Inhibition of nestin suppresses stem cell phenotype of glioblastomas through the alteration of post-translational modification of heat shock protein HSPA8/HSC71

Matsuda, Yoko; Ishiwata, Toshiyuki; Yoshimura, Hisashi; Hagio, Masahito; Arai, Tomio

doi:10.1016/j.canlet.2014.12.030

Cited by 50 publications

(49 citation statements)

References 42 publications

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“…However, several recent findings have challenged the idea because they identified a dynamic interconversion between CSCs and differentiated cells, which indicated the differentiation of CSCs was not the only way in which cells grew and a reversible dedifferentiation process may occur through special signals [30, 32, 35, 36]. These findings were in accordance with our results as we found cancer stem cells can be induced through dedifferentiation under hypoxia conditions.…”

Section: Discussionsupporting

confidence: 92%

“…However, the reliability of CD133 as a stem cell marker remains questionable because CD133 − cells may be tumorigenic in some cases [29, 30]. Although some researchers attributed this to CD133 + cell contamination as a result of missorting [31], we fully considered this issue and sorted with other GSC markers including SSEA-1/CD15 [16], NESTIN [21, 32] and ABCG2 [17], as well as several known dedifferentiation stem cell markers including SOX-2, OCT-4, KLF-4 and Nanog [18, 21]. Both induced neurospheres and cells cultured at 1% hypoxia for 48 h expressed all the stem cell markers, which indicated hypoxia induced neurospheres possessed of stem cell features.…”

Section: Discussionmentioning

confidence: 99%

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HIF1α regulates single differentiated glioma cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential under hypoxia

Wang

Xiong

et al. 2017

Oncotarget

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The standard treatment for Glioblastoma multiforme (GBM) is surgical resection and subsequent radiotherapy and chemotherapy. Surgical resection of GBM is typically restricted because of its invasive growth, which results in residual tumor cells including glioma stem cells (GSCs) and differentiated cells. Recurrence has been previously thought to occur as a result of these GSCs, and hypoxic microenvironment maintains the GSCs stemness also plays an important role. Summarizing traditional studies and we find many researchers ignored the influence of hypoxia on differentiated cells. We hypothesized that the residual differentiated cells may be dedifferentiated to GSC-like cells under hypoxia and play a crucial role in the rapid, high-frequency recurrence of GBM. Therefore, isolated CD133–CD15–NESTIN– cells were prepared as single-cell culture and treated with hypoxia. More than 95% of the surviving single differentiated CD133–CD15–NESTIN– cell dedifferentiated into tumorigenic CD133+CD15+NESTIN+ GSCs, and this process was regulated by hypoxia inducible factor-1α. Moreover, the serum also played an important role in this dedifferentiation. These findings challenge the traditional glioma cell heterogeneity model, cell division model and glioma malignancy development model. Our study also highlights the mechanism of GBM recurrence and the importance of anti-hypoxia therapy. In addition to GSCs, residual differentiated tumor cells also substantially contribute to treatment resistance and the rapid, high recurrence of GBM.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

HIF1α regulates single differentiated glioma cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential under hypoxia

Wang

Xiong

et al. 2017

Oncotarget

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“…This group showed that HSF1 knockdown in the A549 model did not prevent the morphological changes or enhanced migratory profile of heat-stressed cells, suggesting that HS significantly impacts cancer cell epithelial plasticity and the migratory phenotype independently of HSF1. Moreover, Matsuda et al reported that nestin regulates stemness, cell growth, and invasion in glioblastoma cells by altering HSPA8 [37]. Those reports support our findings that HSPs could be regulated by an HSF1-independent mechanism.…”

Section: Discussionsupporting

confidence: 91%

Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

Yun

Lee

2017

IJMS

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Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS, although it is still unclear whether this interaction is critical in the regulation of glioblastoma stem cells (GSCs). In this study, we examined whether small interfering RNA-mediated BIS knockdown decreased protein levels of HSF1 and subsequent nuclear localization under GSC-like sphere (SP)-forming conditions. Consistent with BIS depletion, HSF1 knockdown also reduced sex determining region Y (SRY)-box 2 (SOX2) expression, a marker of stemness, accompanying the decrease in SP-forming ability and matrix metalloprotease 2 (MMP2) activity. When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased. Taken together, our findings suggest that targeting BIS or HSF1 could be a viable therapeutic strategy for GSCs resistant to conventional TMZ treatment.

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“…Additionally, HSPA8 was shown to be up‐regulated in HBV‐related HCC cases . It was recently reported that alteration of HSC71 regulates stemness, cell growth and invasion in human glioblastoma cells . However, the role of HSPA8 in hepatic CSCs has not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

miR‐26b‐5p helps in EpCAM+cancer stem cells maintenance via HSC71/HSPA8 and augments malignant features in HCC

Khosla

Hemati

Rastogi

et al. 2019

Liver International

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Background Targeting cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) is difficult because of their similarities with normal stem cells (NSCs). EpCAM can identify CSCs from EpCAM+AFP+HCC cases, but is also expressed on NSCs. We aimed to distinguish the two using integrated protein, mRNA and miRNA profiling. Methods iTRAQ based protein profiling and Next Generation Sequencing (NGS) was performed on EpCAM+/EpCAM− cells isolated from HCC (Ep+CSC, Ep−HCC) and EpCAM+ cells from non‐cancerous/non‐cirrhotic control liver tissues (Ep+NSC). Validations were done using qRT‐PCR, flowcytometry and western blotting followed by in vitro and in vivo functional studies. Results 11 proteins were overexpressed (>3 fold) in Ep+CSCs compared to Ep−HCC and Ep+NSC cells. However, RNA‐sequencing confirmed the Ep+CSC specific up‐regulation of only HSPA8, HNRNPC, MPST and GAPDH mRNAs among these. Database search combined with miRNA profiling revealed Ep+CSC specific down‐regulation of 29 miRNAs targeting these four genes. Of these, only miR‐26b‐5p was found to target both HSPA8 and EpCAM. Validation of HSPA8 overexpression and miR‐26b‐5p down‐regulation followed by linear regression analysis established a negative correlation between the two. Functional studies demonstrated that reduced miR‐26b‐5p expression increased the spheroid formation, migration, invasion and tumourigenicity of Ep+CSCs. Furthermore, anti‐miR‐26b‐5p increased the number of Ep+CSCs with a concomitant overexpression of stemness genes and reduction of proapoptotic protein BBC3, which is a known substrate of HSPA8. Conclusion miR‐26b‐5p imparts metastatic properties and helps in maintenance of Ep+CSCs via HSPA8. Thus, miR‐26b‐5p and HSPA8 could serve as molecular targets for selectively eliminating the Ep+CSC population in human HCCs.

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Inhibition of nestin suppresses stem cell phenotype of glioblastomas through the alteration of post-translational modification of heat shock protein HSPA8/HSC71

Cited by 50 publications

References 42 publications

HIF1α regulates single differentiated glioma cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential under hypoxia

HIF1α regulates single differentiated glioma cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential under hypoxia

Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

miR‐26b‐5p helps in EpCAM+cancer stem cells maintenance via HSC71/HSPA8 and augments malignant features in HCC

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