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FHL3 links cell growth and self-renewal by modulating SOX4 in glioma.

ABSTRACT: Differentiation status significantly affects the properties of malignant glioma cells, with non-stem cells inducing tumor enlargement and stem-like cells driving tumor initiation and treatment resistance. It is not completely understood how the same protein can have a distinct role in these cell populations. Here, we report that four and a half LIM domain protein 3 (FHL3) has an inhibitory effect on proliferation in non-stem glioma cells and a non-proliferative effect in glioma stem cells (GSCs). In GSCs, we show that FHL3 interacts with the Smad2/3 protein complex at the SOX4 promoter region, inhibits SOX4 transcriptional activity by recruiting PPM1A phosphatase to Smad2/3, and then suppresses GSC tumor sphere formation and self-renewal in vitro and in vivo via downregulation of SOX2 expression. Altogether, these findings highlight the role of FHL3 as a stemness-suppressor in regulation of the Smad2/3-SOX4-SOX2 axis in glioma.

SUBMITTER: Han W

PROVIDER: S-EPMC6462005 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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FHL3 links cell growth and self-renewal by modulating SOX4 in glioma.

Han Wei W Hu Peishan P Wu Fan F Wang Shanshan S Hu Yan Y Li Shanshan S Jiang Tao T Qiang Boqin B Peng Xiaozhong X

Cell death and differentiation 20180628 5

Differentiation status significantly affects the properties of malignant glioma cells, with non-stem cells inducing tumor enlargement and stem-like cells driving tumor initiation and treatment resistance. It is not completely understood how the same protein can have a distinct role in these cell populations. Here, we report that four and a half LIM domain protein 3 (FHL3) has an inhibitory effect on proliferation in non-stem glioma cells and a non-proliferative effect in glioma stem cells (GSCs) ...[more]

PMID: 29955125

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Project description:BackgroundGlioma initiating cells (GICs), also known as glioma stem cells (GSCs), play an important role in the progression and recurrence of glioblastoma multiforme (GBM) due to their potential for self-renewal, multiple differentiation and tumor initiation. In the recent years, Notch1 has been found to be overexpressed in GICs. However, the regulatory mechanism of Notch1 in the self-renewal and invasion ability of GICs remains unclear. This study aims to explore the effect of Notch pathway on self-renewal and invasion of GICs and the underlying mechanisms.MethodsBioinformatic analysis and immunohistochemistry (IHC) were performed to evaluate the expression of Notch1 and Hes1 in GBM samples. Immunofluorescent (IF) staining was performed to observe the distribution of Notch1 and CXCR4 in GBM and GICs. Both pharmacological intervention and RNA interference were employed to investigate the role of Notch1 in GICs self-renewal, invasion and tumor growth in vitro or in vivo. The crosstalk effect of Notch1 and CXCL12/CXCR4 system on GIC self-renewal and invasion was explored by sphere formation assay, limiting dilution assay and Transwell assay. Western blots were used to verify the activation of Notch1/CXCR4/AKT pathway in self-renewal, invasion and tumor growth of GICs. Luciferase reporter assay was used to testify the potential binding site of Notch1 signaling and CXCR4. The orthotopic GICs implantations were established to analyze the role and the mechanism of Notch1 in glioma progression in vivo.ResultsNotch1 signaling activity was elevated in GBM tissues. Notch1 and CXCR4 were both upregulated in GICs, compared to Notch1 positive glioma cells comprised a large proportion in the CD133+ glioma cell spheres, CXCR4 positive glioma cells which usually expressed Notch1 both and dispersed in the periphery of the sphere, only represent a small subset of CD133+ glioma cell spheres. Furthermore, downregulation of the Notch1 pathway by shRNA and MK0752 significantly inhibited the PI3K/AKT/mTOR signaling pathway via the decreased expression of CXCR4 in GICs, and weakened the self-renewal, invasion and tumor growth ability of GICs.ConclusionsThese findings suggest that the cross-talk between Notch1 signaling and CXCL12/CXCR4 system could contribute to the self-renewal and invasion of GICs, and this discovery could help drive the design of more effective therapies in Notch1-targeted treatment of GBMs.

Project description:BackgroundAccumulating evidence indicates that cancer stem cells (CSCs) drive tumorigenesis. This suggests that CSCs should make ideal therapeutic targets. However, because CSC populations in tumors appear heterogeneous, it remains unclear how CSCs might be effectively targeted. To investigate the mechanisms by which CSC populations maintain heterogeneity during self-renewal, we established a glioma sphere (GS) forming model, to generate a population in which glioma stem cells (GSCs) become enriched. We hypothesized, based on the clonal evolution concept, that with each passage in culture, heterogeneous clonal sublines of GSs are generated that progressively show increased proliferative ability.Methodology/principal findingsTo test this hypothesis, we determined whether, with each passage, glioma neurosphere culture generated from four different glioma cell lines become progressively proliferative (i.e., enriched in large spheres). Rather than monitoring self-renewal, we measured heterogeneity based on neurosphere clone sizes (#cells/clone). Log-log plots of distributions of clone sizes yielded a good fit (r>0.90) to a straight line (log(% total clones) = k*log(#cells/clone)) indicating that the system follows a power-law (y = xk) with a specific degree exponent (k = -1.42). Repeated passaging of the total GS population showed that the same power-law was maintained over six passages (CV = -1.01 to -1.17). Surprisingly, passage of either isolated small or large subclones generated fully heterogeneous populations that retained the original power-law-dependent heterogeneity. The anti-GSC agent Temozolomide, which is well known as a standard therapy for glioblastoma multiforme (GBM), suppressed the self-renewal of clones, but it never disrupted the power-law behavior of a GS population.Conclusions/significanceAlthough the data above did not support the stated hypothesis, they did strongly suggest a novel mechanism that underlies CSC heterogeneity. They indicate that power-law growth governs the self-renewal of heterogeneous glioma stem cell populations. That the data always fit a power-law suggests that: (i) clone sizes follow continuous, non-random, and scale-free hierarchy; (ii) precise biologic rules that reflect self-organizing emergent behaviors govern the generation of neurospheres. That the power-law behavior and the original GS heterogeneity are maintained over multiple passages indicates that these rules are invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during tumor growth. Discovery of this power-law behavior provides a mechanism that could be targeted in the development of new, more effective, anti-cancer agents.

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FHL3 links cell growth and self-renewal by modulating SOX4 in glioma.

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FHL3 links cell growth and self-renewal by modulating SOX4 in glioma.

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