Evidence for downregulation of the negative regulator SPRED2 in clinical prostate cancer

Kachroo, Naveen; Valencia, Tania; Warren, Anne Y.; Gnanapragasam, Vincent

doi:10.1038/bjc.2012.507

Cited by 31 publications

(42 citation statements)

References 14 publications

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“…2 The expression of Spred2, but not Spred1, was elucidated to be downregulated in human prostate cancer. 58,74 Spred2 overexpression in a human prostate cancer cell line reduced ERK activation and decreased cell proliferation and migration, and Spred2 knockdown indicated the inverse effect. 58 Thus, Spred2 rather than Spred1 appears to be involved in prostate cancer as a tumor suppressor.…”

Section: Sprouty/spred and Prostate Cancermentioning

confidence: 95%

The Sprouty/Spred family as tumor suppressors: Coming of age

Kawazoe

Taniguchi

2019

Cancer Science

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The Ras/Raf/ERK pathway is one of the most frequently dysregulated signaling pathways in various cancers. In some such cancers, Ras and Raf are hotspots for mutations, which cause continuous activation of this pathway. However, in some other cancers, it is known that negative regulators of the Ras/Raf/ERK pathway are responsible for uncontrolled activation. The Sprouty/Spred family is broadly recognized as important negative regulators of the Ras/Raf/ERK pathway, and its expression is downregulated in many malignancies, leading to hyperactivation of the Ras/Raf/ERK pathway. After the discovery of this family, intensive research investigated the mechanism by which it suppresses the Ras/Raf/ERK pathway and its roles in developmental and pathophysiological processes. In this review, we discuss the complicated roles of the Sprouty/Spred family in tumor initiation, promotion, and progression and its future therapeutic potential.

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Section: Sprouty/spred and Prostate Cancermentioning

confidence: 95%

The Sprouty/Spred family as tumor suppressors: Coming of age

Kawazoe

Taniguchi

2019

Cancer Science

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“…Spred2 inhibits the growth and migration of CRC cells, but promotes cellular apoptosis. Spred1 and Spred2, two important members of the Spred family, were revealed to be frequently downregulated in various cancers, such as hepatocellular carcinoma and prostate cancer (9,13). In the present study, Spred1 and Spred2 expression in the tumor tissues of CRC patients were analyzed.…”

Section: Resultsmentioning

confidence: 91%

“…Spred2 is an important member of the sprouty-related EVH1 domain proteins, which are known to be negative regulators of growth factor-induced Ras/Raf-1/ERK activation (11,12). As anticipated, Spred2 was revealed to be significantly downregulated in various tumor cells, including hematological malignancies and solid tumors (13,14). Moreover, the Spred2 expression level was demonstrated to be closely associated with distal metastasis and survival in the clinic (15,16).…”

Section: Introductionmentioning

confidence: 72%

“…The Ras/Raf-1/ERK signaling pathway is always aberrantly activated in various tumors (27)(28)(29)(30). Moreover, Spred1 and Spred2, two important members of the Spred family, are frequently downregulated in various cancers, such as hepatocellular carcinoma and prostate cancer (13). Notably, the protein level of Spred is closely associated with tumor progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

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Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

Wang¹,

Liu²,

Kong³

et al. 2020

Oncol Rep

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Downregulation of the sprouty-related EVH1 domain protein 2 (Spred2) is closely associated with highly metastatic phenotypes in various tumors. However, the roles of Spred2 in the development and progression of colorectal cancer (CRC) are still largely unexplored. As anticipated, Spred2 expression was significantly downregulated in clinical tumor tissues. To restore Spred2 levels, Ad.Spred2, an adenoviral vector expressing Spred2, was transduced into CRC cells. It was revealed that Ad.Spred2 inhibited the proliferation and decreased the survival and migration of SW480 cells. Epithelial-mesenchymal transition (EMT) is an essential event during tumor metastasis to distant sites. It was revealed that Ad.Spred2 markedly inhibited EMT by promoting F-actin reorganization, upregulating E-cadherin levels and reducing vimentin protein expression. Notably, extracellular-regulated kinase (ERK) signaling inhibition by PD98059 induced similar effects on EMT in CRC cells, indicating that Ad.Spred2 regulated EMT in CRC cells in an ERK-dependent manner. Transforming growth factor β (TGF-β), a well-known inducer of EMT, increased E-cadherin expression, decreased vimentin expression and promoted migration in CRC cells. However, neither Ad.Spred2 nor PD98059 had an obvious effect on the expression of SMAD2/3 or SMAD4 in SW480 cells, indicating that Ad.Spred2 inhibited EMT in a SMAD-independent manner. Notably, Ad.Spred2 transduction downregulated SAMD2/3 and SMAD4 levels in HCT116 cells in an ERK-independent manner. It was speculated that Ad.Spred2 inhibited the EMT of HCT116 cells by both blocking ERK signaling and reducing SMAD signaling. It was concluded that Spred2 inhibited EMT in CRC cells by interfering with ERK signaling, with or without reduced SMAD signaling. Therefore, the introduction of the clinical application of Spred2 has great potential for development as a gene therapy approach for CRC.

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“…All tumour areas were then laser capture microdissected and RNA extracted using a FFPE optimised protocol as previously published [4–6]. cDNA was synthesised (Transcriptor, Roche Diagnostics) and pre-amplified using specific target amplification.…”

Section: Methodsmentioning

confidence: 99%

Multi-transcript profiling in archival diagnostic prostate cancer needle biopsies to evaluate biomarkers in non-surgically treated men

2014

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BackgroundMost biomarkers in prostate cancer have only been evaluated in surgical cohorts. The value of these biomarkers in a different therapy context remains unclear. Our objective was to test a panel of surgical biomarkers for prognostic value in men treated by external beam radiotherapy (EBRT) and primary androgen deprivation therapy (PADT).MethodsThe Fluidigm® PCR array was used for multi-transcript profiling of laser microdissected tumours from archival formalin-fixed diagnostic biopsies of patients treated by EBRT or PADT. Cases were matched for disease characteristics and had known 5 year biochemical relapse outcomes (n = 60). Results were validated by immunohistochemistry in a custom needle biopsy tissue microarray. Six biomarkers previously tested only in surgical cohorts were analysed (PTEN, E-Cadherin, EGFR, EZH2, PSMA, MSMB). Transcript and protein expression was correlated with clinical outcome analysed using Kruskal Wallis, Fisher’s test and Cox proportional hazard model.ResultsAltered expression of E-Cadherin (p = 0.008) was associated with early relapse after EBRT. In PADT treated men however only altered MSMB transcript was prognostic for early relapse (p = 0.001). The remaining biomarkers however did not demonstrate prognostic ability in either cohort. In a separate tissue array we validated altered E-Cadherin protein as a predictor of early relapse after EBRT (n = 47) (HR 0.34, CI p = 0.02) but not in PADT treated men (n = 63).ConclusionWe demonstrate proof of principle of multiple transcript profiling in archival diagnostic biopsies of non-surgically treated men for biomarker discovery. We identify a role for E-Cadherin as a novel biomarker of early relapse following EBRT.

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Evidence for downregulation of the negative regulator SPRED2 in clinical prostate cancer

Cited by 31 publications

References 14 publications

The Sprouty/Spred family as tumor suppressors: Coming of age

The Sprouty/Spred family as tumor suppressors: Coming of age

Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

Multi-transcript profiling in archival diagnostic prostate cancer needle biopsies to evaluate biomarkers in non-surgically treated men

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