=25% of cancer cells showing p12CDK2-AP1 expression), while 41 (34.2%) lacked the staining (<25% of cancer cells showing p12CDK2-AP1 expression). Negative staining for p12CDK2-AP1 was found to be significantly associated with advanced lesions [depth of tumor (P=0.001), lymph node metastasis (P<0.001), pathological stage (P<0.0001) and venous invasion (P<0.0001)], and a poor prognosis (disease-free survival and overall survival: log-rank P<0.05). The rate of lymph node metastasis in patients with p12CDK2-AP1 negative-T1 ESCC was significantly higher than that in patients with p12CDK2-AP1 positive one (P<0.05). These results suggest the down-regulation of p12CDK2-AP1 to be related to tumor aggressiveness and a poor prognosis in patients with ESCC.

[Assessment of esophageal cancer with remote metastases treated with multidisciplinary therapy].

We present three cases of patients diagnosed with esophageal cancer with distant metastases. We conducted chemotherapy, radiotherapy, RFA, and operation for main tumor and lymph node, lung, brain metastasis. They were for a long-term survival with multidisciplinary therapy. The longest survival time was about three years. We discussed our cases in light of review of the literature.

[Oncologic emergency in the abdomen].

In general, cancer does not progress very rapidly, however, it sometimes causes an oncologic emergency that requires immediate treatment, depending on the location and progression of the disease. Hemorrhage, obstruction, and perforation are typical abdominal oncologic emergencies. As for gastrointestinal bleeding, endoscopic hemostasis is a common treatment of choice. Transcatheter arterial embolization is the first treatment to select in case of intra-abdominal hemorrhage caused by rupture of a hepatocellular carcinoma. Patients with upper-gastrointestinal obstruction for unresectable cancer need to be treated considering their prognoses and treatment effects. Those with colorectal obstructions with cancers first need decompression. Patients with colorectal perforation should be operated immediately to prevent septic shock. Acute obstructive suppurative cholangitis needs endoscopic retrograde cholangiography for immediate diagnosis and treatment. Abdominal oncologic emergencies have decreased due to recent diagnostic and therapeutic improvements. However, it remains a crucial disease requiring appropriate diagnoses and prompt treatment based on the conditions of the patients and disease.

Mutation analysis of Rad18 in human cancer cell lines and non small cell lung cancer tissues.

BACKGROUND: Genetic instability is known as a cause of oncogenesis. Though Rad18 is reported to function in a post replication mismatch repair system, the relation between the status of Rad18 and human tumorigenesis has not been described so far. METHODS: Mutation analysis of 34 human cancer cell lines and 32 non small cell lung cancer (NSCLC) tissues were performed by RT-PCR SSCP. Expression level of Rad18 was measured by real time RT-PCR. Stable transfectant was constructed for in vitro study. RESULTS: No mutation was found in both cancer cell lines and NSCLC tissues. A single nucleotide polymorphism (SNP) at codon 302 was detected in 51.5% of the cell lines and 62.5% of NSCLC tissues. Interestingly, Rad18 was homozygously deleted in a pulmonary adenocarcinoma cell line PC3. Furthermore, there was no difference in the expression level of wild type Rad18 and Rad18 with SNP. The growth, cell morphology, sensitivity to anti-cancer drugs and in vitro DNA repair activity between wild type Rad18 and Rad18 with SNP revealed to have no difference in vitro. CONCLUSION: Though the frequency of SNP was tended to be higher in NSCLC patients than healthy volunteers (57.7%), as the difference was not significant, we have concluded that there is no relation between Rad18 SNP and lung cancer development.

Heterogeneous prognoses of patients with tumors invaded within muscularis propria according to tumor depth in the layers of the muscularis propria.

BACKGROUND: The muscularis propria of the stomach is histologically divided into three layers; namely, the innermost oblique, the inner circular, and the outer longitudinal layers. In patients with gastric cancer the depth of tumor invasion has been reported to correlate with lymph node metastasis and prognosis. However, it is unclear whether the depth of tumor invasion in the muscularis propria has an effect on lymph node metastasis and prognosis. METHODS: Fifty-nine gastric cancer patients with muscularis propria invasion were analyzed retrospectively. These patients were divided into two groups, the inner group, with invasion up to the inner circular layer; and the outer group, with invasion beyond the inner circular layer. The relationships between tumor invasion and clinicopathological factors and survival were evaluated. RESULTS: Of the 59 patients, 34 were classified as the inner group, and 25 were classified as the outer group. The inner group had a significantly lower probability of lymph node metastasis (P = 0.0053) and a significantly better overall cancer-specific survival (P = 0.017) than the outer group. CONCLUSION: Gastric cancers with muscularis propria invasion had heterogeneous prognoses according to the tumor depth in the muscularis propria layers.