Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer

Darimipourain, M; Wang, S; Ittmann, Michael; Kwabi-Addo, Bernard

doi:10.1038/pcan.2011.33

Cited by 22 publications

(13 citation statements)

References 37 publications

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“…It has previously been reported that in prostate cancer, SPRY1 is regulated by miR-21 [Darimipourain et al, 2011] a microRNA that is regulated by androgens and associated with prostate cancer or disease progression [Ribas et al, 2009]. Using Target Scan (http://www.targetscan.org/), miR-21binding sites in the 3’UTR were found in SPRY1 and in JAG1 (Supplement Fig.…”

Section: Resultsmentioning

confidence: 99%

Correlation of Sprouty1 and Jagged1 With Aggressive Prostate Cancer Cells With Different Sensitivities to Androgen Deprivation

Terada

Shiraishi

Zeng

et al. 2014

J of Cellular Biochemistry

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Prostate cancer is a heterogeneous disease and thus, it is important to understand whether among the heterogeneous collection of cell types, androgen-deprivation insensitive cells exist prior to hormonal manipulation. We established several LNCaP subclones with distinct insensitivities to androgen deprivation from a parental LNCaP cell line. In the resulting clones, the sensitivity to androgen-deprivation negatively correlated with their PSA expression levels. In two of these clones, an androgen insensitive clone, LNCaP-cl1, and an androgen sensitive clone, LNCaP-cl5, the DNA copy number differed significantly, indicating that these clones contain genetically distinct cells. LNCaP-cl1 had higher PSA expression but lower invasiveness and tumor growth potential than LNCaP-cl5. The expression levels of two genes that are known to be regulated by miR-21, an androgen-regulated microRNA, Sprouty1 (SPRY1) and Jagged1 (JAG1) were significantly lower in LNCaP-cl1 than in LNCaP-cl5. Knocking down SPRY1 in LNCaP cells enhanced PSA expression and cell proliferation. JAG1 administration in LNCaP cells enhanced cell invasion and JAG1 knockdown in PC3 cells suppressed cell invasion and tumor formation. These results indicated that the expression differences in SPRY1 and JAG1 may contribute to the phenotypic differences between the LNCaP-cl1 and LNCaP-cl5 clones. In tissue samples, SPRY1 expression levels were significantly lower in prostate cancer patients with PSA recurrence after surgical treatment (P = 0.0076) and JAG1 expression levels were significantly higher in Gleason sum (GS) 8–9 disease than in GS 5–6 (P = 0.0121). In summary a random population of LNCaP cells comprises a heterogeneous group of cells with different androgen-deprivation sensitivities and potential for invasiveness.

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Section: Resultsmentioning

confidence: 99%

Correlation of Sprouty1 and Jagged1 With Aggressive Prostate Cancer Cells With Different Sensitivities to Androgen Deprivation

Terada

Shiraishi

Zeng

et al. 2014

J of Cellular Biochemistry

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“…PTEN loss-of-function, which is one of the most common and important oncogenic changes in human prostate cancer (2, 3), can be accompanied by silencing of Sprouty genes potentially as a result of multiple mechanisms including hypermethylation (27,34) and aberrant microRNA expression (35). Because we have shown here that Sprouty genes are modulators of tumorigenesis caused by loss of Pten function, future studies aimed at obtaining a deeper understanding of the molecular consequences of Sprouty loss-of-function should provide insight into the rewiring of key oncogenic signaling pathways that occurs in the cancer cell.…”

Section: Discussionmentioning

confidence: 99%

Sprouty genes function in suppression of prostate tumorigenesis

Martin

2012

Proc. Natl. Acad. Sci. U.S.A.

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Expression of Sprouty genes is frequently decreased or absent in human prostate cancer, implicating them as suppressors of tumorigenesis. Here we show they function in prostate tumor suppression in the mouse. Concomitant inactivation of Spry1 and Spry2 in prostate epithelium causes ductal hyperplasia and low-grade prostatic intraepithelial neoplasia (PIN). However, when Spry1 and Spry2 loss-of-function occurs in the context of heterozygosity for a null allele of the tumor suppressor gene Pten, there is a striking increase in PIN and evidence of neoplastic invasion. Conversely, expression of a Spry2 gain-of-function transgene in Pten null prostatic epithelium suppresses the tumorigenic effects of loss of Pten function. We show that Sprouty gene loss-of-function results in hyperactive RAS/ERK1/ 2 signaling throughout the prostate epithelium and cooperates with heterozygosity for a Pten null allele to promote hyperactive PI3K/AKT signaling. Furthermore, Spry2 gain-of-function can suppress hyperactivation of AKT caused by the absence of PTEN. Together, these results point to a key genetic interaction between Sprouty genes and Pten in prostate tumorigenesis and provide strong evidence that Sprouty genes can function to modulate signaling via the RAS/ERK1/2 and PI3K/AKT pathways. The finding that Sprouty genes suppress tumorigenesis caused by Pten loss-of-function suggests that therapeutic approaches aimed at restoring normal feedback mechanisms triggered by receptor tyrosine kinase signaling, including Sprouty gene expression, may provide an effective strategy to delay or prevent high-grade PIN and invasive prostate cancer. P rostate cancer is the most commonly diagnosed malignancy in men, with more than 240,000 new diagnoses anticipated in 2012. Despite advances in both diagnosis and treatment, ∼28,000 prostate cancer deaths are expected in the United States in 2012 (1). Although androgen deprivation remains a cornerstone of therapy, inevitably the disease becomes resistant to interventions aimed at depleting androgens and treatments are limited for this lethal form of the disease. A better understanding of the genetic and molecular basis for prostate cancer may lead to more effective therapies and prevention strategies.The tumor suppressor gene PTEN, which encodes a key negative regulator of PI3 kinase (PI3K)/AKT signaling, is frequently deleted or mutated in human prostate cancer, resulting in increased AKT activity (2, 3). The importance of PTEN in prostate cancer has been demonstrated in the mouse, where loss of Pten function can recapitulate the progression of the human disease from prostatic intraepithelial neoplasia (PIN) to invasive cancer (4, 5). In addition to increased PI3K/AKT activity, a common feature of aggressive human prostate cancers is hyperactivation of the RAS/ ERK1/2 pathway (6). However, oncogenic mutations in RAS or RAF are rare and the molecular basis for aberrant ERK1/2 activity in human prostate cancer is unknown (7,8).One possible mechanism for RAS/ERK1/2 pathway hyperactivation is loss-o...

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“…Overexpression of SPRY1 in LNCaP and PC-3 cells significantly inhibits cell growth (Kwabi-Addo et al, 2004). Increased methylation of the SPRY1 promoter and miR-21 mediated repression are in part responsible for abnormal SPRY1 silencing that occurs in prostate cancer (Kwabi-Addo et al, 2009;Darimipourain et al, 2011). More recently, it was confirmed in vivo that Spry1 and Spry2 function together to inhibit prostate cancer progression (Schutzman and Martin, 2012).…”

Section: Prostate Cancermentioning

confidence: 96%