Gene Summary

Gene:SPRY4; sprouty RTK signaling antagonist 4
Aliases: HH17
Summary:This gene encodes a member of a family of cysteine- and proline-rich proteins. The encoded protein is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. Activity of this protein impairs the formation of active GTP-RAS. Nucleotide variation in this gene has been associated with hypogonadotropic hypogonadism 17 with or without anosmia. Alternative splicing results in a multiple transcript variants. [provided by RefSeq, Jun 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein sprouty homolog 4
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Epigenetics
  • BAK1
  • Testicular Cancer
  • Cancer Gene Expression Regulation
  • Genetic Association Studies
  • Apoptosis
  • Molecular Sequence Data
  • Cell Proliferation
  • Serpins
  • Gene Knockdown Techniques
  • Nerve Tissue Proteins
  • Tumor Suppressor Proteins
  • Transfection
  • Neoplasm Invasiveness
  • Ovarian Cancer
  • Epithelial-Mesenchymal Transition
  • Germ Cell Tumours
  • Transcription Factors
  • Skin Cancer
  • Melanoma
  • Stomach Cancer
  • MAP Kinase Signaling System
  • Genetic Predisposition
  • Case-Control Studies
  • Base Sequence
  • Young Adult
  • Neoplasm Metastasis
  • Long Noncoding RNA
  • Single Nucleotide Polymorphism
  • Genome-Wide Association Study
  • Carcinogenesis
  • Mutation
  • Cell Movement
  • Chromosome 5
  • Membrane Proteins
  • Gene Expression Profiling
  • Tumor Microenvironment
  • Oligonucleotide Array Sequence Analysis
  • Biomarkers, Tumor
  • Intracellular Signaling Peptides and Proteins
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SPRY4 (cancer-related)

Zhou X, Xie S, Yuan C, et al.
Lower Expression of SPRY4 Predicts a Poor Prognosis and Regulates Cell Proliferation in Colorectal Cancer.
Cell Physiol Biochem. 2016; 40(6):1433-1442 [PubMed] Related Publications
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.

Zhou M, Zhang XY, Yu X
Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma.
Biomed Pharmacother. 2017; 85:348-354 [PubMed] Related Publications
BACKGROUND: Increasing evidences have demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may act as an important role in tumor progression. The long non-coding RNA SPRY4 intronic transcript 1 (SPRY4-IT1) has been reported in some cancer including regulating cell growth, differentiation, apoptosis, and cancer progression. However, the expression and function of SPRY4-IT1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown.
METHODS: The lncRNA SPRY4-IT1 was detected by quantitative real time PCR (qRT-PCR) in HCC cell lines, CCK8 cell proliferation and transwell invasion assays were performed to detect the GC cell proliferation and invasion abilities. The protein expression of E-cadherin, Vimentin and Twist1 was analyzed by Western blotting assays. Furthermore, RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assays were used to analyze potential molecular mechanism of SPRY4-IT1 in HCC cells.
RESULTS: We found that SPRY4-IT1 was up-regulated in HCC cell lines. Further function analysis demonstrated that knockdown of SPRY4-IT1 significantly inhibited HCC cells proliferation and invasion, but over-expression of SPRY4-IT1 had the opposite effects on HCC cells in vitro. Moreover, our results also indicated that SPRY4-IT1 over-expression significantly promoted the epithelial-mesenchymal transition (EMT) by up-regulating the transcription factor Twist1 and EMT marker Vimentin and inhibited the E-cadherin expression in MHCC97L cell. Whereas, knockdown of SPRY4-IT1 suppressed the transcription factor Twist1 and EMT marker Vimentin and increased the E-cadherin expression in MHCC97H cells. Mechanisms investigations showed that SPRY4-IT1 interacted with the EZH2 and epigenetically repressed the E-cadherin expression. In vivo, we also demonstrated that the tumor growth was inhibited in SPRY4-IT1 knockdown group compared with the control group.
CONCLUSIONS: These results suggested that lncRNA SPRY4-IT1 might be considered as a therapeutic target in HCC.

Jing W, Gao S, Zhu M, et al.
Potential diagnostic value of lncRNA SPRY4-IT1 in hepatocellular carcinoma.
Oncol Rep. 2016; 36(2):1085-92 [PubMed] Related Publications
The manifestation of hepatocellular carcinoma (HCC) involves a multi-factor, multi-step and complex process. Due to the lack of early prediction indices, numerous patients are diagnosed in their late stage. Recently, research in the field of non-coding RNAs (ncRNAs) has changed the original idea that ncRNA genes are just ̔noise̓. Cumulative evidence shows that long non-coding RNAs (lncRNAs) among ncRNAs play an increasingly important role in epigenetics, pre-transcription and post-transcription. In the present study, we focused on the expression pattern of lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) and its clinical significance in HCC diagnostics. We analyzed the expression, its association with clinical characteristics and the diagnostic value of SPRY4-IT1 using HCC tissues, cell lines and plasma. The levels of SPRY4-IT1 were upregulated in HCC and were associated with tumor differentiation (r=0.249, p=0.039), tumor size (r=0.258, p=0.024) and tumor-node-metastasis (TNM) stage (r=0.287, p=0.015). Meanwhile, the sensitive of SPRY4-IT1 was 87.3% in differentiating HCC patients from controls. Our data suggest that SPRY4-IT1 plays a critical role in HCC tumorigenesis and may be considered as a potential diagnostic indicator in HCC.

Cui F, Wu D, He X, et al.
Long noncoding RNA SPRY4-IT1 promotes esophageal squamous cell carcinoma cell proliferation, invasion, and epithelial-mesenchymal transition.
Tumour Biol. 2016; 37(8):10871-6 [PubMed] Related Publications
The biology of esophageal squamous cell carcinoma (ESCC) remains poorly understood. Long noncoding RNAs (lncRNAs) are found to be dysregulated in a variety of cancers, including ESCC. SPRY4-IT1 has been recently revealed as oncogenic regulator or tumor suppressors in different cancers; however, whether SPRY4-IT1 is involved in ESCC remains poorly understood. To investigate the role of SPRY4-IT1 in ESCC, we evaluated the SPRY4-IT1 expression levels in a series of ESCC patients and a panel of ESCC cell line using qRT-PCR. CCK8 and colony formation assay were performed to assess the effect of SPRY4-IT1siRNA on cell proliferation, migration, and invasion of ESCC cell lines. SPRY4-IT1 expression was upregulated in ESCC tissues and the higher expression of SPRY4-IT1 was significantly correlated with tumor grade, depth of invasion, and lymph node metastasis. Moreover, silencing of SPRY4-IT1 expression inhibited ESCC cell proliferation, colony formation, migration, and invasion. Therefore, our study indicates that SPRY4-IT1 promotes proliferation and migration of ESCC cells and is a potential oncogene of ESCC.

Taniue K, Kurimoto A, Sugimasa H, et al.
Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1.
Proc Natl Acad Sci U S A. 2016; 113(5):1273-8 [PubMed] Free Access to Full Article Related Publications
Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.

So WK, Cheng JC, Liu Y, et al.
Sprouty4 mediates amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells.
Tumour Biol. 2016; 37(7):9197-207 [PubMed] Related Publications
Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase (RTK)-mediated activation of cellular signaling pathways. The down-regulation of SPRY4 expression has been reported in human ovarian cancer. However, the specific roles and mechanisms by which SPRY4 affects ovarian cancer progression are completely unknown. Amphiregulin (AREG) binds exclusively to the epidermal growth factor receptor (EGFR) and has been considered to be a dominant autocrine/paracrine EGFR ligand in ovarian cancer. In the present study, we first examined the effects of AREG on SPRY4 expression and the possible underlying molecular mechanisms involved in this process in two human ovarian cancer cell lines. Our results demonstrated that treatment with AREG up-regulated SPRY4 expression by activating the ERK1/2 signaling pathway. In addition, we showed that small interfering RNA (siRNA)-mediated knockdown of SPRY4 attenuated the AREG-induced down-regulation of E-cadherin by inhibiting the expression of SNAIL but not SLUG. In contrast, overexpression of SPRY4 enhanced AREG-induced down-regulation of E-cadherin by increasing the expression of SNAIL. Moreover, SPRY4 knockdown attenuated AREG-induced cell migration and invasion. Overexpression of SPRY4 enhanced AREG-induced cell invasion. This study reveals that SPRY4 is involved in EGFR-mediated human ovarian cancer progression.

Mouraviev V, Lee B, Patel V, et al.
Clinical prospects of long noncoding RNAs as novel biomarkers and therapeutic targets in prostate cancer.
Prostate Cancer Prostatic Dis. 2016; 19(1):14-20 [PubMed] Related Publications
BACKGROUND: The lack of sensitive and specific biomarkers for prostate cancer (PCa) has led to over-diagnosis and overtreatment with uncertain benefit. Therefore, biomarkers for early diagnosis that can distinguish aggressive from indolent tumors and that can detect metastatic or recurrent disease are needed. Long noncoding RNAs (lncRNAs) are non-protein-coding RNA species. lncRNAs are dysregulated in many diseases including PCa and are emerging as major players in cancer development. lncRNAs have several features that make then suitable as both biomarkers and therapeutics, and lncRNAs regulate critical cancer hallmarks in prostate epithelial cells including proliferation and survival.
METHODS: The PubMed database was searched using the terms 'long noncoding RNA', 'biomarker' and 'prostate cancer'. Known lncRNAs implicated as biomarkers and potential therapeutic targets in PCa are reviewed.
RESULTS: We comprehensively review several lncRNAs with potential as biomarkers for PCa. lncRNAs including PCA3, PCATs, SChLAP1, SPRY4-IT1 and TRPM2-AS are upregulated in PCa and are cancer specific; they are, therefore, attractive lead candidate biomarkers for clinical application. Several lncRNA therapeutics are currently being investigated by several companies for the treatment of various cancers including PCa. Small interfering RNAs, antisense oligonucleotides, ribozymes, deoxyribozymes and aptemers are few promising technologies for future lncRNA bases therapeutics.
CONCLUSION: lncRNA expression is altered in cancer. Aberrant regulation promotes tumor formation, progression and metastasis. lncRNAs can use as tumor markers for PCa and may be attractive novel therapeutic targets for the diagnosis and treatment of PCa.

Liu H, Lv Z, Guo E
Knockdown of long noncoding RNA SPRY4-IT1 suppresses glioma cell proliferation, metastasis and epithelial-mesenchymal transition.
Int J Clin Exp Pathol. 2015; 8(8):9140-6 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs), a class of ribonucleic molecules, participate in various cellular processes. They are highly expressed in several types of cancer and their expression was related to pathophysiological characteristics of tumor growth, therefore, they can be considered as a promising diagnostic tool and a convenient prognostic biomarker. SPRY4-IT1, belonging to a group of intron-retained lncRNAs, was reported to affect tumor development of many types of cancer. However, the expression and the role of SPRY4-IT1 in glioma are still unclear. Therefore, in this study, we examined for the first time the expression and role of SPRY4-IT1 in glioma cells. The results of our study showed that SPRY4-IT1 was up-regulated in human glioma tissues and cell lines. Knockdown of SPRY4-IT1 could inhibit glioma cell growth and migration. Moreover, knockdown of SPRY4-IT1 could inhibit epithelial-mesenchymal transition (EMT) phenotype in glioma cells. Based on these findings, SPRY4-IT1 may be used as a new target for diagnosis and treatment of glioma.

Shaverdashvili K, Zhang K, Osman I, et al.
MT1-MMP dependent repression of the tumor suppressor SPRY4 contributes to MT1-MMP driven melanoma cell motility.
Oncotarget. 2015; 6(32):33512-22 [PubMed] Free Access to Full Article Related Publications
Metastatic melanoma is the deadliest of all skin cancers. Despite progress in diagnostics and treatment of melanoma, the prognosis for metastatic patients remains poor. We previously showed that Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) is one of the drivers of melanoma metastasis. Classically, MT1-MMP regulates a verity of cellular functions including cell-to-cell interaction and cell-to-matrix communication. Recently, MT1-MMP has been found to also modulate gene expression. To specifically assess MT1-MMP dependent gene regulation in melanoma, microarray gene expression analysis was performed in a melanoma cell line whose metastatic properties depend on the activity of MT1-MMP. We identified the tumor suppressor gene SPRY4 as a new transcriptional target of MT1-MMP that is negatively regulated by the protease. Knockdown of MT1-MMP enhances SPRY4 expression at the mRNA and protein level. SPRY4 expression inversely correlates with that of MT1-MMP in melanoma samples and importantly, correlates with melanoma patient survival. SPRY4 modulates MT1-MMP dependent cell migration such that inhibition of SPRY4 rescues cell migration that has been impaired by MT1-MMP knock down. MT1-MMP decreases SPRY4 in part through an MMP2/RAC1 axis we previously show promotes cell motility downstream of MT1-MMP. These results identify the tumor suppressor SPRY4 as a novel molecular effector of MT1-MMP affecting melanoma cell motility.

Sun M, Huang F, Yu D, et al.
Autoregulatory loop between TGF-β1/miR-411-5p/SPRY4 and MAPK pathway in rhabdomyosarcoma modulates proliferation and differentiation.
Cell Death Dis. 2015; 6:e1859 [PubMed] Free Access to Full Article Related Publications
The origin of rhabdomyosarcoma (RMS) remains controversial. However, specific microRNAs (miRNAs) are downregulated in RMS and it is possible that re-expression of these miRNAs may lead to differentiation. Transforming growth factor-β1 (TGF-β1) is known to block differentiation of RMS. We therefore analyzed miRNA microarrays of RMS cell lines with or without TGF-β1 knockdown and identified a novel anti-oncogene miR-411-5p. Re-expression of miR-411-5p inhibited RMS cell proliferation in vitro and tumorigenicity in vivo. Using a luciferase reporting system and sequence analysis, the potential target of miR-411-5p was identified as sprouty homolog 4 (SPRY4), which inhibits protein kinase Cα-mediated activation of mitogen-activated protein kinases (MAPKs), especially p38MAPK phosphorylation. These results revealed an inverse correlation between TGF-β1/SPRY4 and miR-411-5p levels. SPRY4 small interfering RNA and miR-411-5p both activated p38MAPK phosphorylation and also promoted apoptosis and myogenic differentiation, indicated by increased caspase-3, myosin heavy chain, and myosin expression. SPRY4 and miR-411 mRNA levels correlated with TGF-β1 expression levels in RMS tissues, which was confirmed by immunohistochemical staining for TGF-β1, SPRY4, and phosphorylated p38MAPK proteins. Overall, these results indicate that miR-411-5p acts as an RMS differentiation-inducing miRNA prompting p38MAPK activation via directly downregulating SPRY4. These results establish an autoregulatory loop between TGF-β1/miR-411-5p/SPRY4 and MAPK in RMS, which governs the switch between proliferation and differentiation.

Ramsdale R, Jorissen RN, Li FZ, et al.
The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma.
Sci Signal. 2015; 8(390):ra82 [PubMed] Related Publications
Most patients with BRAF-mutant metastatic melanoma display remarkable but incomplete and short-lived responses to inhibitors of the BRAF kinase or the mitogen-activated protein kinase kinase (MEK), collectively BRAF/MEK inhibitors. We found that inherent resistance to these agents in BRAF(V600)-mutant melanoma cell lines was associated with high abundance of c-JUN and characteristics of a mesenchymal-like phenotype. Early drug adaptation in drug-sensitive cell lines grown in culture or as xenografts, and in patient samples during therapy, was consistently characterized by down-regulation of SPROUTY4 (a negative feedback regulator of receptor tyrosine kinases and the BRAF-MEK signaling pathway), increased expression of JUN and reduced expression of LEF1. This coincided with a switch in phenotype that resembled an epithelial-mesenchymal transition (EMT). In cultured cells, these BRAF inhibitor-induced changes were reversed upon removal of the drug. Knockdown of SPROUTY4 was sufficient to increase the abundance of c-JUN in the absence of drug treatment. Overexpressing c-JUN in drug-naïve melanoma cells induced similar EMT-like phenotypic changes to BRAF inhibitor treatment, whereas knocking down JUN abrogated the BRAF inhibitor-induced early adaptive changes associated with resistance and enhanced cell death. Combining the BRAF inhibitor with an inhibitor of c-JUN amino-terminal kinase (JNK) reduced c-JUN phosphorylation, decreased cell migration, and increased cell death in melanoma cells. Gene expression data from a panel of melanoma cell lines and a patient cohort showed that JUN expression correlated with a mesenchymal gene signature, implicating c-JUN as a key mediator of the mesenchymal-like phenotype associated with drug resistance.

Xie M, Nie FQ, Sun M, et al.
Decreased long noncoding RNA SPRY4-IT1 contributing to gastric cancer cell metastasis partly via affecting epithelial-mesenchymal transition.
J Transl Med. 2015; 13:250 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as key regulators governing fundamental biological processes, and their disorder expression involves in tumorigenesis. SPRY4-IT1 (SPRY4 intronic transcript 1), a lncRNA derived from an intron within SPRY4 gene, involves in multiple cancers development. However, the expression pattern and biological function of SPRY4-IT1 in gastric cancer is still not well documented. Hence, we carried out the present study to investigate the potential role of SPRY4-IT1 in gastric carcinogenesis.
METHODS: QRT-PCR was performed to detect the expression of SPRY4-IT1 in 61 pairs of gastric cancer samples. Over-expression and RNA interference (RNAi) approaches were used to investigate the biological functions of SPRY4-IT1. The effect of SPRY4-IT1 on proliferation was evaluated by MTT and colony formation assays. Gastric cancer cells transfected with pCDNA-SPRY4-IT1 were injected into nude mice to study the effect of SPRY4-IT1 on tumorigenesis and metastasis in vivo. Protein levels of SPRY4-IT1 targets were determined by western blot or fluorescence immunohistochemistry. ChIP assays were performed to investigate the effect of DNMT1 on SPRY4-IT1 expression. Differences between groups were tested for significance using Student's t test (two-tailed).
RESULTS: SPRY4-IT1 expression is decreased in gastric cancer tissues and associated with larger tumor size, advanced pathological stage, deeper depth of invasion and lymphatic metastasis. Patients with lower SPRY4-IT1 expression had a relatively poor prognosis. DNA methylation may be a key factor in controlling the SPRY4-IT1 expression. Furthermore, SPRY4-IT1 contributed to gastric cancer cells metastasis might partly via regulating epithelial-mesenchymal transition (EMT) process.
CONCLUSION: Low expression of SPRY4-IT1 is involved in progression and metastasis of gastric cancer and may represent a novel biomarker of poor prognosis in patients with gastric cancer.

Zhao XL, Zhao ZH, Xu WC, et al.
Increased expression of SPRY4-IT1 predicts poor prognosis and promotes tumor growth and metastasis in bladder cancer.
Int J Clin Exp Pathol. 2015; 8(2):1954-60 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: long non-coding RNAs (lncRNAs) are emerging as new regulators in the cancer paradigm, the involvement of lncRNAs in urothelial carcinoma of the bladder (UCB) is just beginning to be studied. In this study, we focused on lncRNA SPRY4-IT1 and investigated its expression pattern, clinical significance, and biological function in UCB.
METHODS: SPRY4-IT1 expression in UCB tissues was examined by quantitative Real-time PCR (qRT-PCR) and its correlation with clinicopathological features and patient prognosis was later analyzed. Moreover, in vitro assays were performed to explore its role in bladder cancer progression.
RESULTS: SPRY4-IT1 expression was elevated in UCB tissues, and SPRY4-IT1 levels were highly positively correlated with histological grade, tumor stage, and lymph node metastasis and reduced overall survival. A multivariate analysis showed that SPRY4-IT1 expression is an independent prognostic factor of overall survival in patients with UCB. Additionally, the results of in vitro assays showed that the suppression of SPRY4-IT1 expression in bladder cancer cells significantly inhibit cell proliferation, migration, and invasion.
CONCLUSIONS: Our data suggested that lncRNA SPRY4-IT1 is a novel molecule involved in bladder cancer progression, which provide a potential prognostic biomarker and therapeutic target.

Peng W, Wu G, Fan H, et al.
Long noncoding RNA SPRY4-IT1 predicts poor patient prognosis and promotes tumorigenesis in gastric cancer.
Tumour Biol. 2015; 36(9):6751-8 [PubMed] Related Publications
Gastric cancer (GC) is the second common cause of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) are emerging as novel regulators in the cancer paradigm. However, investigation of lncRNAs on GC is still in its infancy. In this study, we focused on lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) and investigated its expression pattern, clinical significance, biological function, and molecular mechanism in GC. SPRY4-IT1 expression was examined, and its correlation with clinicopathological characteristics and patient prognosis was analyzed. A series of assays were performed to understand the role of SPRY4-IT1 in GC. SPRY4-IT1 expression was elevated in GC tissues and cell lines, and SPRY4-IT1 levels were highly positively correlated with tumor size, invasion depth, distant metastasis, TNM stage, and reduced overall survival (OS) and disease-free survival (DFS). A multivariate analysis showed that SPRY4-IT1 expression is an independent prognostic factor of OS and DFS in patients with GC. Additionally, the results of in vitro assays showed that the suppression of SPRY4-IT1 expression in GC cell line MKN-45 significantly reduced cell proliferation, colony formation, and cell migration/invasion. Moreover, the tumorigenic effects of SPRY4-IT1 were partially mediated by the regulation of certain cyclins and matrix metalloproteinases (MMPs)-related genes. Our data suggest that SPRY4-IT1 plays a critical role in GC tumorigenesis and may represent a novel prognostic marker and potential therapeutic target in patients with GC.

Elzinga-Tinke JE, Dohle GR, Looijenga LH
Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis.
Asian J Androl. 2015 May-Jun; 17(3):381-93 [PubMed] Free Access to Full Article Related Publications
Malignant testicular germ cell tumors (TGCT) are the most frequent cancers in Caucasian males (20-40 years) with an 70% increasing incidence the last 20 years, probably due to combined action of (epi)genetic and (micro)environmental factors. It is expected that TGCT have carcinoma in situ(CIS) as their common precursor, originating from an embryonic germ cell blocked in its maturation process. The overall cure rate of TGCT is more than 90%, however, men surviving TGCT can present long-term side effects of systemic cancer treatment. In contrast, men diagnosed and treated for CIS only continue to live without these long-term side effects. Therefore, early detection of CIS has great health benefits, which will require an informative screening method. This review described the etiology and early pathogenesis of TGCT, as well as the possibilities of early detection and future potential of screening men at risk for TGCT. For screening, a well-defined risk profile based on both genetic and environmental risk factors is needed. Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development. Prenatal, perinatal, and postnatal environmental factors also influence the onset of CIS. A noninvasive early detection method for CIS would be highly beneficial in a clinical setting, for which specific miRNA detection in semen seems to be very promising. Further research is needed to develop a well-defined TGCT risk profile, based on gene-environment interactions, combined with noninvasive detection method for CIS.

Shi Y, Li J, Liu Y, et al.
The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression.
Mol Cancer. 2015; 14:51 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged recently as a new class of genes that regulate cellular processes, such as cell growth and apoptosis. The SPRY4 intronic transcript 1 (SPRY4-IT1) is a 708-bp lncRNA on chromosome 5 with a potential functional role in tumorigenesis. The clinical significance of SPRY4-IT1 and the effect of SPRY4-IT1 on cancer progression are unclear.
METHODS: Quantitative reverse transcriptase PCR (qRT-PCR) was performed to investigate the expression of SPRY4-IT1 in 48 breast cancer tissues and four breast cancer cell lines. Gain and loss of function approaches were used to investigate the biological role of SPRY4-IT1 in vitro. Microarray bioinformatics analysis was performed to identify the putative targets of SPRY4-IT1, which were further verified by rescue experiments, and by western blotting and qRT-PCR.
RESULTS: SPRY4-IT1 expression was significantly upregulated in 48 breast cancer tumor tissues comparedwith normal tissues. Additionally, increased SPRY4-IT1 expression was found to be associated with a larger tumor size and an advanced pathological stage in breast cancer patients. The knockdown of SPRY4-IT1 significantly suppressed proliferation and caused apoptosis of breast cancer cells in vitro. Furthermore, we discovered that ZNF703 was a target of SPRY4-IT1 and was downregulated by SPRY4-IT1 knockdown. Moreover, we provide the first demonstration that ZNF703 plays an oncogenic role in ER (-) breast carcinoma cells.
CONCLUSIONS: SPRY4-IT1 is a novel prognostic biomarker and a potential therapeutic candidate for breast cancer.

Tong YS, Wang XW, Zhou XL, et al.
Identification of the long non-coding RNA POU3F3 in plasma as a novel biomarker for diagnosis of esophageal squamous cell carcinoma.
Mol Cancer. 2015; 14:3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies have demonstrated that long non-coding RNAs (lncRNAs) were present in the blood of cancer patients and have shown great potential as powerful and non-invasive tumor markers. However, little is known about the value of lncRNAs in the diagnosis of esophageal squamous cell carcinoma (ESCC). We hypothesized that ESCC-related lncRNAs might be released into the circulation during tumor initiation and could be utilized to detect and monitor ESCC.
METHODS: Ten lncRNAs (HOTAIR, AFAP1-AS1, POU3F3, HNF1A-AS1, 91H, PlncRNA1, SPRY4-IT1, ENST00000435885.1, XLOC_013104 and ENST00000547963.1) which previously found to be differently expressed in esophageal cancer were selected as candidate targets for subsequent circulating lncRNA assay. A four-stage exploratory study was conducted to test the hypothesis: (1) optimization of detected method to accurately and reproducibly measure ESCC-related lncRNAs in plasma and serum; (2) evaluation of the stability of circulating lncRNAs in human plasma or serum; (3) exploration the origin of ESCC-related lncRNAs in vitro and in vivo; (4) evaluation the diagnostic power of circulating lncRNAs for ESCC.
RESULTS: ESCC-related lncRNAs were detectable and stable in plasma of cancer patients, and derived largely from ESCC tumor cells. Furthermore, plasma levels of POU3F3, HNF1A-AS1 and SPRY4-IT1 were significantly higher in ESCC patients compared with normal controls. By receiver operating characteristic curve (ROC) analysis, among the three lncRNAs investigated, plasma POU3F3 provided the highest diagnostic performance for detection of ESCC (the area under the ROC curve (AUC), 0.842; p < 0.001; sensitivity, 72.8%; specificity, 89.4%). Moreover, use of POU3F3 and SCCA in combination could provide a more effective diagnosis performance (AUC, 0.926, p < 0.001, sensitivity, 85.7%; specificity, 81.4%). Most importantly, this combination was effective to detect ESCC at an early stage (80.8%).
CONCLUSIONS: Plasma POU3F3 could serve as a potential biomarker for diagnosis of ESCC, and the combination of POU3F3 and SCCA was more efficient for ESCC detection, in particular for early tumor screening.

Sarkar D, Leung EY, Baguley BC, et al.
Epigenetic regulation in human melanoma: past and future.
Epigenetics. 2015; 10(2):103-21 [PubMed] Free Access to Full Article Related Publications
The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

So WK, Cheng JC, Fan Q, et al.
Loss of Sprouty2 in human high-grade serous ovarian carcinomas promotes EGF-induced E-cadherin down-regulation and cell invasion.
FEBS Lett. 2015; 589(3):302-9 [PubMed] Related Publications
Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase signaling. Our Human Exonic Evidence-Based Oligonucleotide (HEEBO) microarray results showed that the mRNA levels of SPRY2, but not of SPRY1 or SPRY4, are down-regulated in high-grade serous ovarian carcinoma (HGSC) tissues and epithelial ovarian cancer (EOC) cell lines. Molecular inversion probe (MIP) copy number analysis showed the deletion of the SPRY2 locus in HGSC. Overexpression of SPRY2 reduced EGF-induced cell invasion by attenuating EGF-induced E-cadherin down-regulation. Moreover, a positive correlation between SPRY2 and E-cadherin protein levels was observed in HGSC tissues. This study reveals the loss of SPRY2 in HGSC and indicates an important tumor-suppressive role for SPRY2 in mediating the stimulatory effect of EGF on human EOC progression.

Zhang HM, Yang FQ, Yan Y, et al.
High expression of long non-coding RNA SPRY4-IT1 predicts poor prognosis of clear cell renal cell carcinoma.
Int J Clin Exp Pathol. 2014; 7(9):5801-9 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Long non-coding RNAs (lncRNAs) play a key role in cellular processes, such as cell growth, apoptosis, and carcinogenesis. lncRNAs SPRY4-IT1 has recently been identified to be involved in tumorigenesis of several cancers such as non-small cell lung cancer and esophageal squamous cell carcinoma. However, the role of SPRY4-IT1 in clear cell renal cell carcinoma (ccRCC) remains unclear.
METHODS: The expression of SPRY4-IT1 was examined in ccRCC patients and renal cancer cell lines by using quantitative real-time PCR (qRT-PCR). The relationship between SPRY4-IT1 level and clinicopathological parameters of ccRCC was analyzed with the Kaplan-Meier method and Cox proportional hazards model. Small interfering RNA (siRNA) was used to suppress SPRY4-IT1 expression in renal cancer cell line 786-O. In vitro assays were performed to further explore its role in renal cancer progressio.
RESULTS: The relative level of SPRY4-IT1 was significantly higher in ccRCC tissues compared to the adjacent normal renal tissues. And higher expression of SPRY4-IT1 was found in renal cancer cell lines compared with the normal human proximal tubule epithelial cell line HK-2. The ccRCC patients with higher SPRY4-IT1 expression had an advanced clinical stage and poorer prognosis than those with lower SPRY4-IT1 expression. Multivariate analyses by Cox's proportional hazard model revealed that expression of SPRY4-IT1 was an independent prognostic factor in ccRCC. In vitro assays, our results indicated that knockdown of SPRY4-IT1 reduced renal cancer cell proliferation, migration, and invasion.
CONCLUSIONS: Our data suggested that lncRNA SPRY4-IT1 might be considered as a potential prognostic indicator and a potential target for therapeutic intervention in RC.

Plotnik JP, Budka JA, Ferris MW, Hollenhorst PC
ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells.
Nucleic Acids Res. 2014; 42(19):11928-40 [PubMed] Free Access to Full Article Related Publications
The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. However, the array of cis-regulatory elements and trans-acting factors that mediate these transcriptional changes is still unclear. Our genome-wide analysis determined that a sequence consisting of neighboring ETS and AP-1 transcription factor binding sites is enriched near cell migration genes activated by RAS/ERK signaling in epithelial cells. In vivo screening of candidate ETS proteins revealed that ETS1 is specifically required for migration of RAS/ERK activated cells. Furthermore, both migration and transcriptional activation through ETS/AP-1 required ERK phosphorylation of ETS1. Genome-wide mapping of multiple ETS proteins demonstrated that ETS1 binds specifically to enhancer ETS/AP-1 sequences. ETS1 occupancy, and its role in cell migration, was conserved in epithelial cells derived from multiple tissues, consistent with a chromatin organization common to epithelial cell lines. Genome-wide expression analysis showed that ETS1 was required for activation of RAS-regulated cell migration genes, but also identified a surprising role for ETS1 in the repression of genes such as DUSP4, DUSP6 and SPRY4 that provide negative feedback to the RAS/ERK pathway. Consistently, ETS1 was required for robust RAS/ERK pathway activation. Therefore, ETS1 has dual roles in mediating epithelial-specific RAS/ERK transcriptional functions.

Hua KT, Wang MY, Chen MW, et al.
The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis.
Mol Cancer. 2014; 13:189 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood.
METHOD: The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes.
RESULTS: We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens.
CONCLUSION: We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.

Sun M, Liu XH, Lu KH, et al.
EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition.
Cell Death Dis. 2014; 5:e1298 [PubMed] Free Access to Full Article Related Publications
Recent evidence indicates that long noncoding RNAs (lncRNAs) have a critical role in the regulation of cellular processes such as differentiation, proliferation, and metastasis. These lncRNAs are dysregulated in a variety of cancers and many function as tumor suppressors; however, the regulatory factors involved in silencing lncRNA transcription are poorly understood. In this study, we showed that epigenetic silencing of lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) occurs in non-small-cell lung cancer (NSCLC) cells through direct transcriptional repression mediated by the Polycomb group protein enhancer of zeste homolog 2 (EZH2). SPRY4-IT1 is derived from an intron within SPRY4, and is upregulated in melanoma cells; knockdown of its expression leads to cell growth arrest, invasion inhibition, and elevated rates of apoptosis. Upon depletion of EZH2 by RNA interference, SPRY4-IT1 expression was restored, and transfection of SPRY4-IT1 into NSCLC cells resulted in a significant antitumoral effect, both in culture and in xenografted nude mice. Moreover, overexpression of SPRY4-IT1 was found to have a key role in the epithelial-mesenchymal transition through the regulation of E-cadherin and vimentin expression. In EZH2-knockdown cells, which characteristically showed impaired cell proliferation and metastasis, the induction of SPRY4-IT1 depletion partially rescued the oncogenic phenotype, suggesting that SPRY4-IT1 repression has an important role in EZH2 oncogenesis. Of most relevance, translation of these findings into human NSCLC tissue samples demonstrated that patients with low levels of SPRY4-IT1 expression had a shorter overall survival time, suggesting that SPRY4-IT1 could be a biomarker for poor prognosis of NSCLC.

Li M, Zhang H, Zhao X, et al.
SPRY4-mediated ERK1/2 signaling inhibition abolishes 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell.
Gynecol Endocrinol. 2014; 30(8):600-4 [PubMed] Related Publications
OBJECTIVE: Basic fibroblast growth factor (FGF2)-mediated Extracellular signal-regulated kinases1/2 (ERK1/2) signaling is a critical modulator in angiogenesis. SPRY4 has been reported to be a feedback negative regulator of FGFs-induced ERK1/2 signaling. The aim of this study was to explore the role of SPRY4 in endometrial adenocarcinoma cell.
MATERIALS AND METHODS: The effect of SPRY4 expression on FGF2-mediated ERK1/2 signaling was detected by luciferase assay and Western blot analysis. The growth of Ishikawa cells was detected using colony formation assay and cell number counting experiment.
RESULTS: We found that plasmid-driven SPRY4 expression efficiently blocked the activity of FGF2-induced ERK1/2 signaling in Ishikawa cells. SPRY4 expression significantly reduced the proliferation and 17β-estradiol-induced proliferation of Ishikawa cells.
CONCLUSION: SPRY4 may function as a tumor suppressor in endometrial adenocarcinoma.

Van Nieuwenhuysen E, Lambrechts S, Lambrechts D, et al.
Genetic changes in nonepithelial ovarian cancer.
Expert Rev Anticancer Ther. 2013; 13(7):871-82 [PubMed] Related Publications
Nonepithelial ovarian cancers (OCs), including sex cord-stromal tumors (SCSTs) and germ cell tumors (GCTs), are an uncommon subset of OC, together accounting for 10% of all OCs. The etiology of these tumors remains largely unresolved. It is well established that tumorigenesis is the result of multiple genetic alterations driving a normal cell toward a malignant state. Much effort has been made into researching the molecular mechanisms underlying epithelial OC, but far less is known about the genetic changes in SCSTs and GCTs. Recently, a single point missense mutation (C134W) was found in the FOXL2 gene in approximately 95% of adult-type granulosa cell tumors, suggesting a key role for FOXL2 in these tumors. By contrast, the FOXL2 mutation was not found in the juvenile type. DICER1 somatic missense mutations were found in approximately 60% of Sertoli-Leydig tumors. Ovarian GCTs share many morphological features and a similar pattern of chromosomal alterations with testicular GCTs. In the latter, recent genome-wide association studies have identified seven susceptibility loci near KITLG, SPRY4, UKC2, BAK1, DMRT1, TERT and ATF7IP. All of the susceptibility loci detected thus far are all involved in primordial germ cell function or sex determination. TGF-β/BMP and Wnt/β-catenin signaling was absent in dysgerminomas, but present in yolk sac tumors, suggesting intertumoral heterogeneity. In this article, the authors aim to provide an overview of the current knowledge on the possible molecular changes in SCSTs and GCTs of the ovary.

Rathmanner N, Haigl B, Vanas V, et al.
Sprouty2 but not Sprouty4 is a potent inhibitor of cell proliferation and migration of osteosarcoma cells.
FEBS Lett. 2013; 587(16):2597-605 [PubMed] Related Publications
As negative regulators of receptor tyrosine kinase-mediated signalling, Sprouty proteins fulfil important roles during carcinogenesis. In this report, we demonstrate that Sprouty2 protein expression inhibits cell proliferation and migration in osteosarcoma-derived cells. Although earlier reports describe a tumour-promoting function, these results indicate that Sprouty proteins also have the potential to function as tumour suppressors in sarcoma. In contrast to Sprouty2, Sprouty4 expression failed to interfere with proliferation and migration of the osteosarcoma-derived cells, possibly due to a less pronounced interference with mitogen-activated protein kinase activity. Sequences within the NH2-terminus are responsible for the specific inhibitory function of Sprouty2 protein.

Karlsson R, Andreassen KE, Kristiansen W, et al.
Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4.
Hum Mol Genet. 2013; 22(16):3373-80 [PubMed] Related Publications
Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with testicular germ cell tumor (TGCT) risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4 and TERT. In the present study, we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the major histological subtypes seminoma and non-seminoma. A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3919 population controls. Seven hundred and thirty-four additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modifications by parent-of-origin and effect differences between histological subtypes were explored. We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2 × 10(-6); BAK1 2.1 × 10(-10); DMRT1 6.7 × 10(-25); KITLG 2.1 × 10(-48); SPRY4 1.4 × 10(-29); TERT 1.8 × 10(-18)). Stepwise regression indicated three independent signals for BAK1 and TERT, two for SPRY4 and one each for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio = 1.72, paternal odds ratio = 0.99, interaction P = 0.0013). No significant effect differences between seminomas and non-seminomas were found. In summary, we validated previously reported genetic associations with TGCT in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4.

Tong CW, Wang JL, Jiang MS, et al.
Novel genes that mediate nuclear respiratory factor 1-regualted neurite outgrowth in neuroblastoma IMR-32 cells.
Gene. 2013; 515(1):62-70 [PubMed] Related Publications
Nuclear respiratory factor-1 (NRF-1) is a transcription factor that functions in neurite outgrowth; however, the genes downstream from NRF-1 that mediate this function remain largely unknown. This study employs a genome-wide analysis approach to identify NRF-1-targeted genes in human neuroblastoma IMR-32 cells. A total of 916 human genes containing the putative NRF-1 response element (NRE) in their promoter regions were identified using a cutoff score determined by results from electrophoretic mobility shift assays (EMSA). Seventy-four NRF-1 target genes were listed according to the typical locations and high conservation of NREs. Fifteen genes, MAPRE3, NPDC1, RAB3IP, TRAPPC3, SMAD5, PIP5K1A, USP10, SPRY4, GTF2F2, NR1D1, SUV39H2, SKA3, RHOA, RAPGEF6, and SMAP1 were selected for biological confirmation. EMSA and chromatin immunoprecipitation confirmed that all NREs of these fifteen genes are critical for NRF-1 binding. Quantitative RT-PCR demonstrated that mRNA levels of 12 of these genes are regulated by NRF-1. Overexpression or knockdown of candidate genes demonstrated that MAPRE3, NPDC1, SMAD5, USP10, SPRY4, GTF2F2, SKA3, SMAP1 positively regulated, and RHOA and RAPGEF6 negatively regulated neurite outgrowth. Overall, our data showed that the combination of genome-wide bioinformatic analysis and biological experiments helps to identify the novel NRF-1-regulated genes, which play roles in differentiation of neuroblastoma cells.

Zhao H, Rebbeck TR, Mitra N
Analyzing genetic association studies with an extended propensity score approach.
Stat Appl Genet Mol Biol. 2012; 11(5) [PubMed] Free Access to Full Article Related Publications
Propensity scores are commonly used to address confounding in observational studies. However, they have not been previously adapted to deal with bias in genetic association studies. We propose an extension of our previous method (Zhao et al., 2009) that uses a multilevel propensity score approach and allows one to estimate the effect of a genotype under an additive model and also simultaneously adjusts for confounders such as genetic ancestry and patient and disease characteristics. Using simulation studies, we demonstrate that this extended genetic propensity score (eGPS) can adequately adjust and consistently correct for bias due to confounding in a variety of circumstances. Under all simulation scenarios, the eGPS method yields estimates with bias close to 0 (mean=0.018, standard error=0.01). Our method also preserves statistical properties such as coverage probability, Type I error, and power. We illustrate this approach in a population-based genetic association study of testicular germ cell tumors and KITLG and SPRY4 susceptibility genes. We conclude that our method provides a novel and broadly applicable analytic strategy for obtaining less biased and more valid estimates of genetic associations.

Ziebarth JD, Bhattacharya A, Cui Y
Integrative analysis of somatic mutations altering microRNA targeting in cancer genomes.
PLoS One. 2012; 7(10):e47137 [PubMed] Free Access to Full Article Related Publications
Determining the functional impact of somatic mutations is crucial to understanding tumorigenesis and metastasis. Recent sequences of several cancers have provided comprehensive lists of somatic mutations across entire genomes, enabling investigation of the functional impact of somatic mutations in non-coding regions. Here, we study somatic mutations in 3'UTRs of genes that have been identified in four cancers and computationally predict how they may alter miRNA targeting, potentially resulting in dysregulation of the expression of the genes harboring these mutations. We find that somatic mutations create or disrupt putative miRNA target sites in the 3'UTRs of many genes, including several genes, such as MITF, EPHA3, TAL1, SCG3, and GSDMA, which have been previously associated with cancer. We also integrate the somatic mutations with germline mutations and results of association studies. Specifically, we identify putative miRNA target sites in the 3'UTRs of BMPR1B, KLK3, and SPRY4 that are disrupted by both somatic and germline mutations and, also, are in linkage disequilibrium blocks with high scoring markers from cancer association studies. The somatic mutation in BMPR1B is located in a target site of miR-125b; germline mutations in this target site have previously been both shown to disrupt regulation of BMPR1B by miR-125b and linked with cancer.

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