Sprouty4 interferes with cell proliferation and migration of breast cancer-derived cell lines

Vanas, Vanita; Mühlbacher, Elsa; Kral, Rosana; Sutterlüty, Hedwig

doi:10.1007/s13277-013-1587-0

Cited by 28 publications

(38 citation statements)

References 32 publications

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“…In agreement with an earlier study (27), the Spry4 levels were found to be differentially expressed depending on the subtype. The luminal subtypes of breast cancer demonstrated a decreased expression of the two Spry4 variants compared with the basal subtype.…”

Section: Discussionsupporting

confidence: 92%

“…Spry proteins modulate the intensity and duration of the transmitted signals within such cascades, and therefore are important for the tumorigenesis of various tissues. Spry4 has been previously shown to fulfil a tumour suppressive function in lung (26) and breast (27) cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its involvement in breast cancer (27), Spry4 has also been shown to function as a tumour suppressor in lung cancer (26). Therefore, the present study subsequently analysed the expression of each Spry4 variant in lung cancer-derived cell lines and compared the determined levels with those evaluated for nHBEpCs.…”

Section: Expression Of Spry41 and Spry42 In Lung-derived Cellsmentioning

confidence: 99%

“…Although Spry4 has been less intensively studied in comparison to Spry2 and Spry1, the literature documents that the likelihood of Spry4 to act as a tumour suppressor may be dependent on the cancer origin. Spry4 has previously failed to significantly influence malignant phenotypes in cancer originating from the bones (24), ovary (21) or pancreas (25), while it fulfils all features of a tumour suppressor when the cancer has developed from lung (26) or breast tissue (27) cells. This includes an overall decrease in Spry4 expression in cancerous tissues compared with the normal tissue counterparts (26,28).…”

Section: Introductionmentioning

confidence: 99%

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Sprouty4 mRNA variants and protein expressions in breast and lung-derived cells

2016

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Ab st rac t . Sp rout y p rot ei ns a r e mo du lat or s of mitogen-induced signalling processes and are therefore hypothesized to affect malignant diseases. As a member of the Sprouty family, Sprouty4 has been previously shown to function as a tumour suppressor in lung and breast cancer. The present study analysed the expression of two known Sprouty4 splice variants in cells established from malignant and normal lung and breast tissues using semi-quantitative reverse transcription-polymerase chain reaction and immunoblotting. The results indicated that the expression of the two messenger RNA (mRNA) variants was reduced in the cells derived from malignant tissue in comparison to the normal counterparts. Although the expression of the two splice variants were associated in both tissue types, on average, the relative expression of the longer variant was slightly increased in malignant cells compared with normal tissues. Notably, the protein levels reflected the expression observed at the mRNA level only in breast-derived cells. Contrarily, with regards to the measured mRNA levels, Sprouty4 protein was disproportional augmented in lung cells known to harbour the mutated K-Ras gene. IntroductionThe alteration of important molecules involved in signal transduction is a common characteristic of all malignant cells (1). The mitogen activated protein kinase (MAPK) pathway, which is crucially involved in balancing cell death and differentiation on one side and proliferation and migration on the other, is one of the best described signalling routes that is deregulated in cancer (2). Due to the vital role of the MAPK pathway, numerous feedback loops are present to allow a fine-tuning of signal intensity and duration (3). Certain molecules acting in such a regulatory loop are the members of the Sprouty (Spry) protein family. First discovered in Drosophila (4,5), the Spry proteins counteract processes induced by the presence of various growth factors. In humans, 4 Spry family members are known; all of which share a conserved Spry domain at the C-terminus and 2 homolog N-terminal boxes (6). As indicated by knockout studies in mice, the functions of Sprouty proteins overlap but are not redundant (7-10). Although Spry1, Spry2 and Spry4 can be detected in all organs, their expression pattern in the various cell types is clearly distinguishable (11). Like in Drosophila, mammalian Spry proteins interfere with signal transduction, particularly in the MAPK pathway, in response to various mitogens, such as the members of the fibroblast growth factors (6). In contrast to Drosophila, in mammalian systems, signalling activated by epidermal growth factor is increased with augmented Spry expression. Therefore, the Spry proteins in humans are generally considered as modulators of signal transduction (12). Accordingly, dependent on the tumour type, Spry proteins are found to fulfil multiple roles in cancer. For example, Spry2 has been indicated to function as an oncogene in colon cancer (13,14) and Spry1 has a tumour promoting role in rhabd...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Expression Of Spry41 and Spry42 In Lung-derived Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sprouty4 mRNA variants and protein expressions in breast and lung-derived cells

2016

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“…Wang et al reported that SPRY4 can serve as a suppressor of tumor cell motility and is down regulated by DNA methylation in human prostate cancer [6]. In addition, in human breast cancer, ectopic SPRY4 expression can inhibit cell proliferation and migration of breast cancer cell lines [7]. SPRY4 can also inhibit cell proliferation and migration in non-small cell lung cancer [8].…”

Section: Introductionmentioning

confidence: 99%

Lower Expression of SPRY4 Predicts a Poor Prognosis and Regulates Cell Proliferation in Colorectal Cancer

Zhou¹,

Xie

Yuan

et al. 2016

Cell Physiol Biochem

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Background/Aims: Colorectal cancer (CRC) is the third most common type of cancer worldwide. Sprouty proteins are modulators of mitogeninduced signal transduction processes and therefore can influence the process of cancerogenesis. The encoded protein of Sprouty homolog 4 (SPRY4) is associated with various human cancers. However, its biological role and clinical significance in CRC development and progression are unknown. Methods: The aim of this study was to evaluate the expression and biological role of SPRY4 in colorectal cancer. qRT-PCR was performed to investigate the expression of SPRY4 in tumor tissues and corresponding non tumor colorectal tissues from 70 patients. The effect of SPRY4 on proliferation was evaluated by MTT and colony formation assays. CRC cells transfected with SPRY4 were injected into nude mice to study the effect of SPRY4 on tumorigenesis in vivo. Results: The lower expression of SPRY4 was remarkably correlated with deep tumor invasion and advanced TNM stage. Multivariate analyses revealed that SPRY4 expression served as an independent predictor for overall survival. Using 5-aza treatment, we also observed that SPRY4 expression can be affected by DNA methylation. Further experiments revealed that overexpressed SPRY4 significantly inhibited CRC cell proliferation both in vitro and in vivo. Conclusion: Our study demonstrated that SPRY4 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that SPRY4 may be a potential diagnostic and prognostic target in patients with colorectal cancer.

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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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Sprouty4 interferes with cell proliferation and migration of breast cancer-derived cell lines

Cited by 28 publications

References 32 publications

Sprouty4 mRNA variants and protein expressions in breast and lung-derived cells

Sprouty4 mRNA variants and protein expressions in breast and lung-derived cells

Lower Expression of SPRY4 Predicts a Poor Prognosis and Regulates Cell Proliferation in Colorectal Cancer

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

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