Research articleFERMT3 contributes to glioblastoma cell proliferation and chemoresistance to temozolomide through integrin mediated Wnt signaling
Introduction
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor [3]. Despite clinical advances, its prognosis remains very poor, with a median progression-free survival of less than one year at the time of diagnosis [4], [37], [41]. Standard therapy consists of surgical resection followed by radiotherapy and chemotherapy, most often temozolomide (TMZ) [38], [40]. Despite the survival benefits associated with adjuvant radiation and chemotherapy, the majority of patients suffer recurrences of GBM [1]. The main barriers to successful treatment are the invasiveness and chemoresistance of high-grade gliomas [11], [26]. To overcome these barriers, it is crucial to identify the molecular mechanisms that regulate glioma progression. In the present study, we have identified the kindlin family member FERMT3 as one such regulator, as well as its mechanism of action for causing the growth and treatment resistance observed clinically.
Kindlins are cytosolic, adaptor proteins that are important activators and regulators of integrin function, including signaling [2], [23], [29]. They are essential components of the integrin adhesion complex that act through direct binding of β integrin tails [13], [21], [24]. Kindlins have become prominent in recent basic science research largely because of their roles in the development, progression, or suppression of various malignancies, including lung cancer [42], colorectal cancer [31], and gliomas [28], among many others [30]. It has also been shown that kindlins function as cancer therapeutic targets for agents such as docetaxel and cisplatin [34]. FERMT3, also known as kindlin-3, is expressed largely in the hematopoietic system, whereby it regulates activities such as hemostasis and thrombosis [27]. It is unclear whether FERMT3 acts primarily as a tumor promoter or suppressor, and it is likely that its role depends in part on the physiological context of its expression [8], [35]. FERMT3′s role in gliomas has not yet been explored, but recent research has shown that kindlin-2 (FERMT2) acts through the β-catenin/YB-1/EGFR pathway to enhance glioma progression [28]. Given the evidence that FERMT3 is crucial for integrin signaling and that kindlins can regulate cancer progression, we hypothesized that FERMT3 enhances glioma growth and survival through integrin activation of downstream pathways.
Integrins are cell adhesion molecules composed of α and β subunits that mediate interactions between intracellular and extracellular environments, including the surfaces of other cells, extracellular matrices, and pathogens [12], [17]. Extracellularly, they bind ligands, and intracellularly they bind cytoskeletal components and signaling molecules [12], [32]. They act through downstream signaling pathways to regulate numerous physiological processes that are crucial to the survival of individual cells as well as of the organism, such as mitochondrial function [39], immune system activity [36], and angiogenesis [20]. Specifically, they can function in coordination with growth factor receptors to increase β-catenin-dependent transcription and Wnt signaling [5]. However, through such mechanisms, integrins also contribute to pathological processes, including the progression of a variety of cancers [10], [19]. Targeting integrins has recently been shown to effectively treat malignant gliomas in vivo [33]. Furthermore, targeting β-1 integrin is effective in enhancing chemotherapeutic activity [18]. Results such as these suggest an emerging role for integrins in the pathophysiology and treatment of high-grade gliomas.
Section snippets
Glioma tissues
Fresh tumor tissues were obtained from 44 glioma patients during surgery at Daqing Oilfield General Hospital. The selected glioma specimens were immediately frozen in liquid nitrogen and stored at −80 °C for mRNA and protein extraction. The histopathological diagnoses were based on the World Health Organization (WHO) criteria. None of the glioma patients had received chemotherapy or radiotherapy prior to surgery. The present study was approved by the Ethics Committee of Daqing Oilfield General
Upregulation of FERMT3 in glioma
To evaluate the dysregulation of FERMT3 in gliomas, we examined FERMT3 expression levels in a panel of 49 glioma tissues, including eight oligodendrogliomas, six anaplastic oligoastrocytomas, 30 glioblastomas, four astrocytic tumors and one glioneural neoplasm from the published microarray GDS1813. As shown in Fig. 1A, expression of FERMT3 was remarkably increased in glioma tissues, as compared with four normal brain tissues (p < 0.001). We then collected 44 different grades of glioma tissue,
Discussion
Despite substantial advances in surgical and chemotherapeutic treatments of high-grade gliomas, patients with high-grade gliomas still have poor clinical outcomes. The barriers to successful treatment are caused largely by glioma invasion, recurrence, and chemoresistance [1], [3], [4], [11], [26], [37], [38], [40], [41]. In addition to overcoming these barriers, for optimal high-grade glioma treatment, it is also necessary to identify predictive biomarkers [25], [26]. There is ample evidence
Conflicts of interest
The authors declared that there is no conflict of interest regarding the publication of this article.
Acknowledgement
None.
References (42)
- et al.
The phosphotyrosine binding-like domain of talin activates integrins
J. Biol. Chem.
(2002) - et al.
Deadly allies: the fatal interplay between platelets and metastasizing cancer cells
Blood
(2010) - et al.
Kindlin-1 and −2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects
J. Biol. Chem.
(2009) - et al.
Signalling via integrins: implications for cell survival and anticancer strategies
Biochim. Biophys. Acta
(2007) - et al.
Differences in alpha-beta transmembrane domain interactions among integrins enable diverging integrin signaling
Biochem. Biophys. Res. Commun.
(2013) - et al.
Expression of FLNa in human melanoma cells regulates the function of integrin alpha1beta1 and phosphorylation and localisation of PKB/AKT/ERK1/2 kinases
Eur. J. Cell Biol.
(2015) - et al.
Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis
Blood
(2010) - et al.
Kindlin 3 (FERMT3) is associated with unstable atherosclerotic plaques, anti-inflammatory type II macrophages and upregulation of beta-2 integrins in all major arterial beds
Atherosclerosis
(2015) - et al.
Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain
Cell
(2000) - et al.
Integrin signalling and tyrosine phosphorylation: just the FAKs?
Trends Cell Biol.
(1998)
gp96 an endoplasmic reticulum master chaperone for integrins and toll-like receptors, selectively regulates early T and B lymphopoiesis
Blood
The diagnostic ability of follow-up imaging biomarkers after treatment of glioblastoma in the temozolomide era: implications from proton MR spectroscopy and apparent diffusion coefficient mapping
Biomed. Res. Int.
Primary brain tumors in adults
Am. Fam. Phys.
Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma
N. Engl. J. Med.
Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2
PLoS One
Integrin-epigenetics: a system with imperative impact on cancer
Cancer Metastasis Rev.
Integrins in cancer: biological implications and therapeutic opportunities
Nat. Rev. Cancer
A novel tumor suppressor function of Kindlin-3 in solid cancer
Oncotarget
beta(1)Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy
J. Clin. Invest.
A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma
Neuro Oncol.
Integrin signaling
Science
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These authors contributed equally to this work.