Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma

Karakoula, Katherine; Jacques, Thomas S.; Phipps, Kim; Harkness, William; Thompson, Dominic; Harding, Brian; Darling, John L.; Warr, Tracy

doi:10.1016/j.canlet.2013.12.005

Cited by 20 publications

(17 citation statements)

References 48 publications

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“…In the present study, we determined that BEX1 overexpression markedly inhibited ESCC cell proliferation in vitro and tumor growth in vivo. In agreement with our findings, BEX1 expression was recently found to be downregulated in 27 out of 40 pediatric intracranial ependymoma tissues, and overexpression of BEX1 to significantly suppress cell proliferation and colony formation (10). Similarly, Lee et al found that the mRNA expression level of BEX1 was significantly lower in OSCC patients with alcohol consumption, betel quid chewing and cigarette smoking, and BEX1 demonstrated potent growth inhibitory activities in OSCC cell culture and mouse xenografts (11).…”

Section: Discussionsupporting

confidence: 92%

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Low expression of BEX1 predicts poor prognosis in patients with esophageal squamous cell cancer

et al. 2018

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The brain expressed x‑linked gene 1 (BEX1) is a member of the BEX family and is aberrantly expressed in many cancers. However, the clinical significance of BEX1 expression level and its role in the pathology of esophageal squamous cell cancer (ESCC) remain unknown. In the present study, we determined BEX1 expression in the tumor and adjacent normal tissues from 118 ESCC patients by immunohistochemistry and determined the proliferation and growth of ESCC cells following ectopic overexpression of BEX1 in cultured cells and in mouse‑ESCC xenografts. We observed that BEX1 was downregulated in ESCC tissues compared to adjacent normal tissues, and low BEX1 expression was significantly associated with larger ESCC tumor volume (P<0.001), advanced T stage (P=0.011) and advanced clinical stage (P=0.039). Additionally, survival analysis revealed that low expression of BEX1 significantly predicted poor prognosis in patients with ESCC (P<0.001). Multivariate analysis revealed that low BEX1 expression was an independent prognostic factor of poor survival (P=0.039). In vitro analysis revealed that overexpression of BEX1 inhibited ESCC cell proliferation and colony formation. Furthermore, in vivo tumorigenesis assays revealed that ectopic overexpression of BEX1 suppressed ESCC tumor growth in mice. Further immunoblotting analysis demonstrated that BEX1 upregulation led to reduced expression and phosphorylation of NF‑κB p65, indicating inhibition of the NF‑κB signaling pathway by BEX1. Our findings indicated that low BEX1 expression may be an independent prognostic marker for poor survival and may serve as a potential target for ESCC therapy.

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Section: Discussionsupporting

confidence: 92%

“…Aberrant expression of BEX1 has been observed in AML, CML, intracranial ependymoma, malignant glioma and OSCC (8)(9)(10)(11)(12). In breast, gliomas and colorectal cancers, BEX2 was found to be upregulated and BEX2 overexpression enhanced cell proliferation (13)(14)(15)(16)(17)(18), indicating BEX2 to be a putative oncogene.…”

Section: Discussionmentioning

confidence: 99%

Low expression of BEX1 predicts poor prognosis in patients with esophageal squamous cell cancer

et al. 2018

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“…For example, BEX1 was found to be upregulated in neuroendocrine tumors [103]. BEX1 was identified as the most frequently methylated genes (27/40 cases) in pediatric intracranial ependymoma [104]. Ectopic expression of BEX1 significantly suppressed cell proliferation and colony formation in pediatric ependymoma during short-term cell culture [104].…”

Section: Bex Proteins In Other Cancersmentioning

confidence: 99%

“…BEX1 was identified as the most frequently methylated genes (27/40 cases) in pediatric intracranial ependymoma [104]. Ectopic expression of BEX1 significantly suppressed cell proliferation and colony formation in pediatric ependymoma during short-term cell culture [104]. The mouse teratocarcinoma cell line F9 and the human ovarian carcinoma cell line PA-1 express BEX3 where BEX3 was found to be associated with mitochondria [105] and probably regulates mitochondrial function.…”

Section: Bex Proteins In Other Cancersmentioning

confidence: 99%

Brain-Expressed X-linked (BEX) proteins in human cancers

Kazi

Kabir

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The Brain-Expressed X-linked (BEX) family proteins are comprised of five human proteins including BEX1, BEX2, BEX3, BEX4 and BEX5. BEX family proteins are expressed in a wide range of tissues and are known to play a role in neuronal development. Recent studies suggest a role of BEX family proteins in cancers. BEX1 expression is lost in a subgroup of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Expression of BEX1 controls cell surface receptor signaling and restores imatinib response in resistant cells. BEX2 is overexpressed in a group of breast cancer patients and also in gliomas. Increased BEX2 expression led to enhanced NF-κB signaling as well as cell proliferation. Although BEX2 acts as tumor promoter in a subset of breast cancer, BEX3 expression displayed an opposite role. Overexpression of BEX3 resulted in inhibition of tumor formation in breast cancer mouse xenograft models. The role of BEX4 and BEX5 in cancer has not yet been defined. Collectively this suggests that BEX family members have distinct roles in cancers.While BEX1 and BEX3 act as a tumor suppressors, BEX2 seems to act as an oncogene.

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“…Further studies have confirmed that Bex1 regulates cell cycle by interacting with p75 neurotrophin receptor (p75NTR) to regulate the downstream signaling pathway (Vilar et al, 2006). Besides its roles in the nervous system, Bex1 has been identified as a candidate tumor suppressor gene because its inactivation is associated with the development of various types of tumors (Foltz et al, 2006; Karakoula et al, 2014; Lee et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

The brain expressed x-linked gene 1 (Bex1) regulates myoblast fusion

Jiang

Wang

Feng

et al. 2016

Developmental Biology

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Skeletal muscle development (myogenesis) is a complex but precisely orchestrated process involving spatiotemporal regulation of the proliferation, differentiation and fusion of myogenic progenitor cells (myoblasts). Here we identify brain expressed x-linked gene 1 (Bex1) as a transient, developmentally regulated gene involved in myoblast fusion. Bex1 expression is undetectable in adult muscles or in quiescent muscle stem cells (satellite cells). During embryonic myogenesis, however, Bex1 is robustly expressed by myogenin+ differentiating myoblasts, but not by Pax7+ proliferating myoblasts. Interestingly, Bex1 is initially localized in the cytoplasm and then translocates into the nucleus. During adult muscle regeneration, Bex1 is highly expressed in newly regenerated myofibers and the expression is rapidly downregulated during maturation. Consistently, in cultured myoblasts, Bex1 is not expressed at the proliferation stage but transiently expressed upon induction of myogenic differentiation, following a similar cytoplasm to nucleus translocation pattern as seen in vivo. Using gain- and loss-of-function studies, we found that overexpression of Bex1 promotes the fusion of primary myoblasts without affecting myogenic differentiation and myogenin expression. Conversely, Bex1 knockout myoblasts exhibit obvious fusion defects, even though they express normal levels of myogenin and differentiate normally. These results elucidate a novel role of Bex1 in myogenesis through regulating myoblast fusion.

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Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma

Cited by 20 publications

References 48 publications

Low expression of BEX1 predicts poor prognosis in patients with esophageal squamous cell cancer

Low expression of BEX1 predicts poor prognosis in patients with esophageal squamous cell cancer

Brain-Expressed X-linked (BEX) proteins in human cancers

The brain expressed x-linked gene 1 (Bex1) regulates myoblast fusion

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