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Miyagi T.,Tohoku Pharmaceutical University | Yamaguchi K.,Miyagi Cancer Center Research Institute
Glycobiology | Year: 2012

Sialic acids are terminal acidic monosaccharides, which influence the chemical and biological features of glycoconjugates. Their removal catalyzed by a sialidase modulates various biological processes through change in conformation and creation or loss of binding sites of functional molecules. Sialidases exist widely in vertebrates and also in a variety of microorganisms. Recent research on mammalian sialidases has provided evidence for great importance of these enzymes in various cellular functions, including lysosomal catabolism, whereas microbial sialidases appear to play roles limited to nutrition and pathogenesis. Four types of mammalian sialidases have been identified and characterized to date, designated as NEU1, NEU2, NEU3 and NEU4. They are encoded by different genes and differ in major subcellular localization and enzymatic properties including substrate specificity, and each has been found to play a unique role depending on its particular properties. This review is an attempt to concisely summarize current knowledge concerning mammalian sialidases, with an especial focus on their properties and physiological and pathological roles in cellular functions. © 2012 The Author.

Miyagi T.,Tohoku Pharmaceutical University | Takahashi K.,Tohoku Pharmaceutical University | Hata K.,Tohoku Pharmaceutical University | Shiozaki K.,Kagoshima University | Yamaguchi K.,Miyagi Cancer Center Research Institute
Glycoconjugate Journal | Year: 2012

Aberrant glycosylation is a characteristic feature of cancer cells. In particular, altered sialylation is closely associated with malignant properties, including invasiveness and metastatic potential. To elucidate the molecular mechanisms underlying the aberrancy, our studies have focused on mammalian sialidase, which catalyzes the removal of sialic acid residues from glycoproteins and glycolipids. The four types of mammalian sialidase identified to date show altered expression and behave in different manners during carcinogenesis. The present review briefly summarizes results on altered expression of sialidases and their possible roles in cancer progression. These enzymes are indeed factors defining cancer malignancy and thus potential targets for cancer diagnosis and therapy. © Springer Science+Business Media, LLC 2012.

Hamada S.,Tohoku University | Masamune A.,Tohoku University | Miura S.,Tohoku University | Satoh K.,Miyagi Cancer Center Research Institute | Shimosegawa T.,Tohoku University
Cellular Signalling | Year: 2014

The poor prognosis of invasive ductal adenocarcinoma of the pancreas is mainly due to its resistance against therapeutic agents. The molecular mechanism by which morbidity enhances cell survival has been extensively studied, but radical improvements in the therapeutic strategy have not yet been achieved. Recent reports have indicated the substantial contribution of miRNA in multiple cell functions by comprehensively targeting clusters of genes. We identified several miRNAs highly expressed in invasive ductal adenocarcinoma in our previous study, and clarified their contribution to the epithelial-mesenchymal transition. Among the differentially expressed miRNAs, miR-365 was highly expressed in invasive ductal adenocarcinoma, whose functional role has not been reported. In the current study, we found that miR-365 induced gemcitabine resistance in pancreatic cancer cells. MiR-365 directly targeted adaptor protein Src Homology 2 Domain Containing 1 (SHC1) and apoptosis-promoting protein BAX. The siRNA-based knockdown of SHC1 and BAX increased gemcitabine resistance, indicating the miR-365/SHC1/BAX axis influences the survival of pancreatic cancer cells. In addition, miR-365 up-regulated cancer-promoting molecules such as Inhibitor of DNA binding 2 and S100P, suggesting the existence of cross-talk with other cancer-promoting signals. MiR-365 could exert orchestrated effects on pancreatic cancer cell survival. © 2013 Elsevier Inc.

Hamada S.,Tohoku University | Satoh K.,Tohoku University | Satoh K.,Miyagi Cancer Center Research Institute | Fujibuchi W.,Japan National Institute of Advanced Industrial Science and Technology | And 7 more authors.
Molecular Cancer Research | Year: 2012

The epithelial-mesenchymal transition (EMT) is a critical step for pancreatic cancer cells as an entry of metastatic disease. Wide variety of cytokines and signaling pathways are involved in this complex process while the entire picture is still cryptic. Recently, miRNA was found to regulate cellular function including EMT by targeting multiple mRNAs. We conducted comprehensive analysis of miRNA expression profiles in invasive ductal adenocarcinoma (IDA), intraductal papillary mucinous adenoma, intraductal papillary mucinous carcinoma, and human pancreatic cancer cell line to elucidate essential miRNAs which regulate invasive growth of pancreatic cancer cells. Along with higher expression of miR-21 which has been shown to be highly expressed in IDA, reduced expression of miR-126 in IDA and pancreatic cancer cell line was detected. The miR-126 was found to target ADAM9 (disintegrin and metalloproteinase domain-containing protein 9) which is highly expressed in pancreatic cancer. The direct interaction between miR-126 and ADAM9 mRNA was confirmed by 3′ untranslated region assay. Reexpression of miR-126 and siRNA-based knockdown of ADAM9 in pancreatic cancer cells resulted in reduced cellular migration, invasion, and induction of epithelial marker E-cadherin. We showed for the first time that the miR-126/ADAM9 axis plays essential role in the inhibition of invasive growth of pancreatic cancer cells. ©2011 AACR.

Satoh K.,Miyagi Cancer Center Research Institute | Hamada S.,Tohoku University | Shimosegawa T.,Tohoku University
Journal of Gastroenterology | Year: 2014

Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease as a result of its rapid dissemination and resistance to conventional chemotherapy and radiotherapy. Surgical resection is the only curative therapy, but most of the tumors are unresectable at the time of diagnosis. The molecular mechanisms underlying the biological aggressiveness of this tumor type remain to be clarified. Epithelial to mesenchymal transition (EMT) is a developmental process that leads the phenotype shift from an epithelial morphology to a motile, fibroblast-like morphology. Recent studies showed that EMT is involved in the invasion and metastasis of many types of carcinomas including PDAC. In addition, PDAC cells with the EMT phenotype also exhibit chemoresistance and the cancer stem cell property. Various factors such as cytokines, growth factors, or transcriptional factors were found to promote the EMT program in PDAC cells. In this review, we summarize the current knowledge about the EMT in PDAC cells, focusing on the involvement of this process and its regulatory molecules including microRNA during the development of PDAC cells. © 2014, Springer Japan.

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