EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment

Hu, Yuanjie; Pioli, Peter D.; Siegel, Eric R.; Zhang, Qinghua; Nelson, J.S.; Chaturbedi, Abhishek; Mathews, Marlon S.; Ro, Daniel I.; Alkafeef, Selma S.; Hsu, Nelson; Hamamura, Mark J; Yu, Liping; Hess, Kenneth R.; Tromberg, Bruce J.; Linskey, Mark E.; Zhou, Yi

doi:10.1186/1476-4598-10-123

Cited by 64 publications

(89 citation statements)

References 34 publications

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“…Our findings in pituitary cells might, therefore, reflect the fact that these functional end-points represent a cell- or tumour-type-specific phenomenon, as observed by other investigators [24,41,42]. Indeed, and in this context, enforced expression of EFEMP1 in HeLa cell promotes and in NSCLC cells inhibits proliferation [42,45]; a similar finding of an association between growth promotion or growth inhibition in xenograft models of pancreatic tumours and glioma respectively are also reported [24,41]. …”

Section: Discussionsupporting

confidence: 83%

“…Moreover, the contribution of some family members, as either promoters or inhibitors of these pathways, is frequently apparent in a cell- or tumour-type context (reviewed in Obaya et al [21]). As example, several studies show that EFEMP-1 has bona fide activity as either a tumour promoter or tumour suppressor [24,40,41,42]. Indeed, increased expression of EFEMP1 is apparent in pancreatic and cervical cancers and malignant glioma [24,42,43], whereas reduced expression is apparent in breast, prostate, hepatocellular, and non-small cell lung cancer (NSCLC) [22,25,44,45].…”

Section: Discussionmentioning

confidence: 99%

“…The end-points measured included effects of EFEMP1 expression on cell proliferation, apoptosis and expression of multiple EFEMP1-responsive genes. In these cases and for these end-points, several studies have shown EFEMP1-mediated effects in different cell and tumour types [24,40,41,42,45]. Enforced expression of EFEMP1 in GH3 cells did not inhibit proliferation or drug-induced apoptotic end-points, whereas in NSCLC, pancreatic and glioma tumours EFEMP1 inhibits one or more of these functional end-points [23,24,45].…”

Section: Discussionmentioning

confidence: 99%

“…The functional consequences of EFEMP1 expression on tumour invasion and angiogenesis also show tumour-type specificities, where expression may either promote or inhibit these end-points [40,41,42,43]. The impact of EFEMP1 on these end-points is frequently mediated through effects on expression of multiple gene targets, including VEGF-A, HIF1A and MMPs.…”

Section: Discussionmentioning

confidence: 99%

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The EFEMP1 Gene: A Frequent Target for Epigenetic Silencing in Multiple Human Pituitary Adenoma Subtypes

Duong

Yacqub-Usman²,

Emes³

et al. 2013

Neuroendocrinology

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Background/Aims: In a genome-wide investigation we recently identified the EGF-containing fibulin-like extracellular matrix protein 1 gene, EFEMP1, as hypermethylated in growth hormone-secreting adenoma. Methods: In an independent cohort we determined expression of EFEMP1, CpG island methylation and histone tail modification status. The causal consequences of epigenetic modification were determined through epidrug-induced reversal and enforced EFEMP1 expression in GH3 cells. Results: The majority of adenomas, irrespective of subtype, show reduced EFEMP1 expression. However, epigenetic change, as determined by CpG island methylation, was not invariantly associated with decreased EFEMP1 expression. Conversely, chromatin immunoprecipitation assays revealed enrichment for modifications associated with either active or silenced genes in adenoma that did or did not express EFEMP1 respectively. In AtT-20 and GH3 cells a causal relationship between epigenetic silencing and expression of EFEMP1 was established where co-incubation with the epidrugs zebularine and TSA induced expression of EFEMP1 and concomitant histone tail modifications toward those associated with expressed genes. Enforced expression of EFEMP1 in GH3 cells was without effect on cell proliferation or apoptotic end-points, however inhibition of endogenous matrix metalloproteinase (MMP)-2 expression was apparent. Primary adenomas did not show this relationship, however a positive correlation was apparent with the MMP7 transcript and perhaps reflects cell or species differences. Conclusions: The protein product of the EFEMP1 gene, fibulin-3, is reported to impact on multiple pathways in a cell-specific context. Subtype-independent loss of EFEMP1 expression in the majority of primary adenomas should prompt more detailed investigation in this tumour type.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The EFEMP1 Gene: A Frequent Target for Epigenetic Silencing in Multiple Human Pituitary Adenoma Subtypes

Duong

Yacqub-Usman²,

Emes³

et al. 2013

Neuroendocrinology

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“…Research findings on the role of fibulin-1 and fibulin-3 in different tumor tissues have been controversial. Few researchers have reported oncogenic activities (13)(14)(15)(16)(17)(18)(19), whereas others have reported tumor-suppressive activities (20)(21)(22)(23)(24)(25)(26)(27). This discrepancy may be attributable to the influence of the tumor microenvironment on tumor-associated genes in promoting angiogenesis and metastasis (28).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of fibulin-4 is associated with tumor progression and poor prognosis in patients with cervical carcinoma

et al. 2014

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Abstract. Fibulin-4, a member of the fibulin family of extracellular glycoproteins, is implicated in the progression of a number of types of cancer. However, the function of fibulin-4 in cervical cancer progression remains unexplored. Fibulin-4 mRNA and protein expression levels in normal cervical tissue, cervical intraepithelial neoplasia (CIN), cervical carcinoma, highly invasive subclones and low-invasive subclones were evaluated by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. Serum fibulin-4 levels in patients with CIN and cervical carcinoma were measured by enzyme-linked immunosorbent assay. To assess the angiogenic properties of fibulin-4, vascular endothelial growth factor (VEGF) expression and tumor microvessel density (MVD) were analyzed in the cervical carcinoma cases by immunohistochemistry. Fibulin-4 expression was upregulated in the cervical carcinoma cases, and was positively correlated with MVD and VEGF expression. Fibulin-4 overexpression and high serum levels were significantly associated with advanced stage, low differentiation, lymph node metastasis, and poor prognosis in patients with cervical cancer. Fibulin-4 expression was also found to be overexpressed in highly invasive subclones when compared with the low-invasive subclones. Fibulin-4 is a newly identified glycoprotein that is overexpressed in cervical carcinoma. Fibulin-4 promotes angiogenesis and is associated with poor prognostic clinicopathologic features. This study demonstrated that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with cervical carcinoma.

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Epidermal growth factor‐containing fibulin‐like extracellular matrix protein 1 (EFEMP1) suppressed the growth of hepatocellular carcinoma cells by promoting Semaphorin 3B(SEMA3B)

Duan

Jiang

et al. 2019

Cancer Medicine

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Aim Epidermal growth factor‐containing fibulin‐like extracellular matrix protein 1(EFEMP1) has been found to be involved in the occurrence and development of many cancers. The relationship between EFEMP1 and the development of hepatocellular carcinoma (HCC) and the molecular mechanism are not fully understood. Methods Real‐time polymerase chain reaction (PCR) and tissue microarray were used to detect the expression of EFEMP1 in HCC cell lines and tissue. Methylation‐specific PCR assay was used to measure the methylation level of EFEMP1 in HCC cell lines and tissue. To study the function of EFEMP1 on cell function, Huh7 and HepG2 were infected with lentiviral particles expressing EFEMP1. MTT assay and colony formation assay were used to examine the effect of EFEMP1 on cell proliferation. Annexin‐VAPC/7‐AAD double were used to detect the effect of EFEMP1 on cell apoptosis. To further detect the effect of EFEMP1 on the development of HCC in vivo, we performed the tumor formation experiment in nude mice. Gene chip was used to detect the expression profile of Huh7 and HepG2 overexpressing EFEMP1. To further screen out the differences, GO analysis and pathway analysis were performed. To study the effects of SEMA3B, specific siRNA was used to inhibit the expression of SEMA3B. Chi‐squared test and rank sum test were used to analyze the relationship between EFEMP1 expression and HCC clinical characteristic. Results The study found that the expression of EFEMP1 was significantly decreased in HCC cell lines and HCC tissues. The expression level of EFEMP1 was related to the TNM (the extent of the tumor, the extent of spread to the lymph nodes, the presence of metastasis) stage and the prognosis of patients with HCC. The decrease of protein expression suggested that the patient prognosis was worse, and the protein level of EFEMP1 may be an independent factor in the prognosis of HCC patients. Promoter methylation may be one of the reasons for EFEMP1 inhibition. EFEMP1 could inhibit the proliferation of HCC cells and promoted the apoptosis of HCC cells to regulate the development of HCC. And EFEMP1 promoted the apoptosis of HCC cells mainly through the mitochondrial apoptosis pathway. EFEMP1 may inhibit the proliferation of HCC cells through the SEMA3B gene in the Axon guidance pathway. Conclusion In summary, our research revealed the regulation of EFEMP1 on cell proliferation and apoptosis in HCC. EFEMP1 may suppress the growth of HCC cells by promoting SEMA3B.

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EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment

Cited by 64 publications

References 34 publications

The <b><i>EFEMP1</i></b> Gene: A Frequent Target for Epigenetic Silencing in Multiple Human Pituitary Adenoma Subtypes

The <b><i>EFEMP1</i></b> Gene: A Frequent Target for Epigenetic Silencing in Multiple Human Pituitary Adenoma Subtypes

Overexpression of fibulin-4 is associated with tumor progression and poor prognosis in patients with cervical carcinoma

Epidermal growth factor‐containing fibulin‐like extracellular matrix protein 1 (EFEMP1) suppressed the growth of hepatocellular carcinoma cells by promoting Semaphorin 3B(SEMA3B)

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