Sprouty2 but not Sprouty4 is a potent inhibitor of cell proliferation and migration of osteosarcoma cells

Rathmanner, Nadine; Haigl, Barbara; Vanas, Vanita; Doriguzzi, Angelina; Gsur, Andrea; Sutterlüty, Hedwig

doi:10.1016/j.febslet.2013.06.040

Cited by 26 publications

(43 citation statements)

References 46 publications

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“…Spry2 has been found to inhibit cellular functions central to malignant behavior of cancer cells, including cell proliferation, differentiation, migration and invasion, in leiomyosarcoma, osteosarcoma, hepatocellular carcinoma, neuroblastoma, B‐cell lymphoma, non‐small cell lung cancer (NSCLC), cervical cancer – and breast cancer cells. Lo et al .…”

Section: Discussionmentioning

confidence: 99%

Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer

et al. 2015

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Sprouty proteins are evolutionary-conserved modulators of receptor tyrosine kinase signaling, deregulation of which has been implicated in the pathophysiology of cancer. In the present study, the expression status of Spry2 and Spry4 proteins and its clinical relevance in human epithelial ovarian cancer (EOC) were investigated retrospectively. We examined the immunohistochemical expression of Spry2 and Spry4 in matched tumor and normal tissue samples from 99 patients. The expression of ERK, p-ERK, Ki67, fibroblast growth factor-2, vascular endothelial growth factor and interleukin-6 and their correlation with Sprouty homologs were also evaluated. Moreover, the correlation between Spry2 and Spry4 and the clinicopathological characteristics were analyzed along with their predictive value for overall survival (OS) and disease-free survival (DFS). Our data indicated significant downregulation of Spry2 and Spry4 in tumor tissues (p < 0.0001). A significant inverse correlation was evident between Spry2 and p-ERK/ERK (p 5 0.048), Ki67 (p 5 0.011), disease stage (p 5 0.013), tumor grade (p 5 0.003), recurrence (p < 0.001) and post-treatment ascites (p 5 0.001), individually. It was found that Spry2 low-expressing patients had significantly poorer OS (p 5 0.002) and DFS (p 5 0.004) than those with high expression of Spry2. Multivariate analysis showed that high Spry2 (p 5 0.018), low stage (p 5 0.049) and no residual tumor (p =0.006) were independent prognostic factors for a better OS. With regard to DFS, high Spry2 (p 5 0.044) and low stage (p 5 0.046) remained as independent predictors. In conclusion, we report for the first time significant downregulation of Spry2 and Spry4 proteins in human EOC. Spry2 expression was revealed to significantly impact tumor behavior with predictive value as an independent prognostic factor for survival and recurrence.Epithelial ovarian cancer (EOC) is the second most common cause of gynecological cancer-related deaths worldwide. In Australia, it is the second most commonly diagnosed and the most lethal gynecological cancer, comprising 4.8% of all cancer deaths in women.1 Most patients with EOC have the advanced disease at diagnosis. The late presentation and widespread abdominal metastasis account for the high death rate. 2 Despite invasive surgery and platinum-based cytotoxic chemotherapy as the standard of care for the advanced disease, episodes of recurrent disease, progressively shorter disease-free intervals and resistance to chemotherapy will develop in most cases. 3 Since discovery in 1998, 4 Sprouty proteins have been increasingly implicated in the multilayered, complex regulation of MAPK/ERK pathway and receptor tyrosine kinase (RTK) signaling.5 As such, this protein family has been shown to regulate processes central to the development, progression and dissemination of malignant conditions, including cell proliferation, migration, invasion and survival. 6 For the past decade, deregulation of Sprouty has been investigated in a variety of cancers.7 However, the status and clinico...

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Section: Discussionmentioning

confidence: 99%

Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer

et al. 2015

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“…Identifying Spry2 as an inducible, negative regulator of HGF/SF-induced activation of ERK and AKT, Lee et al [63] reported in 2004 that Spry2 inhibits proliferation, anchorage-independent growth, migration, and invasion of SK-LMS-1 human leiomyosarcoma cells in vitro . Rathmanner et al reported that Spry2, but not Spry4, potently inhibits proliferation and interfere with migration of human osteosarcoma-derived cells, with the N-terminal sequence variation being implicated in the specific inhibitory effect of Spry2 [169]. Osteosarcoma cell invasion was also shown to be impeded by overexpressed Spry1 as a result of interaction with uPAR [59].…”

Section: Deregulation Of Sprouty In Cancermentioning

confidence: 99%

The developing story of Sprouty and cancer

Masoumi-Moghaddam

Amini

Morris

2014

Cancer Metastasis Rev

140

181

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Sprouty proteins are evolutionarily conserved modulators of MAPK/ERK pathway. Through interacting with an increasing number of effectors, mediators, and regulators with ultimate influence on multiple targets within or beyond ERK, Sprouty orchestrates a complex, multilayered regulatory system and mediates a crosstalk among different signaling pathways for a coordinated cellular response. As such, Sprouty has been implicated in various developmental and physiological processes. Evidence shows that ERK is aberrantly activated in malignant conditions. Accordingly, Sprouty deregulation has been reported in different cancer types and shown to impact cancer development, progression, and metastasis. In this article, we have tried to provide an overview of the current knowledge about the Sprouty physiology and its regulatory functions in health, as well as an updated review of the Sprouty status in cancer. Putative implications of Sprouty in cancer biology, their clinical relevance, and their proposed applications are also revisited. As a developing story, however, role of Sprouty in cancer remains to be further elucidated.

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“…The proliferative effect of Spry 2 knock down may also be attributed to enhanced Erk activity, as Erk is also a potent regulator of MSC proliferation in response to many stimuli [Rodrigues et al, ]. Interestingly, Spry 2 expression has been shown to interfere with Erk activation after stimulation of osteoblasts and to inhibit cell proliferation and migration in osteosarcoma‐derived cells [Yang et al, ; Rathmanner et al, ].…”

Section: Discussionmentioning

confidence: 99%

Sprouty 2 , an Early Response Gene Regulator of FosB and Mesenchymal Stem Cell Proliferation During Mechanical Loading and Osteogenic Differentiation

et al. 2017

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Sprouty 2 (Spry2), an inhibitor of MAP kinase signaling was previously shown by our group to be induced during mechanical loading of mesenchymal stem cells (MSCs). Here, we studied the implication of Spry2 activation during mechanical loading and chemically induced MSC differentiation. Spry 2 expression showed an immediate early response during mechanical loading and chemical induction of osteogenic differentiation and followed the same pattern as osteogenic associated gene FosB and was necessary for the induction of FosB, as Spry 2 knock down also abrogated the upregulation of FosB expression. Spry 2 knock down was, also associated with an early response of the osteogenic genes Runx-2 and ALP. Neither the knock-down of Spry 2 nor the subsequent reduction in FosB had any effect on mid-late osteogenesis or mineralization but was associated with a significant increase in proliferation of MSC. These effects were possibly governed by negative regulation of MEK/Erk signaling as Spry 2 knock down resulted in an increase in phosphorylation of Erk1/2. In summary, our results shows the involvement of Spry2 in regulation of FosB and Runx2 genes, MAPK signaling and proliferation of MSC. Taken together these results suggest a possible role for Spry2 in regulation of MSC functions in response to mechanical loading and osteogenic differentiation. J. Cell. Biochem. 118: 2606-2614, 2017. © 2017 Wiley Periodicals, Inc.

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Sprouty2 but not Sprouty4 is a potent inhibitor of cell proliferation and migration of osteosarcoma cells

Cited by 26 publications

References 46 publications

Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer

Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer

The developing story of Sprouty and cancer

Sprouty 2 , an Early Response Gene Regulator of FosB and Mesenchymal Stem Cell Proliferation During Mechanical Loading and Osteogenic Differentiation

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