title: Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma.
abstract: CD44 exists as a standard (CD44s) isoform and different variant isoforms (CD44v) due to alternative splicing. While the complex nature of these different isoforms has not been fully elucidated, CD44v expression has been shown to exert oncogenic effects by promoting tumor progression, metastasis and resistance of tumor cells to chemotherapy. One of the CD44v isoforms, CD44v8-10, was recently shown to protect cancer cells from oxidative stress by increasing the synthesis of glutathione (GSH). However, data regarding CD44 isoform expression in malignant mesothelioma (MM) are still lacking. Here, we show that most of the MM cell lines express both the CD44s and CD44v isoforms, in contrast to non-tumorigenic mesothelial cells, which express only CD44s. Moreover, we show here that these MM cell lines are positive for CD44 variable exon 9, with CD44v8-10 among the variant isoforms expressed. The expression of CD44 variable exon 9 was found to be statistically associated with NF2 inactivation, a common occurrence in MM. Knockdown of CD44 reduced the protein level of xCT, a cystine transporter, and increased oxidative stress. However, an increase in GSH was also observed and was associated with enhanced chemoresistance in CD44-knockdown cells. Increased GSH was mediated by the Nrf2/AP-1-induced upregulation of GCLC, a subunit of the enzyme catalyzing GSH synthesis. Our results thus suggest that the response to CD44 depletion is cell type-dependent and, in cases such as MM cells, compensatory pathway(s) might be activated rheostatically to account for the loss of CD44 and counteract enhanced oxidative stress.
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shan Hwu
authors.initials: SH
authors.lastname: Chew
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shenqi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Ohara
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Ito
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics*
chemical_list: D027182:Amino Acid Transport System y+; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020033:Protein Isoforms; C118895:SLC7A11 protein, human; D018808:Transcription Factor AP-1; C000609392:GCLC protein, human; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: CD44; Glutathione; Malignant mesothelioma; Nrf2; Oxidative stress