Increased glucose utilization is a feature of cancer cells to support cell survival, proliferation, and metastasis. An association between diabetes mellitus and cancer progression was previously demonstrated in cancers including cholangiocarcinoma (CCA). This study was aimed to determine the effects of high glucose on protein O-GlcNAcylation and metastatic potentials of CCA cells. Two pairs each of the parental low metastatic and highly metastatic CCA sublines were cultured in normal (5.6 mM) or high (25 mM) glucose media. The migration and invasion abilities were determined and underlying mechanisms were explored. Results revealed that high glucose promoted migration and invasion of CCA cells that were more pronounced in the highly metastatic sublines. Concomitantly, high glucose increased global O-GlcNAcylated proteins, the expressions of vimentin, hexokinase, glucosamine-fructose-6-phosphate amidotransferase (GFAT) and O-GlcNAc transferase of CCA cells. The glucose level that promoted migration/invasion was shown to be potentiated by the induction of GFAT, O-GlcNAcylation and an increase of O-GlcNAcylated vimentin and vimentin expression. Treatment with a GFAT inhibitor reduced global O-GlcNAcylated proteins, vimentin expression, and alleviated cell migration. Altogether, these results suggested the role of high glucose enhanced CCA metastasis via modulation of O-GlcNAcylation, through the expressions of GFAT and vimentin.

No abstract

O-GlcNAcylation, an O-linked protein glycosylation with a single molecule of N-acetylglucosamine (GlcNAc), is reversibly controlled by O-GlcNAc transferase (OGT) and N-acetyl D-glucosaminidase (OGA). Aberrant O-GlcNAcylation contributes an important role in initiation and progression of many human cancers. Elevation of O-GlcNAcylation in tumor tissues and poor prognosis of cholangiocarcinoma (CCA) patients have been reported. In this study, the role of O-GlcNAcylation in promoting tumor progression was further investigated in CCA cell lines. Suppression of O-GlcNAcylation using small interfering RNAs of OGT (siOGT) significantly reduced cell migration and invasion of CCA cells whereas siOGA treated cells exhibited opposite effects. Manipulating levels of O-GlcNAcylation did affect the nuclear translocation of NF-κB and Akt-phosphorylation together with expression of matrix-metalloproteinases (MMPs). O-GlcNAcylation and nuclear translocation of NF-κB, the upstream signaling cascade of MMP activation were shown to be important for MMP activation. Immunoprecipitation revealed the elevation of O-GlcNAc-modified NF-κB with increased cellular O-GlcNAcylation. Involvement of O-GlcNAcylation in MMP-mediated migration and invasion of CCA cells was shown to be via O-GlcNAcylation and nuclear translocation of NF-κB. This information indicates the significance of O-GlcNAcylation in controlling the metastatic ability of CCA cells, hence, O-GlcNAcylation and its products may be new targets for treatment of metastatic CCA.

Angiostrongyliasis, caused by Angiostrongylus cantonensis, is endemic in northeastern Thailand and southern and eastern Taiwan and is also reported throughout the world. Humans get infected by eating raw freshwater snails or other paratenic hosts. The three main clinical forms of angiostrongyliasis are: eosinophilic meningitis (EoM), eosinophilic encephalitis (EoE) and ocular angiostrongyliasis. EoM, the most common form, causes acute severe headache, and corticosteroid is the cornerstone treatment. EoE is rare but fatal and has no effective treatment. The clinical presentations are coma and cerebrospinal fluid eosinophils without any other causes of the deterioration of consciousness, such as infection or metabolic derangements. Ocular angiostrongyliasis is very rare and causes a permanent visual impairment and a wide range of ocular inflammation, depending on the worm's route. It can occur with or without EoM. An identification of a living worm, usually a single worm in any part of an eye, is an important diagnostic clue. The treatment options are surgical removal or laser therapy. Corticosteroids may be necessary in the case of coexistence of EoM or other ocular inflammations such as retinitis or optic neuritis. The visual outcome is poor and depends on the initial visual acuity.

Ocular angiostrongyliasis, diagnosed by identification of Angiostrongylus cantonensis in any part of the eye, is a very rare manifestation. We report seven cases of intraocular angiostrongyliasis in Srinagarind Hospital, Khon Kaen University, Thailand. From a total of 654 cases of angiostrongyliasis diagnosed between January 1995 and April 2005, 7 cases (1.1%) with ocular manifestations were found. Four men and three women were diagnosed, with a mean age of 32.1 years (range 21-46 years). All of the patients lived in the northeast of Thailand and acquired the infection by eating raw Pila spp. snails, the intermediate host of A. cantonensis. The incubation period lasted from 2 weeks to 2 months. The most common symptom, blurred vision without eosinophilic meningitis, occurred as a presenting symptom in five cases. The other two cases presented with eosinophilic meningitis prior to development of poor visual acuity. Both cases had papilloedema, neck stiffness and eosinophilia without fever. The visual acuity of the patient was mostly lower than 2/60 and, evidently, visual impairment in all patients was caused by retinal pigment epithelial defects. All cases had only one immature A. cantonensis worm in the eye, with the most common site being the intravitreous area. Several treatments, including oral prednisolone, topical prednisolone, argon laser, diode laser, Nd:YAG laser, surgical removal of the parasite and combination therapy, were used. There is no evidence that surgical and laser interventions improve the course of the disease, and both have associated risks. Visual outcome depends on the initial visual defects.