Ken Omura

Bio: Ken Omura is an academic researcher from Tokyo Medical and Dental University. The author has contributed to research in topics: Neck dissection & Metastasis. The author has an hindex of 35, co-authored 245 publications receiving 4661 citations.

Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer.

Abstract: In the last few years, microRNAs (miRNA) have started a revolution in molecular biology and emerged as key players in the carcinogenesis They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers To identify the miRNA signature that was specific for oral squamous cell carcinoma (OSCC), we first examined expression profiles of 148 miRNAs in a panel of 18 OSCC cell lines and the immortalized oral keratinocyte line RT7 as a control Compared with RT7, the expression of 54 miRNAs (365%) was frequently down-regulated in OSCC lines ( miR-34b, miR-137, miR-193a , and miR-203 ), located around CpG islands, to identify tumor-suppressive miRNAs silenced through aberrant DNA methylation The expression of those four genes was restored by treatment with 5-aza-2′-deoxycytidine in OSCC cells lacking their expression In addition, expression levels of the four miRNAs were inversely correlated with their DNA methylation status in the OSCC lines In primary tumors of OSCC with paired normal oral mucosa, down-regulation of miRNA expression through tumor-specific hypermethylation was more frequently observed for miR-137 and miR-193a than for miR-34b and miR-203 Moreover, the ectopic transfection of miR-137 or miR-193a into OSCC lines lacking their expressions significantly reduced cell growth, with down-regulation of the translation of cyclin-dependent kinase 6 or E2F transcription factor 6, respectively Taken together, our results clearly show that miR-137 and miR-193a are tumor suppressor miRNAs epigenetically silenced during oral carcinogenesis [Cancer Res 2008;68(7):2094–105]

The tumor suppressive microRNA miR-218 targets the mTOR component rictor and inhibits AKT phosphorylation in oral cancer

Abstract: The incidence of oral squamous cell carcinoma (OSCC) is rising rapidly in developed countries, posing a growing challenge due to the poor management of this type of malignancy at present. In this study, we profiled tumor suppressive microRNAs (miRNAs) that are silenced by DNA hypermethylation in OSCC using a function-based screening approach. This approach employed a cell proliferation assay for 327 synthetic miRNAs in two OSCC cell lines. Among the 110 miRNAs identified in this set that exhibited inhibitory properties, we compared DNA methylation and expression status in a wider panel of OSCC cell lines and primary tumor tissues, resulting in the identification of miR-218 and miR-585 as functionally significant miRNA genes that are frequently silenced in OSCC by DNA hypermethylation. Ectopic expression of miR-218 and miR-585 in OSCC cells lacking endogenous expression reduced cell growth in part through caspase-mediated apoptosis. Notably, miR-218 reduced levels of the rapamycin-insensitive component of mTOR, Rictor, in a manner associated with a suppression of Akt S473 phosphorylation. Together our findings define miR-585 as a tumor suppressive function that is often epigenetically silenced in OSCC, and they identify Rictor as a novel target of miR-218, suggesting that activation of the mTOR-Akt signaling pathway induced by Rictor contributes centrally to oral carcinogenesis. Cancer Res; 71(17); 5765–78. ©2011 AACR.

Current status of oral cancer treatment strategies: surgical treatments for oral squamous cell carcinoma

Abstract: The primary treatment modality of oral cancer is generally determined according to the stage of the disease, with surgical treatment remaining the mainstay of multimodal treatment. When selecting the treatment, many factors are taken into consideration, and the treatment should be tailored individually to the patient’s needs and consider the quality of life as well as the survival of the patient. Early-stage disease is primarily managed with surgery or brachytherapy without functional morbidity, whereas for advanced-stage disease multidisciplinary treatment is recommended, not only for enhanced survival but also for improved quality of life. After resection of large primary tumors, reconstructive surgery is required. Free tissue transfer currently represents one of the most popular and reliable techniques for oral reconstruction. For cN0 neck, elective neck dissection is recommended when the risk of occult metastases is >20 %, when the neck is entered either for resection of the primary tumor or for reconstruction, or when the patient is unlikely to return for a close follow-up. Sentinel node biopsy is performed investigationally. Modified radical neck dissection is the gold standard for cN+ neck. For patients with multiple node metastases or extracapsular spread, postoperative radiotherapy or chemoradiotherapy is recommended, with the lymph nodes situated outside the confines of the radical neck dissection, such as the lingual and retropharyngeal nodes, receiving considerable attention. Targeted therapy for oral cancer is still a relatively new concept, and more studies are needed to confirm the clinical effectiveness of these drugs.

Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells

Abstract: Cyclooxygenase (COX)-2 is generally known as an inducible enzyme, and it produces arachidonic acid to prostaglandin E2 (PGE2), which modulates bone metabolism. Here, we investigated the expression and role of COX isomers in human mesenchymal stem cells. Human mesenchymal stem cells constitutively expressed COX-2 as well as COX-1, and secretion of PGE2 was completely inhibited by NS-398, a specific inhibitor of COX-2. Levels of secreted PGE2 were strikingly higher in human mesenchymal stem cells than in osteoblastic cells differentiated from the mesenchymal cells. This higher production of PGE2 in mesenchymal stem cells was due to higher expression of membrane-associated PGE synthase (mPGES) regulated by early growth response factor-1 (Egr-1). Treatment of human mesenchymal stem cells with NS-398 suppressed expression of bone morphogenetic protein-2 (BMP-2). The suppression of BMP-2 by NS-398 was abrogated by an EP4 receptor agonist as well as by PGE2. Moreover, BMP-2 expression was suppressed by an EP4 receptor antagonist. These data indicate that PGE2 produced by COX-2 increases BMP-2 expression via binding the EP4 receptor.

Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer

Abstract: BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...

Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative

Abstract: Fibroblasts can condense a hydrated collagen lattice to a tissue-like structure 1/28th the area of the starting gel in 24 hr. The rate of the process can be regulated by varying the protein content of the lattice, the cell number, or the con- centration of an inhibitor such as Colcemid. Fibroblasts of high population doubling level propagated in vitro, which have left the cell cycle, can carry out the contraction at least as efficiently as cycling cells. The potential uses of the system as an immu- nologically tolerated "tissue" for wound hea ing and as a model for studying fibroblast function are discussed.

CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition.

Abstract: The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) immune checkpoints are negative regulators of T-cell immune function. Inhibition of these targets, resulting in increased activation of the immune system, has led to new immunotherapies for melanoma, non-small cell lung cancer, and other cancers. Ipilimumab, an inhibitor of CTLA-4, is approved for the treatment of advanced or unresectable melanoma. Nivolumab and pembrolizumab, both PD-1 inhibitors, are approved to treat patients with advanced or metastatic melanoma and patients with metastatic, refractory non-small cell lung cancer. In addition the combination of ipilimumab and nivolumab has been approved in patients with BRAF WT metastatic or unresectable melanoma. The roles of CTLA-4 and PD-1 in inhibiting immune responses, including antitumor responses, are largely distinct. CTLA-4 is thought to regulate T-cell proliferation early in an immune response, primarily in lymph nodes, whereas PD-1 suppresses T cells later in an immune response, primarily in peripheral tissues. The clinical profiles of immuno-oncology agents inhibiting these 2 checkpoints may vary based on their mechanistic differences. This article provides an overview of the CTLA-4 and PD-1 pathways and implications of their inhibition in cancer therapy.