Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes
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Zhendong Su1, Satoshi Kishida1, Shoma Tsubota1, Kazuma Sakamoto1, Dongliang Cao1, Shinichi Kiyonari1, Miki Ohira2, Takehiko Kamijo2, Atsushi Narita3, Yinyan Xu3, Yoshiyuki Takahashi3 and Kenji Kadomatsu1
1Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
2Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Saitama, Japan
3Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Kenji Kadomatsu, email: [email protected]
Keywords: NCAN; CSPG; neuroblastoma; tumor sphere
Received: July 14, 2017 Accepted: October 27, 2017 Published: November 15, 2017
Neurocan (NCAN), a secreted chondroitin sulfate proteoglycan, is one of the major inhibitory molecules for axon regeneration in nervous injury. However, its role in cancer is not clear. Here we observed that high NCAN expression was closely associated with the unfavorable outcome of neuroblastoma (NB). NCAN was also highly and ubiquitously expressed in the early lesions and terminal tumor of TH-MYCN mice, a NB model. Interestingly, exogenous NCAN (i.e., overexpression, recombinant protein and conditioned medium) transformed adherent NB cells into spheres whose malignancies in vitro (anchorage-independent growth and chemoresistance) and in vivo (xenograft tumor growth) were potentiated. Both chondroitin sulfate sugar chains and NCAN's core protein were essential for the sphere formation. The CSG3 domain was essential in the moiety of NCAN. Our comprehensive microarray analysis and RT-qPCR of mRNA expression suggested that NCAN treatment promoted cell division, and urged cells to undifferentiated state. The knockdown of NCAN in tumor sphere cells cultured from TH-MYCN mice resulted in growth suppression in vitro and in vivo. Our findings suggest that NCAN, which stimulates NB cells to promote malignant phenotypes, is an extracellular molecule providing a growth advantage to cancer cells.
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