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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein sprouty homolog 4
Source:NCBIAccessed: 01 September, 2019


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 (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: SPRY4 (cancer-related)

Kumar R, Njauw CN, Reddy BY, et al.
Growth suppression by dual BRAF(V600E) and NRAS(Q61) oncogene expression is mediated by SPRY4 in melanoma.
Oncogene. 2019; 38(18):3504-3520 [PubMed] Related Publications
The underlying forces that shape mutational patterns within any type of cancer have been poorly characterized. One of the best preserved exclusionary relationships is that between BRAF(V600E) and NRAS(Q61) in melanomas. To explore possible mechanisms which could explain this phenomenon, we overexpressed NRAS(Q61) in a set of BRAF(V600E) melanoma lines and vice versa. Controlled expression of a second activating oncogene led to growth arrest ("synthetic suppression") in a subset of cells, which was accompanied by cell cycle arrest and senescence in several melanoma cell lines along with apoptosis. Through differential gene expression analysis, we identified SPRY4 as the potential mediator of this synthetic response to dual oncogene suppression. Ectopic introduction of SPRY4 recapitulated the growth arrest phenotype of dual BRAF(V600E)/NRAS(Q61) expression while SPRY4 depletion led to a partial rescue from oncogenic antagonism. This study thus defined SPRY4 as a potential mediator of synthetic suppression, which is likely to contribute to the observed exclusivity between BRAF(V600E) and NRAS(Q61R) mutations in melanoma. Further leverage of the SPRY4 pathway may also hold therapeutic promise for NRAS(Q61) melanomas.

Zhang C, Wang H, Liu X, et al.
Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP.
Oncogene. 2019; 38(11):1892-1904 [PubMed] Related Publications
Lung cancer is one of the most common malignant diseases globally, composed of non-small cell lung cancer (NSCLC, 85%) and small cell lung cancer (SCLC, 15%). MicroRNAs (miRNAs) are single-stranded noncoding RNAs having important roles in lung cancer development. miR-411-5p/3p were reported to be increased significantly in human NSCLC tissues and cell lines. Moreover, miR-411-5p/3p overexpression could accelerate cell proliferation and migration, and impede cell apoptosis in NSCLC cell lines. Mechanically, SPRY4 is confirmed a direct target of miR-411-5p/3p. Furthermore, our findings showed that miR-411-5p/3p promoted lung tumor growth in vivo, decreased SPRY4 expression dramatically, and induced EGFR, AKT signaling activation, as well as epithelial-mesenchymal transition (EMT) simultaneously in tumor tissues. In addition, we showed that miR-411-5p also targeted tumor suppressor TXNIP, involved in regulating positively cell cycle progress in SPC-A1 cells rather than in H1299. Whether cell specificity of low TXNIP mRNA level in H1299 is responsible for the different response to cell cycle between H1299 and SPC-A1 would need further explorations. Collectively, these results suggest that miR-411-5p/3p are required for NSCLC development by suppressing SPRY4 and TXNIP; thus, the miR-411-SPRY4-AKT axis might act as a promising target for lung cancer therapy clinically.

Tian Y, Fu X, Li Q, et al.
MicroRNA‑181 serves an oncogenic role in breast cancer via the inhibition of SPRY4.
Mol Med Rep. 2018; 18(6):5603-5613 [PubMed] Free Access to Full Article Related Publications
Numerous microRNAs (miRs) have been implicated in breast cancer; however, the molecular mechanism is not fully understood. The present study examined the function and regulatory mechanism of miR‑181 in breast cancer. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to examine the RNA and protein expression. MTT assay, wound healing assay and transwell assay were conducted to study cell proliferation, migration and invasion. Luciferase reporter gene assay was used to confirm targeting relationship. The results suggested that the miR‑181 expression levels were significantly higher in breast cancer cell lines and clinical tissue samples. The increased expression of miR‑181 was markedly associated with higher clinical stage and lymph node metastasis. The patients with high miR‑181 expression demonstrated worse prognosis compared with those with a low expression of miR‑181. Small interfering RNA‑induced miR‑181 downregulation significantly inhibited breast cancer cell proliferation, migration and invasion in vitro, and tumor growth in vivo. Protein sprouty homolog 4 (SPRY4), downregulated in breast cancer tissues and cell lines, was observed to be a novel target gene of miR‑181. Downregulation of SPRY4 was significantly associated with breast cancer progression in addition to poor prognosis. Knockdown of SPRY4 rescued the inhibitory effects of miR‑181 downregulation on the malignant phenotypes of breast cancer cells. Thus, the present study demonstrated that miR‑181 serves a promoting role in breast cancer at least in part through the inhibition of SPRY4 expression. The present results expand the understanding of the miR‑181/SPRY4 axis' function during for the malignant progression of breast cancer.

Zhan Y, Du L, Wang L, et al.
Expression signatures of exosomal long non-coding RNAs in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer.
Mol Cancer. 2018; 17(1):142 [PubMed] Free Access to Full Article Related Publications
Recently, expression signatures of exosomal long non-coding RNAs (lncRNAs) have been proposed as potential non-invasive biomarkers for cancer detection. In this study, we aimed to develop a urinary exosome (UE)-derived lncRNA panel for diagnosis and recurrence prediction of bladder cancer (BC). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to screen and evaluate the expressions of eight candidate lncRNAs in a training set (208 urine samples) and a validation set (160 urine samples). A panel consisting of three differently expressed lncRNAs (MALAT1, PCAT-1 and SPRY4-IT1) was established for BC diagnosis in the training set, showing an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.854. Subsequently, the performance of the panel was further verified with an AUC of 0.813 in the validation set, which was significantly higher than that of urine cytology (0.619). In addition, Kaplan-Meier analysis suggested that the up-regulation of PCAT-1 and MALAT1 was associated with poor recurrence-free survival (RFS) of non-muscle-invasive BC (NMIBC) (p < 0.001 and p = 0.002, respectively), and multivariate Cox proportional hazards regression analysis revealed that exosomal PCAT-1 overexpression was an independent prognostic factor for the RFS of NMIBC (p = 0.018). Collectively, our findings indicated that UE-derived lncRNAs possessed considerable clinical value in the diagnosis and prognosis of BC.

Thiele JA, Hosek P, Kralovcova E, et al.
lncRNAs in Non-Malignant Tissue Have Prognostic Value in Colorectal Cancer.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
Although colorectal cancer (CRC) is the third most frequent cause of cancer related death in Europe, clinically relevant biomarkers for therapy guidance and prognosis are insufficiently reliable. Long non-coding RNAs (lncRNAs) are RNAs over 200 nucleotides long that are not translated into proteins but can influence biological processes. There is emerging evidence for their involvement in solid cancer as oncogenes, tumour suppressors or regulators of cell proliferation and metastasis development. The goal of this study was to evaluate the prognostic effect of selected lncRNAs in a retrospective study on CRC patients from the Czech Republic. We used a quantitative PCR approach to measure the expression in paired non-malignant and tumour tissue samples of CRC patients of nine lncRNAs previously shown to be involved in cancer progression-

Wu H, Wang Y, Chen T, et al.
The N-terminal polypeptide derived from vMIP-II exerts its anti-tumor activity in human breast cancer by regulating lncRNA SPRY4-IT1.
Biosci Rep. 2018; 38(5) [PubMed] Free Access to Full Article Related Publications
Accumulating evidence demonstrates that long non-coding RNA (lncRNA) sprouty4-intron transcript 1 (lncRNA SPRY4-IT1) plays a vital role in the development of breast cancer. However, the underlying mechanism has not been eventually illuminated. We aimed to explore the biological activity of lncRNA SPRY4-IT1 in breast cancer cells and whether N-terminal polypeptide derived from viral macrophage inflammatory protein II (NT21MP) could exert its anti-tumor effect by regulating lncRNA SPRY4-IT1 and its target gene

Xu Y, Yao Y, Jiang X, et al.
SP1-induced upregulation of lncRNA SPRY4-IT1 exerts oncogenic properties by scaffolding EZH2/LSD1/DNMT1 and sponging miR-101-3p in cholangiocarcinoma.
J Exp Clin Cancer Res. 2018; 37(1):81 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) behave as a novel class of transcription products during multiple cancer processes. However, the mechanisms responsible for their alteration in cholangiocarcinoma (CCA) are not fully understood.
METHODS: The expression of SPRY4-IT1 in CCA tissues and cell lines was determined by RT-qPCR, and the association between SPRY4-IT1 transcription and clinicopathologic features was analyzed. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to explore whether SP1 could bind to the promoter region of SPRY4-IT1 and activate its transcription. The biological function of SPRY4-IT1 in CCA cells was evaluated both in vitro and in vivo. ChIP, RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were performed to determine the molecular mechanism of SPRY4-IT1 in cell proliferation, apoptosis and invasion.
RESULTS: SPRY4-IT1 was abnormally upregulated in CCA tissues and cells, and this upregulation was correlated with tumor stage and tumor node metastasis (TNM) stage in CCA patients. SPRY4-IT1 overexpression was also an unfavorable prognostic factor for patients with CCA. Additionally, SP1 could bind directly to the SPRY4-IT1 promoter region and activate its transcription. Furthermore, SPRY4-IT1 silencing caused tumor suppressive effects via reducing cell proliferation, migration and invasion; inducing cell apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) process in CCA cells. Mechanistically, enhancer of zeste homolog 2 (EZH2) along with the lysine specific demethylase 1 (LSD1) or DNA methyltransferase 1 (DNMT1) were recruited by SPRY4-IT1, which functioned as a scaffold. Importantly, SPRY4-IT1 positively regulated the expression of EZH2 through sponging miR-101-3p.
CONCLUSIONS: Our data illustrate how SPRY4-IT1 plays an oncogenic role in CCA and may offer a potential therapeutic target for treating CCA.

Haque SU, Niu L, Kuhnell D, et al.
Differential expression and prognostic value of long non-coding RNA in HPV-negative head and neck squamous cell carcinoma.
Head Neck. 2018; 40(7):1555-1564 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long non-coding RNA (lncRNA) has emerged as a new avenue of interest due to its various biological functions in cancer. Abnormal expression of lncRNA has been reported in other malignancies but has been understudied in head and neck squamous cell carcinoma (HNSCC).
METHODS: The lncRNA expression was interrogated via quantitative real-time polymerase chain reaction (qRT-PCR) array for 19 human papillomavirus (HPV)-negative HNSCC tumor-normal pairs. The Cancer Genome Atlas (TCGA) was used to validate these results. The association between differentially expressed lncRNA and survival outcomes was analyzed.
RESULTS: Differential expression was validated for 5 lncRNA (SPRY4-IT1, HEIH, LUCAT1, LINC00152, and HAND2-AS1). There was also an inverse association between MEG3 expression (not significantly differentially expressed in TCGA tumors but highly variable expression) and 3-year recurrence-free survival (RFS).
CONCLUSION: We identified and validated differential expression of 5 lncRNA in HPV-negative HNSCC. Low MEG3 expression was associated with favorable 3-year RFS, although the significance of this finding remains unclear.

Yao Y, Gao P, Chen L, et al.
Upregulated long non-coding RNA SPRY4-IT1 predicts dismal prognosis for pancreatic ductal adenocarcinoma and regulates cell proliferation and apoptosis.
Gene. 2018; 659:52-58 [PubMed] Related Publications
Recently, long noncoding RNAs (lncRNAs) have been emerged as pivotal regulators in various human cancers, including pancreatic ductal adenocarcinoma (PDAC). SPRY4-intronic transcript 1 (SPRY4-IT1) was reported to be upregulated in some kind of human cancers. Here, we elucidated the biological functions and possible clinical values of SPRY4-IT1 on PDAC. In present study, expression of SPRY4-IT1 in PDAC tissues and corresponding normal tissues were explored by qRT-PCR experiments. The link between SPRY4-IT1 expression levels and clinicopathological significance was further analyzed. In addition, the oncogenic role of SPRY4-IT1 was detected both in vitro and in vivo. The results demonstrated that SPRY4-IT1 was abnormally upregulated in PDAC tissues and cell lines. Tumor stage and differentiation grade was closely correlated with SPRY4-IT1 expression. Additionally, decreased SPRY4-IT1 contributed to tumor suppressive effect through attenuating cell growth, clonogenic ability and facilitating apoptosis via Bcl-2/caspase-3 pathway in PANC1 and Capan-2 cells. Furthermore, the xenograft study confirmed the tumor proliferation-promoting role of SPRY4-IT1 in PANC1 cells. Taken together, these findings indicated that SPRY4-IT1 is a potential therapeutic target and prognosis biomarker for the patients with PDAC.

Guo W, Zhong K, Wei H, et al.
Long non-coding RNA SPRY4-IT1 promotes cell proliferation and invasion by regulation of Cdc20 in pancreatic cancer cells.
PLoS One. 2018; 13(2):e0193483 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in the development of human cancers including pancreatic cancer. Long non-coding RNA SPRY4-IT1 (sprouty4-intron transcript 1) has been reported to play an oncogenic role in various types of human carcinomas. However, the role of SPRY4-IT1 in pancreatic cancer is unclear. The objective of this study was to determine the function of SPRY4-IT1 on proliferation and invasion in pancreatic cancer. In the current study, we dissected the function and mechanism of SPRY4-IT1 by multiple approaches including Real-time RT-PCR, Western blotting analysis, MTT assay, Wound healing assay, Transwell assay, and transfection. We found that down-regulation of SPRY4-IT1 inhibited cell growth and induced cell apoptosis in pancreatic cancer cells. Moreover, SPRY4-IT1 knockdown induced cell cycle arrest at G0/G1 phase. Furthermore, inhibition of SPRY4-IT1 retarded cell migration and invasion in pancreatic cancer cells. Overexpression of SPRY4-IT1 enhanced cell growth and invasion, and inhibited cell apoptosis in pancreatic cancer cells. Mechanistically, suppression of SPRY4-IT1 inhibited the expression of Cdc20 in pancreatic cancer cells. Our findings demonstrated that inhibition of SPRY4-IT1 could be a potential therapeutic approach for the treatment of pancreatic cancer.

Li Z, Shen J, Chan MTV, Wu WKK
The long non-coding RNA SPRY4-IT1: An emerging player in tumorigenesis and osteosarcoma.
Cell Prolif. 2018; 51(4):e12446 [PubMed] Related Publications
Accumulating evidence from genome-wide analysis and functional studies has begun to unveil the important role of long non-coding RNAs (lncRNAs) in cancer development. The lncRNA SPRY4-IT1 is derived from an intron of SPRY4 gene and was originally reported to be upregulated in melanoma in which it functioned as an oncogene. Since this discovery, an increasing number of studies have investigated the expression and function of SPRY4-IT1 in human cancers. Aberrant expression of SPRY4-IT1 has now been documented in different cancer types, including osteosarcoma, breast, renal, oesophageal and prostate cancers. However, its deregulation and function in lung and gastric cancers remain controversial. Pertinent to clinical practice, SPRY4-IT1 expression has been shown to predict survival of cancer patients. In this review, we summarize recent evidence concerning SPRY4-IT1 deregulation and the associated mechanisms in human cancers. We also discuss the potential clinical utilization of this lncRNA as a diagnostic and prognostic biomarker for cancer patients.

Das MK, Furu K, Evensen HF, et al.
Knockdown of SPRY4 and SPRY4-IT1 inhibits cell growth and phosphorylation of Akt in human testicular germ cell tumours.
Sci Rep. 2018; 8(1):2462 [PubMed] Free Access to Full Article Related Publications
Testicular germ cell tumour (TGCT) is the most common cancer in young men in large parts of the world, but the aetiology is mainly unknown. Genome-wide association studies have so far identified about 50 susceptibility loci associated with TGCT, including SPRY4. SPRY4 has shown tumour suppressor activity in several cancer cells, such as lung and prostate, while it was found to act as an oncogene in ovarian cancer. An intronic region within the SPRY4 gene produces a long non-coding RNA, SPRY4-IT1, which has been reported to act as an oncogene in melanoma, breast cancer, and colorectal cancer, and as a tumour suppressor in lung cancer. The roles of SPRY4 and SPRY4-IT1 in TGCT development are yet unknown. We found higher expression levels of SPRY4, both mRNA and protein, and of SPRY4-IT1 in human TGCT than in normal adult testis. Small-interfering RNA (siRNA)-mediated transient knockdown of SPRY4 and SPRY4-IT1 in two TGCT cell lines 833 K and NT2-D1 resulted in decreased cell growth, migration, and invasion. Knockdown of SPRY4 and SPRY4-IT1 also led to a significant reduction in the phosphorylation of Akt. Our findings indicate that SPRY4 and SPRY4-IT1 may act as oncogenes in TGCTs via activation of the PI3K / Akt signalling pathway.

Wang Y, He H, Liyanarachchi S, et al.
The role of SMAD3 in the genetic predisposition to papillary thyroid carcinoma.
Genet Med. 2018; 20(9):927-935 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus.
METHODS: We performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets.
RESULTS: We report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4.
CONCLUSION: Our data provide a functional annotation of the 15q22 thyroid cancer risk locus.

Gutschner T, Richtig G, Haemmerle M, Pichler M
From biomarkers to therapeutic targets-the promises and perils of long non-coding RNAs in cancer.
Cancer Metastasis Rev. 2018; 37(1):83-105 [PubMed] Related Publications
Biomarker-driven personalized cancer therapy is a field of growing interest, and several molecular tests have been developed to detect biomarkers that predict, e.g., response of cancers to particular therapies. Identification of these molecules and understanding their molecular mechanisms is important for cancer prognosis and the development of therapeutics for late stage diseases. In the past, significant efforts have been placed on the discovery of protein or DNA-based biomarkers while only recently the class of long non-coding RNA (lncRNA) has emerged as a new category of biomarker. The mammalian genome is pervasively transcribed yielding a vast amount of non-protein-coding RNAs including lncRNAs. Hence, these transcripts represent a rich source of information that has the potential to significantly contribute to precision medicine in the future. Importantly, many lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we will highlight prime examples of lncRNAs that serve as marker for cancer progression or therapy response and which might represent promising therapeutic targets. Furthermore, we will introduce lncRNA targeting tools and strategies, and we will discuss potential pitfalls in translating these into clinical trials.

Atay S, Wilkey DW, Milhem M, et al.
Insights into the Proteome of Gastrointestinal Stromal Tumors-Derived Exosomes Reveals New Potential Diagnostic Biomarkers.
Mol Cell Proteomics. 2018; 17(3):495-515 [PubMed] Free Access to Full Article Related Publications
Developing tumors continuously release nano-sized vesicles that represent circulating "fingerprints" of the tumor's identity. In gastrointestinal stromal tumor (GIST), we have previously reported that these tumors release "oncosomes" carrying the constitutively activated tyrosine kinase (TK) receptor KIT. Despite the clinical utility of TK inhibitors, such as imatinib mesylate (IM), recurrence and metastasis are clinical problems that urge the need to identify new tumor-derived molecules. To this aim, we performed the first high quality proteomic study of GIST-derived exosomes (GDEs) and identified 1,060 proteins composing the core GDE proteome (cGDEp). The cGDEp was enriched in diagnostic markers (

Zhou H, Sun Z, Li S, et al.
LncRNA SPRY4-IT was concerned with the poor prognosis and contributed to the progression of thyroid cancer.
Cancer Gene Ther. 2018; 25(1-2):39-46 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have been demonstrated to be critical regulators in tumorigenesis. LncRNA SPRY4-IT1 has been identified as critical regulator for hepatocellular carcinoma and ovarian cancer. However, the potential role and clinical value of SPRY4-IT1 in human thyroid cancer (TC) still remain unclear and need to be uncovered. Our current study was aimed to ascertain the biological role of expression of SPRY4-IT1 in TC tissues and cells. Our findings revealed that the level of SPRY4-IT1 was significantly upregulated in TC tissues and cell lines, which was correlated with poor prognosis. And cellular experiments exhibited that silenced SPRY4-IT1 inhibited the proliferative and migratory abilities of TC cells. Mechanism assays noted that silenced SPRY4-IT1 could increase the levels of transforming growth factor-β1 (TGF-β1) and p-Smad2/3 and function mediated by si-SPRY4-IT1 could be rescued by the interference of TGF-β1. Generally speaking, these findings elucidated that SPRY4-IT1 might become a novel prognostic factor in the clinical behaviors of TC patients and participated in the progression of TC through targeting TGF-β/Smad signaling pathway.

Yu G, Lin J, Liu C, et al.
Long non-coding RNA SPRY4-IT1 promotes development of hepatic cellular carcinoma by interacting with ERRα and predicts poor prognosis.
Sci Rep. 2017; 7(1):17176 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) has become one of the most common leading causes of cancer-related deaths worldwide. This study investigates the role of lncRNA, SPRY4-IT1 in the development of HCC. Quantitative real-time PCR (qRT-PCR) was performed and the results showed that SPRY4-IT1 expression was up-regulated in HCC tissues and high expression of SPRY4-IT1 was associated with poor 5-year overall survival in the HCC patient cohort. Clinicopathological analysis showed that the expression of SPRY4-IT1 was significantly correlated with TNM stage in HCC patients. In vitro CCK-8 assay, colony formation assay, cell invasion and migration assays demonstrated that knock-down of SPRY4-IT1 suppressed cell proliferation, colony formation, cell invasion and migration in HCC cells. Flow cytometric analysis showed that knock-down of SPRY4-IT1 induced cell cycle arrest at G

Chai Z, Fan H, Li Y, et al.
miR-1908 as a novel prognosis marker of glioma via promoting malignant phenotype and modulating SPRY4/RAF1 axis.
Oncol Rep. 2017; 38(5):2717-2726 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are reported to be involved in the development of glioma. However, study on miRNAs in glioma is limited. The present study aimed to identify miRNAs which can act as potential novel prognostic markers for glioma and analyze its possible mechanism. We show that miR-1908 correlates with shorter survival time of glioma patients via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRY4/RAF1 axis. Analysis of GEO and TCGA database found that miR-1908 was significantly upregulated in glioma tissues, and strongly associated with shorter survival time of glioma patients. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that miR-1908 is mainly involved in regulating cell proliferation, invasion and apoptosis. To further confirm the above results, in vitro, glioma U251 cells were transfected with miR-1908 mimics or inhibitor, and upregulated miR-1908 promoted U251 cell proliferation, and enhanced the ability of invasion by transwell assay. In addition, upregulated miR-1908 also enhanced anti-apoptosis ability of U251 cells through decreasing pro-apoptosis protein Bax expression. Since miRNAs regulate numerous biological processes by targeting broad set of messenger RNAs, validated target genes of miR-1908 in glioma were analyzed by Targetscan and miRTarBase databases. Among them SPRY4 was significantly decreased in glioma tissues and associated with short survival time, which was selected as the key target gene of miR-1908. Moreover, protein-protein interaction (PPI) showed that SPRY4 could interacted with pro-oncogene RAF1 and negatively correlated with RAF1 expression. Consistent with above analysis, in vitro, western blot analysis identified that miR-1908 upregulated significantly decreased SPRY4 expression and increased RAF1 expression. Hence, miR-1908 was correlated with poor prognosis of glioma via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRF4/RAF1 axis. Our results elucidated the tumor promoting role of miR-1908 and established miR-1908 as a potential novel prognostic marker for glioma.

Sun C, Ding Y, Wang S, Hu W
Long Non-Coding RNA SPRY4-IT1 Can Predict Poor Prognosis in Digestive System Malignancies: a Meta-Analysis.
Pathol Oncol Res. 2019; 25(1):89-95 [PubMed] Related Publications
Recent studies have reported that long non-coding RNA SPRY4 intron transcript 1 (SPRY4-IT1) is abnormally expressed in malignant digestive tumors and associated with prognosis. But its clinical relevance is unclear. Here, we performed a meta-analysis aims to evaluate the prognostic value of SPRY4-IT1 in digestive system malignancies. We systematic search the PubMed, Web of Science, ScienceDirect and Wiley Online Library database to eligible studies. The pooled hazard ratios (HRs) with a 95% confidence interval (95% CI) were calculated to explored the association of lncRNA SPRY4-IT1 with prognosis. Five studies were eligible for analysis, a total of 518 patients were included. Meta-analysis indicated that overexpression of SPRY4-IT1 was associated with poor over survival (OS) (HR = 1.24, 95%CI:0.49-1.98; random-effects model). The clinicopathological parameters analysis further showed that increased expression level of SPRY4-IT1 was positively correlated with lymph node metastasis (HR = 1.45, 95% CI =0.88-2.02; fixed-effects model), TNM stage (HR = 1.24,95% CI = 0.78-1.70; fixed-effects model), and invasion depth (HR = 1.25,95% CI = 0.63-1.88; fixed-effects model). lncRNA SPRY4-IT1 may serve as a potential prognostic marker in malignant digestive tumors.

Kayser S, Feszler M, Krzykalla J, et al.
Clinical impact of KMT2C and SPRY4 expression levels in intensively treated younger adult acute myeloid leukemia patients.
Eur J Haematol. 2017; 99(6):544-552 [PubMed] Related Publications
OBJECTIVE: To evaluate the prognostic impact of gene expression levels (ELs) of two tumor suppressor genes, sprouty 4 (SPRY4, located on 5q) and lysine methyltransferase 2C (KMT2C, located on 7q) in correlation with clinical characteristics and genetic abnormalities assessed at initial diagnosis in acute myeloid leukemia (AML).
METHOD: Gene expression levels were measured on cDNA by RT-qPCR from diagnostic bone marrow samples of 275 intensively treated adult AML patients (median age, 48 years).
RESULTS: KMT2C ELs were significantly lower in abn7q/-7 (P = .001), whereas SPRY4 ELs were not associated with abn5q/-5. Higher KMT2C and SPRY4 ELs were significantly associated with lower genetic risk groups as defined by the European LeukemiaNet classification. Additionally, KMT2C ELs were lower in cytogenetically normal patients with DNMT3A (P = .01) or FLT3-ITD mutations (P = .05). KMT2C ELs were not associated with prognosis, whereas higher SPRY4 ELs showed a favorable impact on event-free (EFS, P = .01), relapse-free (RFS, P = .01) and in-trend on overall survival (P = .06) for cytogenetically abnormal patients, which was confirmed in multivariable analysis for EFS (HR, 0.84; 95%-CI, 0.73-0.97; P = .02) and RFS (HR, 0.85; 95%-CI, 0.73-0.98; P = .02).
CONCLUSION: Our data indicate that KMT2C ELs are associated with specific genetic features and that SPRY4 ELs may add prognostic information.

Wen X, Han XR, Wang YJ, et al.
Effects of long noncoding RNA SPRY4-IT1-mediated EZH2 on the invasion and migration of lung adenocarcinoma.
J Cell Biochem. 2018; 119(2):1827-1840 [PubMed] Related Publications
We aim to investigate the interaction between the EZH2 and the long noncoding RNA (lncRNA) SPRY4-IT1. We also explore their respective effects on human lung adenocarcinoma (LA) cell invasion and migration. Both LA and adjacent normal tissues were obtained from 256 LA patients. SPTY4-IT expression and EZH2 mRNA expressions in tissues and cells were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The siRNAs against SPRY4-IT1 and EZH2 were co-transfected into A549 and H1975 cells. The interaction between SPRY4-IT1 and EZH2 was determined using a RNA pull-down assay and a RNA immunoprecipitation (RIP) assay. A Transwell assay and scratch assay were used to evaluate the cell migration and invasion abilities. The expressions of E-cadherin and Vimentin in the epithelial-mesenchymal transition (EMT) and EZH2 protein expression were detected through western blotting. SPRY4-IT1 expression was observed to be significantly lower, while the expression of EZH2 was higher in the LA tissues than in the adjacent normal tissues. Compared with the HBE cell line, expressions of SPRY4-IT1 in each human LA cell line had decreased, with the lowest observed reduction in the A549 cell line, while EZH2 mRNA and protein expression increased in each human LA cell lines. After SPRY4-IT1-siRNA was transfected into A549 and H1975 cells, invasion and migration abilities were enhanced, in addition to a reduction in the expression of E-cadherin, while expressions of Vimentin exhibited an increased rate. Consequently, we find that EZH2 promotes LA cell invasion and metastasis by inhibiting SPRY4-IT1 expression.

Jin J, Chu Z, Ma P, et al.
Long non-coding RNA SPRY4-IT1 promotes proliferation and invasion by acting as a ceRNA of miR-101-3p in colorectal cancer cells.
Tumour Biol. 2017; 39(7):1010428317716250 [PubMed] Related Publications
Long non-coding RNAs are associated with a spectrum of biological processes such as gene regulation on transcriptional and post-transcriptional levels. Increasing evidence indicates that SPRY4-IT1 plays an important role in carcinogenesis, and the mechanisms whereby SPRY4-IT1 induces colorectal carcinoma progression remain largely unknown. The aim of this study is to evaluate the expression and function of SPRY4-IT1 in colorectal carcinoma. In this study, we analyzed SPRY4-IT1 expression levels in a series of colorectal carcinoma patients by quantitative reverse transcription polymerase chain reaction. Knockdown of SPRY4-IT1 by RNA interference was performed to explore its roles in cell proliferation, migration, and invasion. Our results found that SPRY4-IT1 was upregulated in human primary colorectal carcinoma tissues. Knockdown of SPRY4-IT1 inhibited colorectal carcinoma cell proliferation, migration, and invasion. Moreover, we confirmed that the expression of epithelial-mesenchymal transition-related genes was modulated through alteration of SPRY4-IT1 expression. SPRY4-IT1 could negatively regulate the expression of miR-101-3p in colorectal carcinoma cells. The bioinformatics prediction revealed putative miR-101-3p binding sites within SPRY4-IT1 transcripts. Above all, knockdown of SPRY4-IT1 could represent a rational therapeutic strategy for colorectal carcinoma.

Yu J, Han Q, Cui Y
Decreased long non-coding RNA SPRY4-IT1 contributes to ovarian cancer cell metastasis partly via affecting epithelial-mesenchymal transition.
Tumour Biol. 2017; 39(7):1010428317709129 [PubMed] Related Publications
Long non-coding RNAs play important roles in the regulation of cellular processes including cell proliferation, differentiation, and metastasis. The dysregulation of long non-coding RNAs, such as the SPRY4-IT1 (SPRY4 intronic transcript 1), has been associated with various types of malignancies. However, the functional roles and regulatory mechanism of SPRY4-IT1 in ovarian cancer remain to be elucidated. Here, we quantified the expression level of SPRY4-IT1 in ovarian cancer patients and found its downregulation in ovarian cancer tissues compared to the adjacent normal tissues. Patients with lower SPRY4-IT1 expression were associated with a relatively poor prognosis. In consistency, the expression of SPRY4-IT1 was found to be reduced in four human ovarian cancer cell lines compared to normal ovarian epithelial cells. Next, two ovarian cancer cell lines SKOV3 and HO8910 were employed in vitro assays to investigate biological functions of SPRY4-IT1 in ovarian cancer. The cell proliferation was reduced following SPRY4-IT1 overexpression in SKOV3/HO8910 cells based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. The SPRY4-IT1 overexpression also dramatically arrested cell cycle and promoted cell apoptosis. Both wound-healing and transwell-based assays demonstrated that cell migration and invasion were inhibited following SPRY4-IT1 overexpression. Meanwhile, overexpression of SPRY4-IT1 increased E-cadherin and decreased N-cadherin and vimentin protein levels, indicating that SPRY4-IT1 may regulate ovarian cancer cell metastasis through the inhibition of epithelial-mesenchymal transition. Taken together, our findings suggest that SPRY4-IT1 regulates various cellular processes of ovarian cancer cells and its downregulation may contribute to ovarian cancer progression and metastasis partly via affecting the epithelial-mesenchymal transition.

Li J, Chen Y, Chen Z, et al.
SPRY4-IT1: A novel oncogenic long non-coding RNA in human cancers.
Tumour Biol. 2017; 39(6):1010428317711406 [PubMed] Related Publications
Long non-coding RNAs are classified as a kind of RNA, which are longer than 200 nucleotides in length and cannot be translated into proteins. Multiple studies have demonstrated that long non-coding RNAs are involved in various cellular processes, including proliferation, differentiation, cell death, and metastasis. Among numerous long non-coding RNAs, we focus on Sprouty4-Intron 1 (SPRY4-IT1), a well-known long non-coding RNA that is overexpressed in various kinds of tumor tissues and cell lines. Accumulating evidences show that SPRY4-IT1 was dysregulated in various cancers, including melanoma, breast cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, gastric cancer, colon cancer, and hepatocellular carcinoma, and amplification of SPRY4-IT1 was associated with different clinicopathological features of cancer patients. Importantly, SPRY4-IT1 exerts important roles in tumor progression and metastasis. However, detailed molecular mechanisms of SPRY4-IT1 in cancer progression and metastasis were poorly understood. In this review, we have focused on the characteristics of SPRY4-IT1 and illustrated the biological function and mechanism of SPRY4-IT1 in cancer development.

Lee B, Sahoo A, Marchica J, et al.
The long noncoding RNA
Sci Adv. 2017; 3(5):e1602505 [PubMed] Free Access to Full Article Related Publications
Molecular mechanisms by which long noncoding RNA (lncRNA) molecules may influence cancerous condition are poorly understood. The aberrant expression of

Weidle UH, Birzele F, Kollmorgen G, Rüger R
Long Non-coding RNAs and their Role in Metastasis.
Cancer Genomics Proteomics. 2017 May-Jun; 14(3):143-160 [PubMed] Free Access to Full Article Related Publications
The perception of long non-coding RNAs as chunk RNA and transcriptional noise has been steadily replaced by their role as validated targets for a diverse set of physiological processes in the past few years. However, for the vast majority of lncRNAs their precise mode of action and physiological function remain to be uncovered. A large body of evidence has revealed their essential role in all stages of cancirogenesis and metastasis. In this review we focus on the role of lncRNAs in metastasis. We grouped selected lncRNAs into three categories based on in vitro and in vivo mode of action-related studies and clinical relevance for metastasis. Grouped according to their mode of action, in category I we discuss lncRNAs such as CCAT2, DREH, LET, NKILA, treRNA, HOTAIR, H19, FENDRR, lincROR, MALAT, GClnc1, BCAR4, SCHLAP1 and lncRNA ATP, all lncRNAs with in vitro and in vivo metastasis-related data and clinical significance. In category II we discuss lncRNAs CCAT1, PCAT1, PTENgp1, GPLINC, MEG3, ZEB2-AS, LCT13, ANRIL, NBAT1 and lncTCF7 all characterized by their mode of action in vitro and clinical significance, but pending or preliminary in vivo data. Finally, under category III, we discuss lncRNAs BANCR, FRLnc1, SPRY4-IT1 and LIMT with partially or poorly-resolved mode of action and varying degree of validation in clinical metastasis. Finally we discuss metastasis-related translational aspects of lncRNAs.

Wang M, Dong X, Feng Y, et al.
Prognostic role of the long non-coding RNA, SPRY4 Intronic Transcript 1, in patients with cancer: a meta-analysis.
Oncotarget. 2017; 8(20):33713-33724 [PubMed] Free Access to Full Article Related Publications
Recent studies have emphasized the important role of long non-coding RNAs (lncRNAs) in cancer development. The present study performed a meta-analysis to investigate whether lncRNA, SPRY4 Intronic Transcript 1(SPRY4-IT1) can be served as a potential biomarker for prognosis in human cancers. The eligible studies were collected by searching multiple online databases (Pubmed, EMBASE, CNKI, Web of Science and Google Scholar) and meta-analysis was performed to explore the association between the expression levels of SPRY4-IT1 and overall survival (OS), disease-free survival (DFS) and clinicopathological parameters. A total of 1329 patients from 13 studies were included for meta-analysis. The meta-analysis results showed that high expression level of SPRY4-IT1 was significantly associated with shorter OS in cancer patients (HR = 3.20, 95% CI: 2.59-3.90, P<0.001) except in the patients with non-small cell lung cancer (NSCLC). Increased SPRY4-IT1 expression level was correlated with shorter DFS in patients with gastric cancer and ovarian cancer. SPRY4-IT1 expression level was not correlated with the clinicopathological parameters including age (P = 0.37), gender (P = 0.87), tumor size (P = 0.47) and invasion depth (P = 0.52), and increased SPRY4-IT1 expression level was significantly associated with distant metastasis (odds ratio (OR) = 1.96, 95% CI: 1.24-3.08, P = 0.004), lymph node metastasis (OR = 3.96, 95% CI: 1.48-5.54, P<0.001), advanced tumor/node/metastasis stage (OR = 3.72, 95% CI = 2.91-4.76, P<0.001) and poor tumor differentiation (OR = 1.86, 95% CI = 1.35-2.58, P<0.001) in cancer patients except in patients with NSCLC. In summary, the meta-analysis results suggested that increased expression level of SPRY4-IT1 was positively associated with unfavorable prognosis and advanced features of cancers in cancer patients but not in patients with NSCLC.

Marcotte EL, Pankratz N, Amatruda JF, et al.
Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group.
Genes Chromosomes Cancer. 2017; 56(7):548-558 [PubMed] Free Access to Full Article Related Publications
Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P < 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent-of-origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.

Bikkavilli RK, Zerayesus SA, Van Scoyk M, et al.
K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer.
J Biol Chem. 2017; 292(18):7423-7434 [PubMed] Free Access to Full Article Related Publications
AU-rich element-binding proteins (ARE-BPs) offer post-transcriptional regulation of gene expression via physical interaction and recruitment of RNA decay machinery to the AU-rich elements within the 3'-UTR of the target transcripts. However, the role of ARE-BPs in lung cancer remains poorly understood. In this study, we have identified that K-homology splicing regulatory protein (KSRP), an ARE-BP, is robustly up-regulated in human lung cancer. Importantly, Kaplan-Meier survival analysis indicated that elevated KSRP expression was correlated with poor overall survival of lung cancer patients. Furthermore, cigarette smoke, a leading risk factor for lung cancer, was also identified to be an important contributor to increased KSRP expression. Remarkably, silencing of KSRP decreased cell proliferation, reversed anchorage-independent growth, and reduced migration/invasion, suggesting an oncogenic role for KSRP in lung cancer. Finally, we provide mechanistic evidence that KSRP promotes the down-regulation of Spry4 by a previously unidentified mechanism,

Li H, Liu C, Lu Z, et al.
Upregulation of the long non-coding RNA SPRY4-IT1 indicates a poor prognosis and promotes tumorigenesis in ovarian cancer.
Biomed Pharmacother. 2017; 88:529-534 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have been identified to be critical mediators in various tumors associated with cancer progression. LncRNA SPRY4-IT1 serves as a novel prognostic biomarker for hepatocellular carcinoma. However, the biological role and clinical significance of lncRNA SPRY4-IT1 in human ovarian cancer (OC) need to be completely elucidated. The aim of the present study was to explore the lncRNA SPRY4-IT1 expression in human OC patients and its role in OC cells. We show that lncRNA SPRY4-IT1 expression is significantly upregulated in ovarian tumor tissues and OC cell lines in comparison with adjacent non-tumor control tissues and the human ovarian immortalized nontumorigenic ovarian surface epithelial (IOSE), respectively. Further analysis by Kaplan-Meier survival analysis and multivariate analysis indicated that high lncRNA SPRY4-IT1 expression may be an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in OC patients. Furthermore, the area under the receiver operating characteristic (ROC) curve of lncRNA SPRY4-IT1 was up to 0.8512, indicating lncRNA SPRY4-IT1 has diagnostic values to discriminate tumor tissues from nontumorous tissues. Also, knockdown of lncRNA SPRY4-IT1 inhibited the proliferation of OC cells by CCK-8 assay and clonogenic assay and arrested cell cycle at a G0/G1 stage in OC cells. In conclusion, these results suggest that lncRNA SPRY4-IT1 may be considered as a new predictor in the clinical prognosis of OC patients.

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