TY - JOUR
T1 - DSE promotes aggressive glioma cell phenotypes by enhancing HB-EGF/ERBB signaling
AU - Liao, Wen Chieh
AU - Liao, Chih Kai
AU - Tsai, You Huan
AU - Tseng, To Jung
AU - Chuang, Li Ching
AU - Lan, Chyn Tair
AU - Chang, Hung Ming
AU - Liu, Chiung Hui
N1 - Funding Information:
This study was supported by the following grants from the Ministry of Science and Technology, Taiwan: MOST-105-2320-B-040-033-MY2 and MOST-106-2320-B-040-009-MY3 (Chiung-Hui Liu), MOST-105-2320-B-040-029-MY3 (Wen-Chieh Liao). TissueFAX Plus Cytometer was performed in the Instrument Center of Chung Shan Medical University, which is supported by Ministry of Science and Technology, Ministry of Education, and Chung Shan Medical University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. TissueFAX Plus Cytometer, immunofluorescence microscopy (ZEISS Axio Imager A2), and confocal microscopy (Zeiss LSM 510 META) were performed in the Instrument Center of Chung Shan Medical University, which is supported by Ministry of Science and Technology, Ministry of Education, and Chung Shan Medical University.
Publisher Copyright:
© 2018 Liao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Remodeling of the extracellular matrix (ECM) in the tumor microenvironment promotes glioma progression. Chondroitin sulfate (CS) proteoglycans appear in the ECM and on the cell surface, and can be catalyzed by dermatan sulfate epimerase to form chondroitin sulfate/dermatan sulfate (CS/DS) hybrid chains. Dermatan sulfate epimerase 1 (DSE) is overexpressed in many types of cancer, and CS/DS chains mediate several growth factor signals. However, the role of DSE in gliomas has never been explored. In the present study, we determined the expression of DSE in gliomas by consulting a public database and conducting immunohistochemistry on a tissue array. Our investigation revealed that DSE was upregulated in gliomas compared with normal brain tissue. Furthermore, high DSE expression was associated with advanced tumor grade and poor survival. We found high DSE expression in several glioblastoma cell lines, and DSE expression directly mediated DS chain formation in glioblastoma cells. Knockdown of DSE suppressed the proliferation, migration, and invasion of glioblastoma cells. In contrast, overexpression of DSE in GL261 cells enhanced these malignant phenotypes and in vivo tumor growth. Interestingly, we found that DSE selectively regulated heparin-binding EGF-like growth factor (HB-EGF)-induced signaling in glioblastoma cells. Inhibiting epidermal growth factor receptor (EGFR) and ErbB2 with afatinib suppressed DSE-enhanced malignant phenotypes, establishing the critical role of the ErbB pathway in regulating the effects of DSE expression. This evidence indicates that upregulation of DSE in gliomas contributes to malignant behavior in cancer cells. We provide novel insight into the significance of DS chains in ErbB signaling and glioma pathogenesis.
AB - Remodeling of the extracellular matrix (ECM) in the tumor microenvironment promotes glioma progression. Chondroitin sulfate (CS) proteoglycans appear in the ECM and on the cell surface, and can be catalyzed by dermatan sulfate epimerase to form chondroitin sulfate/dermatan sulfate (CS/DS) hybrid chains. Dermatan sulfate epimerase 1 (DSE) is overexpressed in many types of cancer, and CS/DS chains mediate several growth factor signals. However, the role of DSE in gliomas has never been explored. In the present study, we determined the expression of DSE in gliomas by consulting a public database and conducting immunohistochemistry on a tissue array. Our investigation revealed that DSE was upregulated in gliomas compared with normal brain tissue. Furthermore, high DSE expression was associated with advanced tumor grade and poor survival. We found high DSE expression in several glioblastoma cell lines, and DSE expression directly mediated DS chain formation in glioblastoma cells. Knockdown of DSE suppressed the proliferation, migration, and invasion of glioblastoma cells. In contrast, overexpression of DSE in GL261 cells enhanced these malignant phenotypes and in vivo tumor growth. Interestingly, we found that DSE selectively regulated heparin-binding EGF-like growth factor (HB-EGF)-induced signaling in glioblastoma cells. Inhibiting epidermal growth factor receptor (EGFR) and ErbB2 with afatinib suppressed DSE-enhanced malignant phenotypes, establishing the critical role of the ErbB pathway in regulating the effects of DSE expression. This evidence indicates that upregulation of DSE in gliomas contributes to malignant behavior in cancer cells. We provide novel insight into the significance of DS chains in ErbB signaling and glioma pathogenesis.
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U2 - 10.1371/journal.pone.0198364
DO - 10.1371/journal.pone.0198364
M3 - Article
AN - SCOPUS:85048104788
SN - 1932-6203
VL - 13
JO - PLoS One
JF - PLoS One
IS - 6
M1 - e0198364
ER -
