Gene Summary

Gene:YWHAZ; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta
Aliases: HEL4, YWHAD, KCIP-1, HEL-S-3, POPCHAS, HEL-S-93, 14-3-3-zeta
Summary:This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. Several transcript variants that differ in the 5' UTR but that encode the same protein have been identified for this gene. [provided by RefSeq, Oct 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:14-3-3 protein zeta/delta
Source:NCBIAccessed: 31 August, 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 31 August 2019 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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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: YWHAZ (cancer-related)

Liu J, Song S, Lin S, et al.
Circ-SERPINE2 promotes the development of gastric carcinoma by sponging miR-375 and modulating YWHAZ.
Cell Prolif. 2019; 52(4):e12648 [PubMed] Related Publications
OBJECTIVES: Circular RNAs (circRNAs) exist extensively in the eukaryotic genome. The study aimed to identify the role of hsa_circ_0008365 (Circ-SERPINE2) in gastric carcinoma (GC) cells and its downstream mechanisms.
MATERIALS AND METHODS: Gene Expression Omnibus (GEO) database was applied to screen differentially expressed circRNAs. CircInteractome, TargetScan and miRecords websites were used to predict target relationships. qRT-PCR and RNase R treatment were utilised to detect molecule expression and confirm the existence of circ-SERPINE2. RNA pull-down assay and dual-luciferase reporter assay were performed for interaction between circRNA and miRNA or mRNA. EdU assay, colony formation assay, and flow cytometry for apoptosis and cell cycle detections were utilised to assess cell function. Western blot and immunohistochemistry (IHC) assays were applied for detection of proteins in tissues or cells.
RESULTS: Circ-SERPINE2 and YWHAZ were upregulated, and miR-375 was downregulated in GC tissues and cells. Circ-SERPINE2 and YWHAZ targetedly bound to miR-375. Circ-SERPINE2 promoted cell proliferation and cell cycle progress and inhibited cell apoptosis by sponging miR-375 and regulating YWHAZ expression in vitro. Circ-SERPINE2 repressed solid tumour growth through enhancing miR-375 expression and reducing YWHAZ expression in vivo.
CONCLUSIONS: Circ-SERPINE2 is a novel proliferative promoter through the regulation of miR-375/YWHAZ. Circ-SERPINE2/miR-375/YWHAZ axis might provide a novel therapeutic target of GC.

Sha QK, Chen L, Xi JZ, Song H
Long non-coding RNA LINC00858 promotes cells proliferation, migration and invasion by acting as a ceRNA of miR-22-3p in colorectal cancer.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1057-1066 [PubMed] Related Publications
Though long non-coding RNA LINC00858 (LINC00858) has been shown to be involved in tumours of other tissues, its involvement in colorectal cancer (CRC) is still unknown. We aimed to investigated expression and mechanism LINC00858 in human CRC. In this study, we firstly found that LINC00858 expression was significantly up-regulated in both CRC tissues and cell lines by both online data and RT-PCR assay. Then, clinical assay revealed that high LINC00858 expression was significantly associated with advanced clinical progression and poor prognosis. Multivariate analysis demonstrated that high LINC00858 expression was an independent poor prognostic factor for CRC patients. Moreover, lost-of-function assay indicated that knockdown of LINC00858 suppressed CRC cells proliferation, migration and invasion, and promoted apoptosis. Mechanistically, bioinformatics analysis, dual-luciferase reporter assays, and western blot assays showed that LINC00858 functioned as competing endogenous RNA to repress miR-22-3p, which controlled its down-stream target YWHAZ. Then, we suggested that LINC00858 exerted its function through the miR-22-3p/YWHAZ axis. To our knowledge, this is the first report which showed the role of LINC00858 in the progression of CRC. Our findings indicated that LINC00858 played an important role in CRC, and may serve as a novel prognostic factor and therapeutic target.

Ji N, Wang Y, Bao G, et al.
LncRNA SNHG14 promotes the progression of cervical cancer by regulating miR-206/YWHAZ.
Pathol Res Pract. 2019; 215(4):668-675 [PubMed] Related Publications
Accumulating evidence suggests that lncRNAs play key roles in many cancers. It has been reported that long non-coding RNA SNHG14 promotes cell proliferation and metastasis in multiple cancers. However, the role and underlying molecular mechanism of SNHG14 in cervical cancer (CC) remain largely unclear. In this study, we discovered that the relative expression of SNHG14 was significantly upregulated in CC tissues and cells, and associated with the overall survival of CC patients. Moreover, knockdown of SNHG14 significantly inhibited cell proliferation, migration and invasion, and promoted cell apoptosis in CC. Molecular mechanism explorations revealed that SNHG14 acted as a sponge of miR-206 and that YWHAZ was a downstream target gene of miR-206 in CC. Spearman's correlation analysis uncovered a significantly negative correlation between SNHG14 (or YWHAZ) and miR-206 expression, while a significantly positive correlation between SNHG14 and YWHAZ expression in CC tissues. We also found that the effect of SNHG14 knockdown on the CC progression could be partly rescued by overexpression of YWHAZ at the same time. Our findings revealed that SNHG14 acted as a sponge of miR-206 to regulate the expression of YWHAZ in CC, hinting the promising therapeutic target role of SNHG4 for CC patients.

Shi J, Ye J, Fei H, et al.
YWHAZ promotes ovarian cancer metastasis by modulating glycolysis.
Oncol Rep. 2019; 41(2):1101-1112 [PubMed] Related Publications
Ovarian cancer is one of the three most deadly gynecological cancers, with the highest mortality rate. As the main cause of death, metastasis is considered to be a crucial factor that reduces the survival time of ovarian carcinoma patients. YWHAZ (also known as 14‑3‑3ζ) influences diverse vital cellular processes such as metabolism, signal transduction, apoptosis and cell cycle regulation. In the present study, we determined that YWHAZ is upregulated in ovarian cancers in contrast to normal tissues by immunohistochemical staining. High YWHAZ expression was found to be associated with TNM stage and metastasis‑free prognosis of ovarian cancer patients. Silencing of YWHAZ inhibited the proliferation and facilitated serum starvation‑induced apoptosis of ovarian cancer cells. Cell migration was also suppressed by YWHAZ silencing. Furthermore, using an in vivo metastatic model, we found that YWHAZ silence also inhibited ovarian cancer metastasis in vivo. Notably, glycolysis was clearly inhibited in YWHAZ‑silenced ovarian cancer cells as determined by lactate production assay and Seahorse XF analysis. YWHAZ also regulated the PI3K/Akt1/vimentin signaling pathway in ovarian cancer cells as detected by western blot analysis. Taken together, our results demonstrated that YWHAZ plays an important role in the progression of ovarian cancer and can be used as a potential target for the diagnosis and treatment of epithelial ovarian cancer.

Xue R, Hua L, Xu W, et al.
Derivation and Validation of the Potential Core Genes in Pancreatic Cancer for Tumor-Stroma Crosstalk.
Biomed Res Int. 2018; 2018:4283673 [PubMed] Free Access to Full Article Related Publications
Background: Pancreatic cancer is a fatal malignancy with a poor prognosis. The interactions between tumor cells and stromal cells contribute to cancer progression. Pancreatic stellate cells (PSCs) play a key role in tumor-stroma crosstalk of pancreatic cancer. The in-depth exploration for tumor-stroma crosstalk is helpful to develop novel therapeutic strategies. Our aim was to identify the potential core genes and pathways in tumor-stroma crosstalk.
Methods: 3 microarray datasets were from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were screened through bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network were used to obtain the biological roles of DEGs. The top 15 DEGs were explored by principal component analysis. We validated the top 15 DEGs expression in the tumor-stroma crosstalk model in which PSCs were treated with the mixture of Aspc-1 and Panc-1 supernatant.
Results: A total of 221 genes were filtered as DEGs for tumor-stroma crosstalk. The results of principal component analysis for the top 15 DEGs can distinguish three groups. According to the KEGG enrichment, there were 8, 7, and 7 DEGs enriched in cancer related pathway, PI3K-Akt signaling pathway, and microRNAs, respectively. In the tumor-stroma crosstalk model, significant differences can be validated in the AKAP12, CLDN1, CP, FKBP1A, LAMB3, LSM4, MTMR3, PRKARIA, YWHAZ, and JUND expressions.
Conclusions: These results identified the potential core genes and pathways in pancreatic cancer for tumor-stroma crosstalk, which could provide potential targets for the treatment of pancreatic cancer.

Khoontawad J, Intuyod K, Rucksaken R, et al.
Discovering proteins for chemoprevention and chemotherapy by curcumin in liver fluke infection-induced bile duct cancer.
PLoS One. 2018; 13(11):e0207405 [PubMed] Free Access to Full Article Related Publications
Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.

Liu XD, Xie DF, Wang YL, et al.
Integrated analysis of lncRNA-mRNA co-expression networks in the α-particle induced carcinogenesis of human branchial epithelial cells.
Int J Radiat Biol. 2019; 95(2):144-155 [PubMed] Related Publications
PURPOSE: To identify the mRNA and long noncoding RNA (lncRNA) expression profiles and explore the lncRNA-mRNA co-expression networks associated with the carcinogenesis induced by α-particles.
MATERIALS AND METHODS: Immortalized human bronchial epithelial cell line, BEP2D, and its two malignant transformed cell lines, BERP35T-1 and BERP35T-4, were investigated. The lncRNA and mRNA expression profiles of BEP2D, BERP35T-1 and BERP35T-4 were generated. lncRNAs and mRNAs co-expression analysis was performed.
RESULTS: The microarray identified 668 lncRNAs in BERP35T-1 cells and 555 in BERP35T-4 cells that were differentially expressed compared to BEP2D cells. The GO terms and KEGG pathway annotation data indicated that mitotic cell cycle, DNA repair, apoptotic processes, and RNA splicing functional pathways were significantly associated with the α-particle induced cell carcinogenesis. Co-expression network analysis revealed 8902 interactions between 495 differentially expressed mRNAs and 430 corresponding lncRNAs in BERP35T-1 cells compared with BEP2D cells. The genes, situated at the important nodes of the co-expression network, include B3GNT5, RAD23, YWHAZ (14-3-3ζ), FBXW11, TGFBR2, LRP6, PSMD11, MYL12A, etc. Conclusions: This pilot study is the first to explore epigenetic mechanisms of α-particle induced carcinogenesis of human bronchial epithelial cells. It provides basic information for further investigation into the detail mechanisms underlying radiation-induced lung cancer.

Root A, Beizaei A, Ebhardt HA
Structure-based assessment and network analysis of targeting 14-3-3 proteins in prostate cancer.
Mol Cancer. 2018; 17(1):156 [PubMed] Free Access to Full Article Related Publications
Developing combination therapy for castrate-resistant prostate cancer (CRPC) may require exploiting new drug targets outside androgen receptor and PI3K / AKT / mTOR signal transduction pathways implicated in prostate cancer (PCa) progression. One such possible new target is YWHAZ of the 14-3-3 protein family as this gene has prognostic significance for metastatic CRPC patients. However, there are no small molecules targeting YWHAZ commercially available. Hence, we explored whether the small molecule BV02 targeting another 14-3-3 protein family member SFN also binds to YWHAZ. Using advanced docking algorithms we find that BV02 docks many other 14-3-3 family members. In addition, the amphipathic groove where drug binding occurs also has a high binding affinity for other drugs used to treat PCa such as docetaxel. The proteome of metastatic PCa models (LNCaP clone FGC and PC-3) was perturbed as a result of BV02 treatment. Through data integration of three proteomics data sets we found that BV02 modulates numerous protein-protein interactions involving 14-3-3 proteins in our PCa models.

Dong L, Ding H, Li Y, et al.
TRIP13 is a predictor for poor prognosis and regulates cell proliferation, migration and invasion in prostate cancer.
Int J Biol Macromol. 2019; 121:200-206 [PubMed] Related Publications
Thyroid hormone receptor interactor 13 (TRIP13) has been reported to be overexpressed in serval types of human cancers, and regulate tumor cell proliferation, migration and invasion. However, the role of TRIP13 in prostate cancer was still unclear. In our study, the correlation between TRIP13 expression and clinical parameters including prognosis was evaluated in 160 prostate cancer patients. Moreover, the MTT assay, cell migration and invasion assays were performed to assess the effect of TRIP13 on prostate cancer cell biological behaviour. In our results, the expression status of TRIP13 was observed to be elevated in prostate cancer tissue samples through analyzing microarray (GSE55945). Furthermore, mRNA and protein TRIP13 expression were confirmed to be overexpressed in prostate cancer tissue samples and cell lines. High-expression of TRIP13 was correlated with present lymph node involvement, distant metastasis, high Gleason score, levels of serum PSA and poor prognosis in prostate cancer patients. The gain-of-function and loss-of-function studies suggested that TRIP13 functioned as oncogene to regulate prostate cancer cell proliferation, migration, invasion through controlling YWHAZ and epithelial-mesenchymal transition (EMT)-associated genes. In conclusion, TRIP13 is correlated with clinical progression and poor prognosis, and serves as oncogene in prostate cancer.

Lemma S, Avnet S, Meade MJ, et al.
Validation of Suitable Housekeeping Genes for the Normalization of mRNA Expression for Studying Tumor Acidosis.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Similar to other types of cancer, acidification of tumor microenvironment is an important feature of osteosarcoma, and a major source of cellular stress that triggers cancer aggressiveness, drug resistance, and progression. Among the different effects of low extracellular pH on tumor cells, we have recently found that short-term exposure to acidosis strongly affects gene expression. This alteration might also occur for the most commonly used housekeeping genes (HKG), thereby causing erroneous interpretation of RT-qPCR data. On this basis, by using osteosarcoma cells cultured at different pH values, we aimed to identify the ideal HKG to be considered in studies on tumor-associated acidosis. We verified the stability of 15 commonly used HKG through five algorithms (NormFinder, geNorm, BestKeeper, ΔCT, coefficient of variation) and found that no universal HKG is suitable, since at least four HKG are necessary for proper normalization. Furthermore, according to the acceptable range of values,

Hong L, Chen W, Xing A, et al.
Inhibition of Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) Overcomes Drug Resistance and Tumorigenicity in Ovarian Cancer.
Cell Physiol Biochem. 2018; 49(1):53-64 [PubMed] Related Publications
BACKGROUND/AIMS: Cancer stem-like cells are the main cause of tumor occurrence, progression, and therapeutic resistance. However, the precise signals required for the maintenance of the stem-like traits of these cells in ovarian cancer remain elusive. We have thus worked to elucidate the functional role of Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), a gene encoding the 14-3-3ζ protein, in the regulation of multidrug resistance and stem cell-like traits in ovarian cancer.
METHODS: We detected the YWHAZ levels in human ovarian cancer specimens and cell lines using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blots. MTS assays, soft agar colony formation assays, migration assays, cell cycle analysis, sphere formation assays, and flow cytometry were applied to investigate the functional role of YWHAZ in ovarian cancer.
RESULTS: Our data reveals substantially increased YWHAZ expression in both cisplatin- and paclitaxel-resistant ovarian cancer cells. Silencing YWHAZ restored the sensitivity of resistant ovarian cancer cells to cisplatin and paclitaxel. Furthermore, in vitro studies showed that down-regulation of YWHAZ inhibited cell cycle progression, migration, and the expression of stem cell markers. Moreover, tumorigenicity was suppressed in tumor-bearing BALB/c nude mice following YWHAZ knockdown. Additionally, we demonstrated that the expression of YWHAZ was directly down-regulated by miR-30e in resistant ovarian cancer cells.
CONCLUSION: Our results have led to new insights into the essential role of YWHAZ in the regulation of tumourigenesis, stem-like traits, and drug resistance in ovarian cancer, thereby helping to identify a potential target for ovarian cancer therapy.

Zhang X, Xing ND, Lai CJ, et al.
MicroRNA-375 Suppresses the Tumor Aggressive Phenotypes of Clear Cell Renal Cell Carcinomas through Regulating YWHAZ.
Chin Med J (Engl). 2018; 131(16):1944-1950 [PubMed] Free Access to Full Article Related Publications
Background: MicroRNAs (miRNAs) are key regulators during tumor initiation and progression. MicroRNA-375 (MiR-375) has been proven to play a tumor-suppressive role in various types of human malignancies; however, its biological role in clear cell renal cell carcinoma (ccRCC) remains unclear. The purpose of this study was to explore the biologic role as well as the underlying mechanism of miR-375 in ccRCC progression.
Methods: Quantitative polymerase chain reaction (qPCR) was applied to test the expression of miR-375 in tissues and cell lines by t-test. Functional experiments were used to investigate the biological role of miR-375 utilizing a gain-of-function strategy. The target of miR-375 was investigated by bioinformatic analysis and further verified by luciferase reporter assay, qPCR, Western blotting, and functional experiments in vitro.
Results: Our study demonstrated that miR-375 was significantly downregulated in ccRCC tissues (cancer vs. normal, 0.804 ± 0.079 vs. 1.784 ± 0.200, t = 5.531 P < 0.0001) and cell lines, and loss of miR-375 expression significantly associated with advanced Fuhrman nuclear grades (Grade III and IV vs. Grade I and II, 1.000 ± 0.099 vs. 1.731 ± 0.189, t = 3.262 P = 0.003). Functional studies demonstrated that miR-375 suppressed ccRCC cell proliferation, migration, and invasion (all P < 0.05 in both 786-O and A498 cell lines). Multiple miRNA target prediction algorithms indicated the well-studied oncogene YWHAZ as a direct target of miR-375, which was further confirmed by the luciferase reporter assay, qPCR, and Western blotting. Moreover, restoration of YWHAZ could rescue the antiproliferation effect of miR-375.
Conclusions: The data provide the solid evidence that miR-375 plays a tumor-suppressive role in ccRCC progression, partially through regulating YWHAZ. This study expands the antitumor profile of miR-375, and supports its role as a potential therapeutic target in ccRCC treatment.

Wang WL, Yang Z, Zhang YJ, et al.
Competing endogenous RNA analysis reveals the regulatory potency of circRNA_036186 in HNSCC.
Int J Oncol. 2018; 53(4):1529-1543 [PubMed] Free Access to Full Article Related Publications
This study aimed to characterize circular RNA (circRNA) expression profiles and biological functions in head and neck squamous cell carcinoma (HNSCC). Differentially expressed circRNAs were screened using an Arraystar Human CircRNA Array and verified by reverse transcription-quantitative polymerase chain reaction. Multiple bioinformatics methods and a hypergeometric test were employed to predict the interactions between RNAs and the functional circRNA‑microRNA (miRNA)-mRNA axes in HNSCC. As a result, 287 circRNAs and 1,053 mRNAs were determined to be differentially expressed in HNSCC compared with the adjacent tissue. In addition, the expression levels of circRNA_036186 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, ζ polypeptide (14‑3‑3ζ) were identified to be significantly different. A competing endogenous RNA (ceRNA) network was constructed, consisting of 5 circRNAs, 385 miRNAs and 96 mRNAs. Furthermore, we predicted that miR‑193b‑3p exerts a significant effect on 14‑3‑3ζ, and was significantly associated with the Hippo signaling pathway in HNSCC. On the whole, these findings suggest that circRNA_036186 likely regulates 14‑3‑3ζ expression by functioning as a ceRNA in the development and progression of HNSCC.

Guo F, Jiao D, Sui GQ, et al.
Anticancer effect of YWHAZ silencing via inducing apoptosis and autophagy in gastric cancer cells.
Neoplasma. 2018; 65(5):693-700 [PubMed] Related Publications
YWHAZ (14-3-3ζ) has been reported to be a prognostic marker for various tumors and play a crucial role in many oncogenic processes, including proliferation, migration and invasion. However, the functional role and mechanism of YWHAZ in gastric cancer (GC) are not in detail and still remain to be studied. In the present study, the endogenous expression of YWHAZ in gastric cancer cell line BGC-823 was silenced by YWHAZ-specific short hairpin RNA (shRNA). Our data showed that YWHAZ silencing resulted in cell cycle arrest in BGC-823 cells. Further, YWHAZ-silenced BGC-823 cells acquired increased apoptosis rate, which was confirmed by increased levels of cleaved caspase-3, cleaved PARP, and Bax, and decreased level of Bcl-2. Suppression of YWHAZ also promoted autophagy, confirming by the upregulation of LC3II /LC3I ratio, and downregulation of p62 level. Moreover, YWHAZ suppression inhibited the activation of PI3K/AKT/mTOR signaling pathway in BGC-823 cells. LY294002 (PI3K/AKT inhibitor, 200 nM) further promoted YWHAZ silencing-induced apoptosis and autophagy in BGC-823 cells, while insulin-like growth factor-1 (IGF-1; PI3K/AKT agonist, 10 ng/ml) had the opposite role. Finally, suppression of YWHAZ inhibited the growth of the xenograft tumor in vivo. This study provides extended evidence that YWHAZ can be a potential therapeutic target for GC.

Jiang X, Wu J, Zhang Y, et al.
MiR-613 functions as tumor suppressor in hepatocellular carcinoma by targeting YWHAZ.
Gene. 2018; 659:168-174 [PubMed] Related Publications
MicroRNAs (miRNAs) play crucial regulators of affecting hepatocellular carcinoma (HCC) development and progression. However, the biological role and underlying molecular mechanism of miR-613 in HCC still remain well unknown. In the study, our results demonstrated that expression of miR-613 was significantly lower in HCC tissues compared with adjacent normal tissues by quantitative Real-time PCR (qRT-PCR) assay. The association between miR-613 expression and clinicopathologic characteristics analysis showed that lower miR-613 expression significantly associated with tumor size, vascular infiltration and poor prognostic outcome in HCC patients. In vitro, ectopic overexpression of miR-613 significantly inhibited cell proliferation and invasion capability, while down-regulated miR-613 had reversed effects. Furthermore, luciferase reporter gene assay, qRT-PCR, and western blot assays demonstrated that miR-613 target 3'-untranslated region (UTR) of YWHAZ and regulated its expression in HCC cells. Overexpression of YWHAZ partially abolished the tumor suppressing effects induced by upregulating miR-613 in HCC cells. Thus, our results implied that miR-613 may represent a novel potentially therapeutic target for HCC.

Liu S, Jiang H, Wen H, et al.
Knockdown of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) enhances tumorigenesis both in vivo and in vitro in bladder cancer.
Oncol Rep. 2018; 39(5):2127-2135 [PubMed] Free Access to Full Article Related Publications
Bladder cancer is the most common tumor of the urinary tract. Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), a gene encoding the 14-3-3ζ protein, has been observed to be frequently amplified in bladder cancer. However, the role of 14-3-3ζ in various types of cancer is controversial. With reproduction of The Cancer Genome Atlas database, we searched the correlation of YWHAZ expression with survival outcomes of multiple cancers in silico. Our results revealed that only in bladder cancer was there a positive survival trend with YWHAZ overexpression. To study its role in bladder cancer, YWHAZ was successfully downregulated by lentivirus in 5637 and T24 cells. MTT and colony-formation assays showed that YWHAZ downregulation increased cell proliferation. Wound healing and Transwell assays showed that YWHAZ downregulation enhanced cell migration and invasiveness. FACS analysis showed that YWHAZ induced cell cycle arrest, but not apoptosis. A xenograft tumor model revealed that YWHAZ knockdown enhanced tumor growth. Gene set enrichment analysis confirmed that the cell cycle pathway plays a vital role in the function of the YWHAZ gene. In conclusion, knockdown of YWHAZ promoted both in vitro and in vivo tumorigenesis in bladder cancer and may be a novel biomarker for bladder cancer deserving further study.

Zhao R, He H, Zhu Y, et al.
MiR-204/14-3-3ζ axis regulates osteosarcoma cell proliferation through SATA3 pathway.
Pharmazie. 2017; 72(10):593-598 [PubMed] Related Publications
Hyperproliferation of cells is a major problem is osteosarcoma (OS). So, further elucidation of the molecular mechanisms underlying hyperproliferation of OS is needed. Western blots results showed that 14-3-3ζ protein was upregulated in OS cell lines; 14-3-3ζ knockdown significantly suppressed OS cell proliferation, as well as the protein levels of p-STAT3, c-Myc and Cyclin D1. MicroRNA-204 (miR-204) has been regarded as an essential regulator in cancer carcinogenesis, including OS. Here, we revealed that miR-204 directly targets the 3'UTR of 14-3-3ζ to inhibit its expression, thus to suppress 14-3-3ζ -induced OS cell hyperproliferation. Further, we demonstrated that the STAT3 pathway was involved in miR-204/14-3-3ζ regulation of OS cell proliferation. Our findings provide information about the underlying mechanisms of miR-204/14-3-3ζ in OS cell proliferation through the STAT3 pathway, and suggest miR-204 and 14-3-3ζ as potential therapeutic targets in OS.

Wang Y, Zhao Q, Lan N, Wang S
Identification of methylated genes and miRNA signatures in nasopharyngeal carcinoma by bioinformatics analysis.
Mol Med Rep. 2018; 17(4):4909-4916 [PubMed] Free Access to Full Article Related Publications
Nasopharyngeal carcinoma (NPC) is prevalent in several regions, including. Southern China and Southeast Asia, with high mortality. The present study aimed to explore the epigenetic mechanisms of NPC and to provide novel biomarkers for prognosis. Two methylation data sets (GSE52068 and GSE62336) were downloaded from the Gene Expression Omnibus database. Following pretreatment of the raw data, differentially methylated regions (DMRs) and differentially methylated CpG islands (DMCs) were identified between the NPC samples and normal tissue controls using COHCAP software. The overlapped DMRs and DMCs in the two data sets were extracted and associated to relevant genes. Enrichment analysis and protein‑protein interaction (PPI) network analyses were performed on the identified genes using Database for Annotation, Visualization and Integration Discovery and Cytoscape, respectively. MicroRNAs (miRNAs) targeting the overlapped genes were identified based on the miRWalk database. NPC‑related genes were analyzed with the Comparative Toxicogenomics Database. Multiple overlapping DMRs between the two data sets were identified and were associated with 1,854 hypermethylated and 18 hypomethylated genes, which were revealed to be enriched in certain pathways, including the mitogen‑activated protein kinase (MAPK) signaling pathway and the phosphatidylinositol 3‑kinase (PI3K)/AKT signaling pathway. Several nodes in the predicted PPI network were highlighted, including proto‑oncogene tyrosine‑protein kinase SRC, SMAD family member 3 (SMAD3), tyrosine 3‑monooxygenase/tryptophan 5‑monooxygenase activation protein ζ (YWHAZ) and Heat shock protein family A member 4 (HSPA4), all of which were hypomethylated. A total of 14 miRNAs were identified that correlated with the overlapped genes such as miRNA (miR)‑148a‑3p, which was predicted to target of HSPA4; and 17 genes were identified as related to NPC, including SMAD3 and SRC. miR129‑2 was hypermethylated. Several novel methylated genes or miRNAs were suggested as biomarkers for NPC prognosis: Hypomethylation of SRC, SMAD3, YWHAZ and HSPA4, and hypermethylation of miR129‑2 may be linked to poor prognosis of NPC.

Kim HJ, Sung SH, Kim CY, et al.
14-3-3ζ Overexpression is Associated with Poor Prognosis in Ovarian Cancer.
Yonsei Med J. 2018; 59(1):51-56 [PubMed] Free Access to Full Article Related Publications
PURPOSE: 14-3-3ζregulates cell signaling, cell cycle progression, and apoptosis, and its overexpression is associated with disease recurrence and poor clinical outcomes in some solid tumors. However, its clinicopathological role in ovarian cancer is unknown. Our goal was to investigate whether 14-3-3ζis associated with ovarian cancer prognosis.
MATERIALS AND METHODS: We examined 14-3-3ζexpression by immunohistochemistry in ovarian cancer tissues obtained from 88 ovarian cancer patients. The examined tissues were of various histologies and stages. 14-3-3ζexpression was also analyzed by western blot in seven ovarian cancer cell lines and a primary ovary epithelial cell line. Cell viability was measured using an MTS-based assay following cisplatin treatment.
RESULTS: Among the ovarian cancer samples, 53.4% (47/88) showed high 14-3-3ζexpression, and 14-3-3ζoverexpression was positively correlated with more advanced pathologic stages and grades. 14-3-3ζoverexpression was also significantly associated with poor disease-free survival (DFS) and overall survival (OS) of ovarian cancer patients. Median DFS and OS were 1088 and 3905 days, respectively, in the high 14-3-3ζexpression group, but not reached in the low 14-3-3ζexpression group (p=0.004 and p=0.033, log-rank test, respectively). Downregulating 14-3-3ζby RNA interference in ovarian cancer cells led to enhanced sensitivity to cisplatin-induced cell death.
CONCLUSION: 14-3-3ζoverexpression might be a potential prognostic biomarker for ovarian cancer, and the inhibition of 14-3-3ζcould be a therapeutic option that enhances the antitumor activity of cisplatin.

Freitag D, Koch A, Lawson McLean A, et al.
Validation of Reference Genes for Expression Studies in Human Meningiomas under Different Experimental Settings.
Mol Neurobiol. 2018; 55(7):5787-5797 [PubMed] Related Publications
Quantitative polymerase chain reaction (qPCR) is a sensitive technique for the quantitative analysis of gene expression levels. To compare mRNA transcripts across tumour and non-pathological tissue, appropriate reference genes are required for internal standardisation. Validation of these reference genes in meningiomas has not yet been reported. After mRNA transcription of meningioma (WHO grade I-III) and meningeal tissue from three different experimental sample types (fresh tissue, primary cell cultures and FFPE tissue), 13 candidate reference genes (ACTB, B2M, HPRT, VIM, GAPDH, YWHAZ, EIF4A2, MUC1, ATP5B, GNB2L, TUBB, CYC1, RPL13A) were chosen for quantitative expression analysis. Two statistical algorithms (GeNorm and NormFinder) were used for validation of gene expression stability. All candidate housekeepers tested for stability were checked within and across the three tissue analysis groups. Pearson correlation, the ΔC

Wang W, Zhang L, Wang Y, et al.
Involvement of miR-451 in resistance to paclitaxel by regulating YWHAZ in breast cancer.
Cell Death Dis. 2017; 8(10):e3071 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) have been identified as major post-transcriptional regulators of the initiation and progression of human cancers, including breast cancer. However, the detail role of miR-451 has not been fully elucidated in breast cancer. In this study, we aimed to investigate the biological role and molecular mechanisms of miR-451 in drug resistance in breast cancer cell lines and in xenograft model. We show that miR-451 is decreased in human breast cancer specimens and in paclitaxel-resistant (PR) cells. Ectopic expression of miR-451 could inhibit the cell migration and invasion, promoted apoptosis, induced cell-cycle arrest Furthermore, tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ) was identified as a direct target of miR-451. Remarkably, the expression of YWHAZ is inversely correlated with the level of miR-451 in human breast cancer samples. Co-treatment with miR-451 mimics and YWHAZ-siRNA significantly enhanced YWHAZ knockdown in both SKBR3/PR and MCF-7/PR cells Moreover, miR-451 markedly inhibited expression of β-catenin via YWHAZ and subsequently inhibited downstream gene cyclin D1, c-Myc expression. The results of xenograft model in vivo showed that intratumor injection of miR-451 agomir induced a tumor-suppressive effect in SKBR3/PR drug-resistant xenograft model. Taken together, our findings suggested that miR-451 might be considered as important and potential target in paclitaxel-resistant breast cancer treatment.

Liu XX, Ye H, Wang P, et al.
Identification of 14‑3‑3ζ as a potential biomarker in gastric cancer by proteomics‑based analysis.
Mol Med Rep. 2017; 16(5):7759-7765 [PubMed] Related Publications
The identification of tumor biomarkers to support early diagnosis and tumor progression monitoring may potentially reduce the mortality of gastric cancer (GC). The present study aimed to detect novel tumor‑associated antigens from the AGS GC cell line, and to identify their associated autoantibodies in sera from patients with GC by proteomics‑based approaches. Proteins from AGS cell lysates were isolated using two‑dimensional polyacrylamide gel electrophoresis, and western blotting was subsequently performed, to determine autoantibody responses in sera derived from patients with GC and healthy individuals. Positive protein spots were removed from gels stained with Coomassie blue, and were then evaluated by liquid chromatography‑tandem mass spectrometry. Sera from patients with GC produced numerous spots, one of which was identified as 14‑3‑3ζ. Autoantibody frequency to 14‑3‑3ζ was 17.6% (15/85) in patients with GC, which was significantly higher than that in healthy control individuals (2.4%; 2/85; P<0.01). These results suggested that the autoantibody against 14‑3‑3ζ may be a potential serological biomarker for the detection and diagnosis of GC.

Giagulli C, D'Ursi P, He W, et al.
A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17.
Sci Rep. 2017; 7(1):6555 [PubMed] Free Access to Full Article Related Publications
Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s.

Holmila R, Sklias A, Muller DC, et al.
Targeted deep sequencing of plasma circulating cell-free DNA reveals Vimentin and Fibulin 1 as potential epigenetic biomarkers for hepatocellular carcinoma.
PLoS One. 2017; 12(3):e0174265 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, but is still lacking sensitive and specific biomarkers for early diagnosis and prognosis. In this study, we applied targeted massively parallel semiconductor sequencing to assess methylation on a panel of genes (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM and YWHAZ) in plasma circulating cell-free DNA (cfDNA) and to evaluate the potential of these genes as HCC biomarkers in two different series, one from France (42 HCC cases and 42 controls) and one from Thailand (42 HCC cases, 26 chronic liver disease cases and 42 controls). We also analyzed a set of HCC and adjacent tissues and liver cell lines to further compare with 'The Cancer Genome Atlas' (TCGA) data. The methylation in cfDNA was detected for FBLN1, PSMA7, PXDN and VIM, with differences in methylation patterns between cases and controls for FBLN1 and VIM. The average methylation level across analyzed CpG-sites was associated with higher odds of HCC for VIM (1.48 [1.02, 2.16] for French cases and 2.18 [1.28, 3.72] for Thai cases), and lower odds of HCC for FBLN1 (0.89 [0.76, 1.03] for French cases and 0.75 [0.63, 0.88] for Thai cases). In conclusion, our study provides evidence that changes in VIM and FBLN1 methylation levels in cfDNA are associated with HCC and could represent useful plasma-based biomarkers. Also, the potential to investigate methylation patterns in cfDNA could bring new strategies for HCC detection and monitoring high-risk groups and response to treatment.

Tan SC, Ismail MP, Duski DR, et al.
Identification of Optimal Reference Genes for Normalization of RT-qPCR Data in Cancerous and Non-Cancerous Tissues of Human Uterine Cervix.
Cancer Invest. 2017; 35(3):163-173 [PubMed] Related Publications
This study aimed to identify the most stably expressed reference genes from a panel of 32 candidate genes for normalization of reverse transcription-quantitative real-time polymerase chain reaction data in cancerous and non-cancerous tissues of human uterine cervix. Overall, PUM1, YWHAZ, and RPLP0 were identified as the most stably expressed genes in paired cancerous and non-cancerous tissues. The results were further stratified by the state of malignancy of the tissues, histopathological type of the cancer, and the human papillomavirus-type.

Kim HJ, Lee SY, Kim CY, et al.
Subcellular localization of FOXO3a as a potential biomarker of response to combined treatment with inhibitors of PI3K and autophagy in PIK3CA-mutant cancer cells.
Oncotarget. 2017; 8(4):6608-6622 [PubMed] Free Access to Full Article Related Publications
Autophagy is the process of lysosome-mediated degradation and recycling that functions as an adaptive survival mechanism during anti-cancer therapy. Aberrant activation of the phosphoinositide-3-kinase (PI3K) pathway frequently occurs in solid tumors, including cervical cancer. However, single-agent PI3K inhibitors show modest anti-tumor efficacy in clinics. To see whether autophagy inhibition improves the efficacy of PI3K inhibitor in PIK3CA-mutant cancer cells, cells were treated with BKM120, a pan-PI3K inhibitor, and the autophagy inhibitor hydroxychloroquine (HCQ). Autophagy inhibition augmented the efficacy of BKM120 depending on PIK3CA-mutant cancer cell type. BKM120 treatment led to the nuclear accumulation of forkhead box O3 (FOXO3a) in Caski and T47D cells, which showed a synergistic effect of BKM120 and HCQ and the strong induction of autophagy. However, most FOXO3a remained in cytoplasm in C33A and ME180 cells, which did not exhibit synergy. These data suggest that BKM120-induced nuclear translocation of FOXO3a might elicit autophagy and be a critical factor determining the synergistic activity of BKM120 and HCQ in PIK3CA-mutant cancer cells. The release of FOXO3a from 14-3-3 by BV02 or 14-3-3 knockdown induced autophagy by BKM120 in C33A cells and sensitized the cells to the combined BKM120 and HCQ treatment, suggesting that cytoplasmic retention of FOXO3a by 14-3-3 even in the presence of BKM120 inhibit autophagy induction and synergistic effect of BKM120 and HCQ combination. Taken together, our study shows that subcellular localization of FOXO3a might be a potential biomarker for predicting response to the combination treatment with PI3K and autophagy inhibitors in PIK3CA-mutant cervical cancer patients.

Yang MR, Zhang Y, Wu XX, Chen W
Critical genes of hepatocellular carcinoma revealed by network and module analysis of RNA-seq data.
Eur Rev Med Pharmacol Sci. 2016; 20(20):4248-4256 [PubMed] Related Publications
OBJECTIVE: RNA-seq data of hepatocellular carcinoma (HCC) was analyzed to identify critical genes related to the pathogenesis and prognosis.
MATERIALS AND METHODS: Three RNA-seq datasets of HCC (GSE69164, GSE63863 and GSE55758) were downloaded from Gene Expression Omnibus (GEO), while another dataset including 54 HCC cases with survival time was obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were identified by significant analysis of microarrays (SAM) method using package samr of R. As followed, we constructed a protein-protein interaction (PPI) network based on the information in Human Protein Reference Database (HPRD). Modules in the PPI network were identified with MCODE method using plugin clusterViz of CytoScape. Gene Ontology (GO) enrichment analysis and pathway enrichment analysis were performed with DAVID. The difference in survival curves was analyzed with Kaplan-Meier (K-M) method using package survival.
RESULTS: A total of 2572 DEGs were identified in the 3 datasets from GEO (GSE69164, GSE63863 and GSE55758). The PPI network was constructed including 660 nodes and 1008 edges, and 4 modules were disclosed in the network. Module A (containing 244 DEGs) was found to related to HCC closely, which genes were involved in transcription factor binding, protein metabolism as well as regulation of apoptosis. Nine hub genes were identified in the module A, including PRKCA, YWHAZ, KRT18, NDRG1, HSPA1A, HSP90AA1, HSF1, IKGKB and UBE21. The network provides the protein-protein interaction of these critical genes, which were implicated in the pathogenesis of HCC. Survival analysis showed that there is a significant difference between two groups classified by the genes in module A. Further Univariate Cox regression analysis showed that 72 genes were associated with survival time significantly, such as NPM1, PRKDC, SPARC, HMGA1, COL1A1 and COL1A2.
CONCLUSIONS: Nine critical genes related to the pathogenesis and 72 potential prognostic markers were revealed in HCC by the network and module analysis of RNA-seq data. These findings could improve the understanding of the pathogenesis and provide valuable information to further investigate the prognostic markers of HCC.

Chen M, Hu W, Xiong CL, et al.
miR-22 targets YWHAZ to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival.
Oncotarget. 2016; 7(49):80751-80764 [PubMed] Free Access to Full Article Related Publications
Many miRNAs are associated with the carcinogenesis of hepatocellular carcinoma (HCC) and some exhibit potential prognostic value. In this study, to further confirm the prognostic value of miRNAs in HCC, we employed miRNA-sequencing data of tumor tissues of 372 HCC patients released by The Cancer Genome Atlas (TCGA) and identified 3 miRNAs including miR-22, miR-9-1 and miR-9-2 could be used as independent predictors for HCC prognostic evaluation. As a tumor-suppressive miRNA, miR-22 was down-regulated in HCC tissues. This down-regulation correlated with tumor vascular invasion, Edmondson-Steiner grade, TNM stage, and AFP level. Moreover, biofunctional investigations revealed that miR-22 significantly attenuated cellular proliferation, migration and invasion of HCC cells. Additionally, through gene expression profiles and bioinformatics analysis, YWHAZ was identified to be a direct target of miR-22 and its overexpression partially counteracted the inhibitory effects of miR-22 on HCC cells. Finally, molecular studies further confirmed that miR-22 promoted the accumulation of FOXO3a in nucleus and subsequently reversed invasive phenotype of HCC cells by repressing YWHAZ-mediated AKT phosphorylation. Taken together, these data demonstrate that miR-22 exhibits tumor-suppressive effects in HCC cells by regulating YWHAZ/AKT/FOXO3a signaling and might be used as an independent prognostic indicator for HCC patients.

Su R, Gong JN, Chen MT, et al.
c-Myc suppresses miR-451⊣YWTAZ/AKT axis via recruiting HDAC3 in acute myeloid leukemia.
Oncotarget. 2016; 7(47):77430-77443 [PubMed] Free Access to Full Article Related Publications
Aberrant activation of c-Myc plays an important oncogenic role via regulating a series of coding and non-coding genes in acute myeloid leukemia (AML). Histone deacetylases (HDACs) can remove acetyl group from histone and regulate gene expression via changing chromatin structure. Here, we found miR-451 is abnormally down-regulated in AML patient samples; c-Myc recruits HDAC3 to form a transcriptional suppressor complex, co-localizes on the miR-451 promoter, epigenetically inhibits its transcription and finally induces its downregulation in AML. Furthermore, our in vitro and in vivo results suggest that miR-451 functions as a tumor suppressor via promoting apoptosis and suppressing malignant cell proliferation. The mechanistic study demonstrated that miR-451 directly targets YWHAZ mRNA and suppresses YWHAZ/AKT signaling in AML. Knockdown of c-Myc results in restoration of miR-451 and inhibition of YWHAZ/AKT signaling. In AML patients, low level of miR-451 is negatively correlated with high levels of c-Myc and YWHAZ, while c-Myc level is positively related to YWHAZ expression. These results suggested that c-Myc⊣miR-451⊣YWHAZ/AKT cascade might play a crucial role during leukemogenesis, and reintroduction of miR-451 could be as a potential strategy for AML therapy.

Song T, Tian X, Kai F, et al.
Loss of Par3 promotes lung adenocarcinoma metastasis through 14-3-3ζ protein.
Oncotarget. 2016; 7(39):64260-64273 [PubMed] Free Access to Full Article Related Publications
Partitioning defective protein 3 (Par3) can activate the Tiam1/Rac pathway to inhibit invasion and metastasis in many cancers; however, the role of Par3 in lung adenocarcinoma remains unknown. Here we show that Par3 is downregulated in lung adenocarcinoma tissues and is associated with higher rates of lymph node metastasis and recurrence. Our functional study demonstrated that knock-down of Par3 promoted lung adenocarcinoma cell growth, cell migration, tumor formation, and metastasis, all of which were effectively inhibited when 14-3-3ζ was silenced. We found that Par3 binded with 14-3-3ζ protein and also showed that Par3 abrogated the binding of 14-3-3ζ to Tiam1, which was responsible for Rac1 activation. Knock-down of 14-3-3ζ inhibited Tiam1/Rac-GTP activation and blocked the invasive behavior of cells lacking Par3. These data suggest that loss of Par3 promotes metastatic behavior in lung adenocarcinoma cells through 14-3-3ζ protein.

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