Research Article: DSE promotes aggressive glioma cell phenotypes by enhancing HB-EGF/ErbB signaling

Date Published: June 4, 2018

Publisher: Public Library of Science

Author(s): Wen-Chieh Liao, Chih-Kai Liao, You-Huan Tsai, To-Jung Tseng, Li-Ching Chuang, Chyn-Tair Lan, Hung-Ming Chang, Chiung-Hui Liu, Ilya Ulasov.


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.

Partial Text

High grade gliomas, including grade III anaplastic astrocytomas and grade IV glioblastomas, are among the most aggressive human cancers. They are the third greatest cause of cancer death in people under the age of 35 worldwide [1]. Currently, glioblastomas are incurable. The average survival rate of glioblastoma is less than 2 years, even in patients who have received standard surgical resection followed by radiation and chemotherapy, or enrollment in a clinical trial. The high mortality of this disease is mainly attributable to the limited treatment options, and the almost inevitable recurrence after surgical care [2, 3]. In this regard, elucidation of the precise molecular mechanisms underlying glioma progression is crucial for developing new treatments of this fatal disease.

The present study showed that DSE is frequently upregulated in human glioma tissue and cell lines, and DSE upregulation in glioma tissue is associated with a worse tumor grade and poor overall survival. The formation of DS on proteoglycans is regulated by DSE expression in glioma cells. DSE knockdown suppresses malignant phenotypes, whereas DSE overexpression enhances glioma cell malignancy, both in vitro and in vivo. Mechanically, DSE modulates HB-EGF-induced EGFR/ErbB2 activity and downstream signaling, whereas DSE-induced cell viability and invasion are hindered by EGFR/ErbB2 inhibitors. For the first time, the present study has shown that dermatan sulfate epimerase (DSE) is capable of regulating glioma cell malignancy in vitro and in vivo, and the ErbB pathway is involved in this process. Our findings provide a novel insight into the biological functions of DS chains in the pathogenesis of glioma, and may be useful in the development of a selective marker for glioma treatment.




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