Membrane insertion and secretion of the Engrailed-2 (EN2) transcription factor by prostate cancer cells may induce antiviral activity in the stroma

Punia, Natasha; Primon, Monika; Simpson, Guy R.; Pandha, Hardev; Morgan, Richard

doi:10.1038/s41598-019-41678-0

Cited by 20 publications

(10 citation statements)

References 30 publications

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“…However, we did not see such correlation in our panel of cell lines, suggesting that even though IFNs are major regulatory factors of MX2, there are also other mechanisms involved. For instance, a recent study by Punia et al found that Engrailed‐2 (EN2) transcription factor secreted by prostate tumors can induce MX2 expression in stromal cells (Punia, Primon, Simpson, Pandha, & Morgan, ), and MX2 was a single gene showing a dose–response relationship to recombinant EN2 treatment.…”

Section: Discussionmentioning

confidence: 99%

MX 2 is a novel regulator of cell cycle in melanoma cells

Juraleviciute

Poźniak

Nsengimana

et al. 2019

Pigment Cell Melanoma Res

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MX2 protein is a dynamin‐like GTPase2 that has recently been identified as an interferon‐induced restriction factor of HIV‐1 and other primate lentiviruses. A single nucleotide polymorphism (SNP), rs45430, in an intron of the MX2 gene, was previously reported as a novel melanoma susceptibility locus in genome‐wide association studies. Functionally, however, it is still unclear whether and how MX2 contributes to melanoma susceptibility and tumorigenesis. Here, we show that MX2 is differentially expressed in melanoma tumors and cell lines, with most metastatic cell lines showing lower MX2 expression than primary melanoma cell lines and melanocytes. Furthermore, high expression of MX2 RNA in primary melanoma tumors is associated with better patient survival. Overexpression of MX2 reduces in vivo proliferation partially through inhibition of AKT activation, suggesting that it can act as a tumor suppressor in melanoma. However, we have also identified a subset of melanoma cell lines with high endogenous MX2 expression where downregulation of MX2 leads to reduced proliferation. In these cells, MX2 downregulation interfered with DNA replication and cell cycle processes. Collectively, our data for the first time show that MX2 is functionally involved in the regulation of melanoma proliferation but that its function is context‐dependent.

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Section: Discussionmentioning

confidence: 99%

MX 2 is a novel regulator of cell cycle in melanoma cells

Juraleviciute

Poźniak

Nsengimana

et al. 2019

Pigment Cell Melanoma Res

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“…During the development of mouse, EN1 and EN2 have overlapping functions in regulating formation of additional fissures and for extensive cerebellar growth [8,9], but mutations in EN1 and EN2 produce different phenotypes [10]. In humans, aberrant expression of these genes has been associated with the pathogenesis of many types of tumors, including breast cancer [11,12], prostate cancer [13,14], colorectal cancer [15], and ovarian cancer [16,17]. Elevated EN2 expression in particular has been associated with poor survival, and this gene has been proposed as a biomarker for breast cancer screening [18].…”

Section: Introductionmentioning

confidence: 99%

EN1 Regulates Cell Growth and Proliferation in Human Glioma Cells via Hedgehog Signaling

Chang

Guo

et al. 2022

IJMS

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Glioblastoma is an aggressive cancer of the nervous system that accounts for the majority of brain cancer-related deaths. Through cross-species transcriptome studies, we found that Engrailed 1 (EN1) is highly expressed in serum-free cultured glioma cells as well as glioma tissues, and increased expression level predicts a worse prognosis. EN1 controls glioma cell proliferation, colony formation, migration, and tumorigenic capacity in vivo. It also influences sensitivity of glioma cells to γ-ray irradiation by regulating intracellular ROS levels. Mechanistically, EN1 influences Hedgehog signaling by regulating the level of Gli1 as well as primary cilia length and the primary cilia transport-related protein TULP3. In conclusion, we demonstrate that EN1 acts as an oncogenic regulator that contributes to glioblastoma pathogenesis and could serve as a diagnostic/prognostic marker and therapeutic target for glioblastoma.

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“…EN2 is a homeodomain-containing transcription factor that has an essential function in early development, which in mammals includes the delineation of the midbrain/hindbrain border [ 24 ]. For a transcription factor it has a number of unusual properties, including the ability to be secreted from cells and taken up by others [ 25 ]. Indeed, a recent study indicated that prostate cancer cells can secrete EN2 protein through vesicles which are then taken up by other non-EN2 expressing cells, where it can directly influence the transcription of target genes [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…For a transcription factor it has a number of unusual properties, including the ability to be secreted from cells and taken up by others [ 25 ]. Indeed, a recent study indicated that prostate cancer cells can secrete EN2 protein through vesicles which are then taken up by other non-EN2 expressing cells, where it can directly influence the transcription of target genes [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Integration of Urinary EN2 Protein & Cell-Free RNA Data in the Development of a Multivariable Risk Model for the Detection of Prostate Cancer Prior to Biopsy

Connell

Mills

Pandha

et al. 2021

Cancers

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The objective is to develop a multivariable risk model for the non-invasive detection of prostate cancer prior to biopsy by integrating information from clinically available parameters, Engrailed-2 (EN2) whole-urine protein levels and data from urinary cell-free RNA. Post-digital-rectal examination urine samples collected as part of the Movember Global Action Plan 1 study which has been analysed for both cell-free-RNA and EN2 protein levels were chosen to be integrated with clinical parameters (n = 207). A previously described robust feature selection framework incorporating bootstrap resampling and permutation was applied to the data to generate an optimal feature set for use in Random Forest models for prediction. The fully integrated model was named ExoGrail, and the out-of-bag predictions were used to evaluate the diagnostic potential of the risk model. ExoGrail risk (range 0–1) was able to determine the outcome of an initial trans-rectal ultrasound guided (TRUS) biopsy more accurately than clinical standards of care, predicting the presence of any cancer with an area under the receiver operator curve (AUC) = 0.89 (95% confidence interval(CI): 0.85–0.94), and discriminating more aggressive Gleason ≥ 3 + 4 disease returning an AUC = 0.84 (95% CI: 0.78–0.89). The likelihood of more aggressive disease being detected significantly increased as ExoGrail risk score increased (Odds Ratio (OR) = 2.21 per 0.1 ExoGrail increase, 95% CI: 1.91–2.59). Decision curve analysis of the net benefit of ExoGrail showed the potential to reduce the numbers of unnecessary biopsies by 35% when compared to current standards of care. Integration of information from multiple, non-invasive biomarker sources has the potential to greatly improve how patients with a clinical suspicion of prostate cancer are risk-assessed prior to an invasive biopsy.

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Membrane insertion and secretion of the Engrailed-2 (EN2) transcription factor by prostate cancer cells may induce antiviral activity in the stroma

Cited by 20 publications

References 30 publications

MX 2 is a novel regulator of cell cycle in melanoma cells

MX 2 is a novel regulator of cell cycle in melanoma cells

EN1 Regulates Cell Growth and Proliferation in Human Glioma Cells via Hedgehog Signaling

Integration of Urinary EN2 Protein & Cell-Free RNA Data in the Development of a Multivariable Risk Model for the Detection of Prostate Cancer Prior to Biopsy

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