Induction of podoplanin by transforming growth factor-β in human fibrosarcoma

AbstractPodoplanin/aggrus is increased in tumors and its expression was associated with tumor malignancy. Podoplanin on cancer cells serves as a platelet-aggregating factor, which is associated with the metastatic potential. However, regulators of podoplanin remain to be determined. Transforming growth factor-β (TGF-β) regulates many physiological events, including tumorigenesis. Here, we found that TGF-β induced podoplanin in human fibrosarcoma HT1080 cells and enhanced the platelet-aggregating-ability of HT1080. TGF-β type I receptor inhibitor (SB431542) and short hairpin RNAs for Smad4 inhibited the podoplanin induction by TGF-β. These results suggest that TGF-β is a physiological regulator of podoplanin in tumor cells

Role of the kringle‐like domain in glycoprotein NMB for its tumorigenic potential

Glycoprotein NMB (GPNMB) is highly expressed in many types of malignant tumors and thought to be a poor prognostic factor in those cancers, including breast cancer. Glycoprotein NMB is a type IA transmembrane protein that has a long extracellular domain (ECD) and a short intracellular domain (ICD). In general, the ECD of a protein is involved in protein‐protein or protein‐carbohydrate interactions, whereas the ICD is important for intracellular signaling. We previously reported that GPNMB contributes to the initiation and malignant progression of breast cancer through the hemi‐immunoreceptor tyrosine‐based activation motif (hemITAM) in its ICD. Furthermore, we showed that the tyrosine residue in hemITAM is involved in induction of the stem‐like properties of breast cancer cells. However, the contribution of the ECD to its tumorigenic function has yet to be fully elucidated. In this study, we focused on the region, the so‐called kringle‐like domain (KLD), that is conserved among species, and made a deletion mutant, GPNMB(ΔKLD). Enhanced expression of WT GPNMB induced sphere and tumor formation in breast epithelial cells; in contrast, GPNMB(ΔKLD) lacked these activities without affecting its molecular properties, such as subcellular localization, Src‐induced tyrosine phosphorylation at least in overexpression experiments, and homo‐oligomerization. Additionally, GPNMB(ΔKLD) lost its cell migration promoting activity, even though it reduced E‐cadherin expression. Although the interaction partner binding to KLD has not yet been identified, we found that the KLD of GPNMB plays an important role in its tumorigenic potential

メキシレチン ニヨル ヤクザイセイ カビンショウ ショウコウグン ノ 1レイ

73歳,男性.既往歴に高血圧症と不整脈がある. 2005年10月中旬よりメキシレチン,ニルバジピンの内服を開始し, 2ケ月後に高熱と多形紅班型中毒疹が出現した.顔面浮腫,末梢血白血球数増多,好酸球数増多,肝機能障害を伴った.プレドニン45mg/day内服で治療を開始し,その後症状の改善に伴いプレドニンを漸減, 19日後に投与を中止したところ,皮疹の再燃を認めた.薬剤貼付試験はメキシレチンのみで陽性であり,リンパ球刺激試験は陰性であった.末梢血HHV-6IgG抗体(EIA)は入院時2倍4週間後に8倍であった.以上からメキシレチンによる薬剤性過敏症症候群と診断した.自験例を含めた1991年から2006年までのメキシレチンの薬剤性過敏症症候群47例を集計した結果, DIHS全体の報告と比較して多くの所見はほぼ同じ傾向であったがメキシレチンによるDIHSでは腎障害の頻度が明らかに高かった.A 76-year-old man had been administered mexiletine hydrochloride for arrhythmia for 8 weeks, when he developed a skin eruption on his face and whole of the body. A fever of 39@@@ continued, and nail-sized erythematous plaques developed on his whole body. Laboratory studies showed a leukocytosis, an eosinophilia and a liver dysfunction. Patch testing against mexiletine hydrocholoride showed positive results, though DLST showed negative results. Serological test for HHV-6, performed on the admission and 4 weeks after the admission, revealed an increase in the antibody tier with values from 2 to 8. A diagnosis of drug-induced hypersensitivity syndrome due to mexiletine hydrochloride was made. The patient was treated with oral application of prednisolone

がん進展におけるMafK-Gpnmb経路の機能と分子標的治療

科学研究費助成事業 研究成果報告書：若手研究(B)2015-2016課題番号 : 15K1907

TGF-β関連分子によるがん幹細胞様特性獲得を介した腫瘍形成機構の解明

科学研究費助成事業 研究成果報告書：基盤研究(C)2019-2021課題番号 : 19K0765

Analysis of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor beta

International audienceIn recent years, the importance of the cell biological process of epithelial-mesenchymal transition (EMT) has been established via an exponentially growing number of reports. EMT has been documented during embryonic development, tissue fibrosis, and cancer progression in vitro, in animal models in vivo and in human specimens. EMT relates to many molecular and cellular alterations that occur when epithelial cells undergo a switch in differentiation that generates mesenchymal-like cells with newly acquired migratory and invasive properties. In addition, EMT relates to a nuclear reprogramming similar to the one occurring in the generation of induced pluripotent stem cells. Via such a process, EMT is gradually established to promote the generation and maintenance of adult tissue stem cells which under disease states such as cancer, are known as cancer stem cells. EMT is induced by developmental growth factors, oncogenes, radiation, and hypoxia. A prominent growth factor that causes EMT is transforming growth factor beta (TGF-beta).A series of molecular and cellular techniques can be applied to define and characterize the state of EMT in diverse biological samples. These methods range from DNA and RNA-based techniques that measure the expression of key EMT regulators and markers of epithelial or mesenchymal differentiation to functional assays of cell mobility, invasiveness and in vitro stemness. This chapter focuses on EMT induced by TGF-beta and provides authoritative protocols and relevant reagents and citations of key publications aiming at assisting newcomers that enter this prolific area of biomedical sciences, and offering a useful reference tool to pioneers and aficionados of the fiel