Integrin α3 is overexpressed in glioma stem-like cells and promotes invasion

Nakada, Mitsutoshi; Nambu, E; Furuyama, Natsuki; Yoshida, Yuya; Takino, Takahisa; Hayashi, Yutaka; Sato, Hiroki; Su, Yin; Tsuji, Tsutomu; Ki, Miyamoto; Hirao, Atsushi; Ji, Hamada

doi:10.1038/bjc.2013.218

Cited by 96 publications

(95 citation statements)

References 40 publications

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“…In accordance with these in vitro data is the observation that the IK inhibitor TRAM-34 blocks the brain infiltration by xenografted human glioblastoma cells in orthotopic mouse models (36). High IK channel expression has been associated with upregulation of "stemness" markers (8), and the glioblastoma "stem" cells have been suggested to express a highly migratory phenotype and to be primarily responsible for brain invasion (37,38). As a matter of fact, IK channels have been demonstrated to mediate the migration of neuronal precursor cells, so-called neuroblasts, along the rostral migratory stream to become interneurons in the olfactory bulb of normal adult mouse brain (39).…”

Section: Discussionmentioning

confidence: 72%

Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

Stegen

Butz

Klumpp

et al. 2015

Molecular Cancer Research

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Ca 2þ -activated K þ channels, such as BK and IK channels, have been proposed to fulfill pivotal functions in neoplastic transformation, malignant progression, and brain infiltration of glioblastoma cells. Here, the ionizing radiation (IR) effect of IK K þ channel targeting was tested in human glioblastoma cells. IK channels were inhibited pharmacologically by TRAM-34 or genetically by knockdown, cells were irradiated with 6 MV photons and IK channel activity, Ca 2þ signaling, cell cycling, residual doublestrand breaks, and clonogenic survival were determined. In addition, the radiosensitizing effect of TRAM-34 was analyzed in vivo in ectopic tumors. Moreover, The Cancer Genome Atlas (TCGA) was queried to expose the dependence of IK mRNA abundance on overall survival (OS) of patients with glioma. Results indicate that radiation increased the activity of IK channels, modified Ca 2þ signaling, and induced a G 2 -M cell-cycle arrest. TRAM-34 decreased the IR-induced accumulation in G 2 -M arrest and increased the number of gH2AX foci post-IR, suggesting that TRAM-34 mediated an increase of residual DNA double-strand breaks. Mechanistically, IK knockdown abolished the TRAM-34 effects indicating the IK specificity of TRAM-34. Finally, TRAM-34 radiosensitized ectopic glioblastoma in vivo and high IK mRNA abundance associated with shorter patient OS in low-grade glioma and glioblastoma.Implications: Together, these data support a cell-cycle regulatory function for IK K þ channels, and combined therapy using IK channel targeting and radiation is a new strategy for anti-glioblastoma therapy. Mol Cancer Res; 13(9); 1283-95. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 72%

Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

Stegen

Butz

Klumpp

et al. 2015

Molecular Cancer Research

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“…Tanaka and Fukuzawa [22] found that the invasiveness of human neuroblastoma cells was inhibited by up-regulating ITGα1. Additionally, Nakada et al [23] reported that ITGα3 is over-expressed in glioma stem-like cells and promotes invasion. Furthermore, evidence shows that overexpression of ITGαv is closely associated with the metastasis and progression of some cancers [24, 25].…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that interference with the MAPK/ERK and PI3K/AKT pathways might be responsible for the pro-apoptotic and metastatic effects of CLIC1 induced by ITGαv in orthotopically xenografted GC tumors. In addition, ITGα3 was over-expressed in glioma stem-like cells and promoted invasion via MAPK/ERK [23]. The MAPK/p38 pathway is mainly associated with inflammation, stress and apoptosis, which are involved in the occurrence and development of GC by p38-phosphorylation activation in gastric epithelial cells [43, 44].…”

Section: Discussionmentioning

confidence: 99%

CLIC1 Promotes the Progression of Gastric Cancer by Regulating the MAPK/AKT Pathways

Mao

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chloride intracellular channel 1 (CLIC1), which is a member of the chloride channel protein family, is associated with various human tumors. Recent studies have shown that CLIC1 is involved in the occurrence and development of gastric cancer (GC). However, the exact mechanism remains unclear in GC. Methods: Effects of CLIC1 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated by analysing 54 patients with GC, as well as human gastric cell lines SGC-7901 and MGC-803, utilizing proteomics, RT-PCR, Western blotting, flow cytometry, Cell invasion and migration assays and xenograft tumor models. Results: Our study shows that CLIC1 knockdown by targeted-siRNA markedly inhibits GC cell invasion and migration and induces apoptosis in vitro. In total, 54 differentially expressed proteins were identified in GC cells SGC-7901 after CLIC1 silencing by isobaric tags for relative isotope labeled and absolute quantitation (iTRAQ) technology, including integrin α1 (ITGα1) and ITGα3. The expression levels of ITGα3, ITGαv, ITGβ1 and Bcl-2 mRNA and protein were decreased significantly in GC cells after CLIC1 knockdown; ITGα1 and Fas were upregulated, but the level of survivin was not significantly different. GC growth and metabolism were decreased in vivo after CLIC1 silencing, but apoptosis was markedly increased. Further study showed that the expression levels of ITGα3, ITGαv and ITGβ1, as well as AKT-phosphorylation, ERK-phosphorylation and p38-phosphorylation, were reduced in vivo after CLIC1 knockdown, while ITGα1 was upregulated. Conclusions: We speculate that CLIC1 may play an important role in the progression of GC, and its mechanism may be related to the regulation of integrin family proteins, which leads to the sequential regulation of the PI3K/AKT, MAPK/ERK and MAPK/p38 pathways.

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“…Immunohistological analysis previously demonstrated that integrin α3 (ITGA3) is expressed in the plasma membrane of GBM cells, particularly in invading cells and the surrounding blood vessels (21). The increased expression of ITGA3 enhances migration and invasion of glioma cells and glioblastoma stem cells (GSCs) (32). The current study detected that the expression of various proteins associated with EMT was increased following TGF-β1 treatment of U87 cells, including integrins (ITGB1, ITGB3, ITGAV, ITGA5, ITGAX, ITGA3, ITGA8) and fibronectin 1 (FN1) ( Table II).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of the effect of TGF-β1 on U87 human glioblastoma cells

Bryukhovetskiy

Шевченко

2016

Oncology Letters

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Abstract. Glioblastoma multiforme (GBM) is the most widespread and aggressive type of primary brain tumor. The prognosis following diagnosis with GBM is poor, with a median survival time of 14 months. Tumor cell invasion, metastasis and proliferation are the major causes of mortality in patients with GBM. In order to develop effective GBM treatment methods it is necessary to identify novel targets involved in these processes. Recently, there has been increasing interest in investigating the signaling pathways involved in GBM development, and the transforming growth factor-β (TGF-β) signaling pathway is understood to be significant for regulating the behavior of GBM, as well as stimulating its invasion and metastatic development. Particular interest has been given to investigating the modulation of TGF-β-induced epithelial-to-mesenchymal transition (EMT); during this process, epithelial cells transdifferentiate into mobile cells with a mesenchymal phenotype. The induction of EMT increases the invasiveness of various types of carcinoma; however, the role of TGF-β in this process remains to be elucidated, particularly in the case of GBM. The current study presents a comparative proteome mapping of the U87 human glioblastoma cell line, with and without TGF-β1 treatment. Proteome analysis identified numerous proteins involved in the molecular mechanisms of GBM oncogenesis and TGF-β1 signaling in glioblastoma. The results of the present study facilitated the identification of novel potential markers of metastasis and candidates for targeted glioblastoma therapy, which may potentially be validated and used in clinical medicine to develop improved approaches for GBM diagnosis and treatment.

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Integrin α3 is overexpressed in glioma stem-like cells and promotes invasion

Cited by 96 publications

References 40 publications

Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

CLIC1 Promotes the Progression of Gastric Cancer by Regulating the MAPK/AKT Pathways

Molecular mechanisms of the effect of TGF-β1 on U87 human glioblastoma cells

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