R-spodin2 enhances canonical Wnt signaling to maintain the stemness of glioblastoma cells

• Published in: Cancer cell international Vol. 18; no. 1; p. 156
• Main Authors: Liu, Si, U, Kin Pong, Zhang, Jieting, Tsang, Lai Ling, Huang, Jiawei, Tu, Shui Ping, Jiang, Xiaohua
• Format: Journal Article
• Language: English
• Published: England BioMed Central 11-10-2018; BMC
• Subjects: Biotechnology; Brain cancer; Breast cancer; Cancer stem cells; Cell growth; Cell self-renewal; Colorectal cancer; Embryos; Glioblastoma; Glioblastoma cells; Growth factors; Growth media; Isocitrate dehydrogenase; Ligands; Mutation; Pathogenesis; Pluripotency; Primary Research; R-spondin2; Stem cells; Stemness; Subpopulations; Tumorigenesis; Tumorigenicity; Tumors; Wnt; Wnt protein; Xenografts; β-Catenin; Stemness; Cancer stem cells; Wnt; R-spondin2; Glioblastoma
• ISSN: 1475-2867; 1475-2867
• DOI: 10.1186/s12935-018-0655-3

As newly identified Wnt enhancer, R-spondin gene family members have been linked to various cancers; however, their role in isocitrate dehydrogenase-wildtype subtype of human glioblastoma (GBM) cells remains unknown.
Human U87 and U251 cell lines were used to perform the experiments. GBM stem-like cells were enriched in stem cell growth media and induced to differentiate using retinoid acid or growth factor deprivation. Wnt
and Wnt
subpopulations were isolated and evaluated by MTS, sphere formation, transwell migration and xenograft formation assays.
R-spondin 2 but not R-spondin 3 potentiates Wnt/β-catenin signaling in GBM cell lines. While R-spondin 2 does not affect cell growth, it induces the expression of pluripotent stem cell markers in combination with Wnt3A. GBM stem-like cells are endowed with intrinsic high activity of β-catenin signaling, which can be further intensified by R-spondin 2. In addition, R-spondin2 promotes stem cell self-renewal and suppresses retinoid acid- or growth factor deprivation-induced differentiation, indicating R-spondin 2 maintains stem cell traits in GBM. On the other hand, we identify subpopulations of GBM cells that show distinctive responsiveness to Wnt/β-catenin signaling. Interestingly, Wnt
and Wnt
cells display distinctive biologic properties. Moreover, Wnt
cell-inoculated xenografts exhibit enhanced tumorigenicity and increased expression levels of R-spondin 2 compared to Wnt
cell-inoculated xenografts.
Our study reveals a novel regulatory mechanisms underlying the over-activation of β-catenin-mediated signaling in the pathogenesis of GBM.