Koichi Kinoshita

MicroRNA-200b Regulates Cell Proliferation, Invasion, and Migration by Directly Targeting ZEB2 in Gastric Carcinoma

BackgroundThe microRNA-200 (miR-200) family has been reported to induce epithelial differentiation and suppress epithelial–mesenchymal transition (EMT) by inhibiting translation of zinc finger E-box-binding homeobox (ZEB) 1 and 2 mRNAs in several types of cancers. This study aimed to clarify the role of miR-200b in regulating EMT and promoting cellular proliferation, invasion, and migration in gastric cancer.MethodsThe relationships among the expression levels of miR-200b, ZEB1 and ZEB2, and E-cadherin mRNAs were analyzed by quantitative real-time reverse transcription–polymerase chain reaction in frozen tissue samples from 40 gastric cancer patients who underwent gastrectomy from 2008 to 2010. The effects of miR-200b on EMT in gastric cancer cells in vitro were also analyzed.ResultsDiffuse histologic type, depth of tumor, tumor size, lymph node metastasis, and lymphatic invasion were significantly higher in the low-miR-200b expression group compared with the high expression group. There was a strong correlation between the levels of miR-200b, and ZEB2 and E-cadherin mRNAs in gastric cancer patients. Upregulation of miR-200b in gastric cancer cells changed the cell morphology from fibroblast- to epithelial-like, associated with localization of E-cadherin to the plasma membrane. ZEB2 mRNA levels fell, while E-cadherin expression levels increased in gastric cells overexpressing miR-200b, associated with significantly reduced cellular proliferation, and inhibition of cellular migration and invasion.ConclusionsmiR-200b regulates ZEB2 expression and thus controls metastasis in gastric cancer.

Serum microRNA-21 is a novel biomarker in patients with esophageal squamous cell carcinoma

It was recently revealed that microRNAs (miRNAs) can stably exist in serum and may affect the pathogenesis of several diseases. However, there are few reports that have demonstrated the significance of miRNAs in the serum of patients with esophageal squamous cell carcinoma (ESCC). Thus, the aims of this study were to clarify the status of miRNA‐21 in serum of ESCC patients and to reveal the usefulness of this molecule as a biomarker.

Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer

While statin intake has been proven to reduce the risk of colorectal cancer (CRC), the mechanism of antitumor effects and clinical significance in survival benefits remain unclear. Statin‐induced antiproliferative effects and its underlying mechanism were examined using six CRC cell lines. Statins except pravastatin showed antiproliferative effects (simvastatin ≥ fluvastatin > atorvastatin) even though both of simvastatin and pravastatin could activate mevalonate pathways, suggesting the statin‐mediated antiproliferative effects depended on non‐mevalonate pathway. Indeed, statin induced p27KIP1 expression by downregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2), which acts as an epigenetic gene silencer. Additionally, the use of simvastatin plus classII histone deacetylase (HDAC) inhibitor (MC1568) induced further overexpression of p27KIP1 by inhibiting HDAC5 induction originated from downregulated EZH2 in CRC cells and synergistically led to considerable antiproliferative effects. In the clinical setting, Statin intake (except pravastatin) displayed the downregulated EZH2 expression and inversely upregulated p27KIP1 expression in the resected CRC by immunohistochemical staining and resulted in the significantly better prognoses both in overall survival (p = 0.02) and disease free survival (p < 0.01) compared to patients without statin intake. Statins may inhibit tumor progression via an EZH2‐mediated epigenetic alteration, which results in survival benefits after resected CRC. Furthermore, statin plus classII HDAC inhibitor could be a novel anticancer therapy by their synergistic effects in CRC.

Human Microbiome Fusobacterium Nucleatum in Esophageal Cancer Tissue Is Associated with Prognosis.

Purpose: Fusobacterium nucleatum (F. nucleatum) is a component of the human microbiome that primarily inhabits the oral cavity. It causes periodontal disease and has also been implicated in the development of human cancers. Although there are several reports of the relationship between F. nucleatum and the clinical outcome in human cancers, its prognostic significance in esophageal cancer remains unclear. Experimental Design: We quantified F. nucleatum DNA in 325 resected esophageal cancer specimens by qPCR. Significant pathways in F. nucleatum–positive esophageal cancer tissues were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using microarray data. Results: Esophageal cancer tissues contained significantly more F. nucleatum DNA than matched normal esophageal mucosa (P = 0.021; n = 60). F. nucleatum DNA was detected in 74 of 325 cases (23%). F. nucleatum DNA positivity was significantly associated with tumor stage, but not with sex, age, performance status, tobacco use, alcohol use, histology, tumor location, or preoperative treatment. F. nucleatum DNA positivity was also significantly associated with cancer-specific survival [log-rank P = 0.0039; univariate HR = 2.01; 95% confidence interval (CI), 1.22–3.23; P = 0.0068; multivariate HR = 1.78; 95% CI, 1.06–2.94; P = 0.031]. The top-ranked KEGG pathway in F. nucleatum–positive tissues was “cytokine–cytokine receptor interaction.” A significant relationship between F. nucleatum and the chemokine CCL20 was validated by IHC. Conclusions: F. nucleatum in esophageal cancer tissues was associated with shorter survival, suggesting a potential role as a prognostic biomarker. F. nucleatum might also contribute to aggressive tumor behavior through activation of chemokines, such as CCL20. Clin Cancer Res; 22(22); 5574–81. ©2016 AACR.

Usefulness of Transcription–Reverse Transcription Concerted Reaction Method for Detecting Circulating Tumor Cells in Patients With Colorectal Cancer

PurposeThe CellSearch system (Veridex, LLC) is useful for detecting circulating tumor cells (CTCs) in various carcinomas, including colorectal cancer (CRC); however, there are some problems associated with its clinical use. A transcription–reverse transcription concerted reaction (TRC) method, which is a PCR-based technique producing more stable and reliable results, because it is a more simplified process compared with the conventional techniques, has been introduced for detecting micrometastasis in some carcinomas. We aimed to demonstrate the effectiveness of TRC method in the CTC detection.MethodsWe compared the two methods for the sensitivity for CTC detection using the colon cancer cell line and 42 whole-blood samples from patients with advanced or metastatic CRC. Furthermore, 25 patients with metastatic CRC were enrolled to investigate the correlation between CTC detection and prognosis in both methods.ResultsThe sensitivity of the TRC method was similar to that of the CellSearch system. The overall survival rate was significantly worse in the patients diagnosed as CTC-positive by the TRC method than in those diagnosed as CTC-negative; this finding was similar to the prognosis indicated by the CellSearch system. However, clinically, the TRC method could detect CTCs more rapidly and at a reduced cost compared with the CellSearch system.ConclusionsThe TRC method seems to be a useful alternative to the CellSearch system for clinically detecting CTCs in patients with metastatic CRC.

Lymphatic vessel invasion detected by the D2-40 monoclonal antibody is an independent prognostic factor in node-negative esophageal squamous cell carcinoma

D2‐40 staining has been reported to be useful for both identifying lymphatic vessel invasion (LVI) and counting lymphatic vessel density (LVD) in various cancers. The aim of this study was to clarify the prognostic significance of D2‐40 staining in patients with esophageal squamous cell carcinoma (ESCC).

Extensive lymphatic spread of cancer cells in patients with thoracic esophageal squamous cell carcinoma: detection of CEA-mRNA in the three-field lymph nodes.

The aim of this study is to clarify the extent of lymphatic spread of cancer cells using a novel genetic test to examine patients with thoracic esophageal squamous cell carcinoma (ESCC).

The role of intestinal bacteria in the development and progression of gastrointestinal tract neoplasms

More than 100 trillion microorganisms inhabit the human intestinal tract and play important roles in health conditions and diseases, including cancer. Accumulating evidence demonstrates that specific bacteria and bacterial dysbiosis in the gastrointestinal tract can potentiate the development and progression of gastrointestinal tract neoplasms by damaging DNA, activating oncogenic signaling pathways, producing tumor-promoting metabolites such as secondary bile acids, and suppressing antitumor immunity. Other bacterial species have been shown to produce short-chain fatty acids such as butyrate, which can suppress inflammation and carcinogenesis in the gastrointestinal tract. Consistent with these lines of evidence, clinical studies using metagenomic analyses have shown associations of specific bacteria and bacterial dysbiosis with gastrointestinal tract cancers, including esophageal, gastric, and colorectal cancers. Emerging data demonstrate that intestinal bacteria can modulate the efficacy of cancer chemotherapies and novel targeted immunotherapies such as anti-CTLA4 and anti-CD274 therapies, the process of absorption, and the occurrence of complications after gastrointestinal surgery. A better understanding of the mechanisms by which the gut microbiota influence tumor development and progression in the intestine would provide opportunities to develop new prevention and treatment strategies for patients with gastrointestinal tract cancers by targeting the intestinal microflora.

Percutaneous transluminal plasty: a novel approach for refractory anastomotic stricture after esophagectomy

Anastomotic stricture is often observed after esophagectomy. Surgical treatment is considered for refractory stricture to conservative treatments. However, it is not established what type of surgery is safe and effective. In this report, we present a novel approach, percutaneous transluminal plasty, for refractory anastomotic stricture reconstructed via the subcutaneous route in esophagectomy. We believe that the effectiveness and safety of this technique is considerably good and can become a good alternative for refractory stricture after esophagectomy.

Can laparoscopic liver resection for colorectal liver metastases provide early initiation of adjuvant chemotherapy

The long-term outcome of patients with colorectal liver metastases (CRLM) has improved because of advances in surgical technique and perioperative chemotherapy (1-3). Liver resection followed by adjuvant chemotherapy (AC) provides better recurrence-free survival in patients with CRLM than surgery alone (4,5).