Gene Summary

Gene:ELAVL1; ELAV like RNA binding protein 1
Aliases: HUR, Hua, MelG, ELAV1
Summary:The protein encoded by this gene is a member of the ELAVL family of RNA-binding proteins that contain several RNA recognition motifs, and selectively bind AU-rich elements (AREs) found in the 3' untranslated regions of mRNAs. AREs signal degradation of mRNAs as a means to regulate gene expression, thus by binding AREs, the ELAVL family of proteins play a role in stabilizing ARE-containing mRNAs. This gene has been implicated in a variety of biological processes and has been linked to a number of diseases, including cancer. It is highly expressed in many cancers, and could be potentially useful in cancer diagnosis, prognosis, and therapy. [provided by RefSeq, Sep 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ELAV-like protein 1
Source:NCBIAccessed: 30 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 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: ELAVL1 (cancer-related)

Weijin F, Zhibin X, Shengfeng Z, et al.
The clinical significance of PYCR1 expression in renal cell carcinoma.
Medicine (Baltimore). 2019; 98(28):e16384 [PubMed] Free Access to Full Article Related Publications
Pyrroline-5-carboxylate reductase 1 (PYCR1) is an enzyme involved in cell metabolism and is upregulated in cancer. However, the correlations of PYCR1 expression with the clinicopathological features and prognosis of renal cell carcinoma (RCC) remain unclear. The purpose of this study was to identify the expression of PYCR1 and its clinical relevance in RCC patients.PYCR1 mRNA expression differences between RCC and the adjacent normal renal tissues were assessed using the Cancer Genome Atlas database (TCGA). Subsequently, the expression of PYCR1 mRNA and protein were evaluated by quantitative real-time polymerase chain reaction, Western blot, and immunochemistry using 30 paired frozen samples of RCC and the adjacent normal renal tissues. The protein expression of PYCR1 was evaluated by immunostaining formalin-fixed, paraffin-embedded sections of RCC samples from 96 patients who underwent radical nephrectomy, and its relationship with clinical features were analyzed. Nonpaired t tests were used to statistically analyze the differences between the 2 groups. Cox univariable and multivariable analyses of overall survival (OS) among RCC patients were performed.The expression of PYCR1 mRNA was significantly upregulated in RCC tissues compared to adjacent normal renal tissues in the TCGA database (P < .01). The area under the receiver operating characteristic curve value was 0.748. The expression of PYCR1 mRNA and protein was significantly upregulated in RCC compared with that in paired normal renal tissues (P < .01). Higher PYCR1 levels were associated with metastasis (P < .01). Kaplan-Meier survival curves indicated that higher PYCR1 expression was correlated with poorer OS. Therefore, PYCR1 may act as a novel prognostic marker and therapeutic target in the diagnosis and treatment of RCC.

Feng T, Zhang P, Sun Y, et al.
High throughput sequencing identifies breast cancer-secreted exosomal LncRNAs initiating pulmonary pre-metastatic niche formation.
Gene. 2019; 710:258-264 [PubMed] Related Publications
OBJECTIVE: Increasing evidence indicated that cancer-secreted exosomes played an important role in tumor metastasis. However, the function of exosomes in breast cancer pulmonary metastasis remains unknown. The aim of the study was to investigate the role of exosome-derived from breast cancer-secreted long non-coding RNAs (LncRNAs) on pre-metastatic niche formation in pulmonary metastasis.
METHODS: Exosomes-derived from breast cancer were separated by ultracentrifugation. The high-throughput sequencing, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were used to detect and evaluate the differential expression of LncRNAs in lung fibroblasts with exosomes treated. And quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify candidate LncRNAs expression.
RESULTS: We found that exosomes-derived from breast cancer induced lung fibroblasts proliferation and migration. In addition, a large number of LncRNAs expression abnormalities were involved in the breast cancer lung metastasis microenvironment.
CONCLUSION: Our findings suggested that exosomal LncRNAs facilitated tumor pre-metastatic niche formation and represented a novel mechanistic insight into the molecular mechanism of cancer metastasis microenvironment.

Kim HS, Kim KM, Lee SB, et al.
Clinicopathological and biomolecular characteristics of stage IIB/IIC and stage IIIA colon cancer: Insight into the survival paradox.
J Surg Oncol. 2019; 120(3):423-430 [PubMed] Related Publications
BACKGROUND: A survival paradox of stage IIB/IIC and IIIA colon cancer has been consistently observed throughout revisions of the TNM system. This study aimed to understand this paradox with clinicopathological and molecular differences.
METHODS: Clinicopathological characteristics of patients with pathologically confirmed stage IIB/IIC or IIIA colon cancer were retrospectively reviewed from a database. Publicly available molecular data were retrieved, and intrinsic subtypes were identified and subjected to gene sets enrichment analysis (GSEA).
RESULTS: Among the 159 patients included in the clinicopathological analysis, those at stage IIB/IIC had worse 3-year disease-free and overall survival than those at stage IIIA (59.3% vs 91.7%, P < 0.001 and 82.7% vs 98.5%, P < 0.001, respectively), even after adjusting for confounding factors. Data of 95 patients were retrieved from public databases, demonstrating a higher frequency of the microsatellite instable subtype in stage IIB/IIC. The consensus molecular subtype distribution pattern differed between the groups. The GSEA further suggested the protumor inflammatory reaction might be more prominent in stage IIB/IIC.
CONCLUSIONS: The survival paradox in colon cancer was confirmed and appears to be a multifactorial phenomenon not attributed to a single clinicopathologic factor. However, the greater molecular heterogeneity in stage IIB/IIC could contribute to the poor prognosis.

Zhu LX, Liu Q, Hua YF, et al.
Systematic Profiling and Evaluation of Structure-based Kinase-Inhibitor Interactome in Cervical Cancer by Integrating In Silico Analyses and In Vitro Assays at Molecular and Cellular Levels.
Comput Biol Chem. 2019; 80:324-332 [PubMed] Related Publications
Various protein kinases are implicated in the pathogenesis of human cervical cancer and many kinase inhibitors have been used to regulate the activity of protein kinases involved in the disease signaling networks. In the present study, a systematic kinase-inhibitor interactome is created for various small-molecule inhibitors across diverse cervical cancer-related kinases by using ontology enrichment, molecular docking, dynamics simulation and energetics analysis. The interactome profile is examined in detail with heatmap analysis and heuristic clustering to derive promising inhibitors that are highly potential to target the kinome of human cervical cancer in a multi-target manner. A number of hit and unhit inhibitors are selected and their cell-suppressing effects are tested against human cervical carcinoma HeLa, from which several inhibitor compounds with high cytotoxicity are successfully identified. A further kinase assay confirms that these inhibitors can generally target their noncognate kinases HER3 and BRaf in cervical cancer with a high or moderate activity; the activity profile are comparable with or even better than that of cognate kinases inhibitors, with IC

Sheng Y, Ji Z, Zhao H, et al.
Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukaemia cells.
Cell Prolif. 2019; 52(4):e12611 [PubMed] Related Publications
OBJECTIVES: Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.
MATERIALS AND METHODS: The level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34
RESULTS: SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect.
CONCLUSIONS: Our study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.

Wang X, Hua Y, Xu G, et al.
Targeting EZH2 for glioma therapy with a novel nanoparticle-siRNA complex.
Int J Nanomedicine. 2019; 14:2637-2653 [PubMed] Free Access to Full Article Related Publications
Background: For the past few years, gene-therapy has recently shown considerable clinical benefit in cancer therapy, and the applications of gene therapies in cancer treatments continue to increase perennially. EZH2, an ideal candidate for tumor gene therapy, plays an important role in the tumorigenesis.
Methods: In this study, we developed a novel gene delivery system with a self-assembly method by Methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) and DOTAP(DMC). And EZH2si-DMC was used to research anti-glioma both in vitro and in vivo.
Results: DMC with zeta-potential value of 36.7 mV and size of 35.6 nm showed good performance in the delivery siRNA to glioma cell in vitro with high 98% transfection efficiency. EZH2si-DMC showed good anti-glioma effect in vitro through inducing cell apoptosis and inhibiting cell growth. What's more, treatment of tumor-bearing mice with DMC-EZH2si complex had significantly inhibited tumor growth at the subcutaneous model in vivo by inhibiting EZH2 protein expression, promoting apoptosis and reducing proliferation.
Conclusion: The EZH2 siRNA and DMC complex may be used to treat the glioma in clinical as a new drug.

Hua RX, Zhuo Z, Zhu J, et al.
LIG3 gene polymorphisms and risk of gastric cancer in a Southern Chinese population.
Gene. 2019; 705:90-94 [PubMed] Related Publications
DNA ligase III (LIG3) has been implicated in the etiology of cancer. However, few studies have accessed the association of LIG3 single nucleotide polymorphisms (SNPs) with gastric cancer risk, especially in Chinese population. The current study was undertaken to investigate contribution of LIG3 gene polymorphisms to gastric cancer risk. We first applied TaqMan assay to genotype three LIG3 gene SNPs (rs1052536 C > T, rs3744356 C > T, rs4796030 A > C) in 1142 patients with gastric cancer and 1173 healthy controls. And then, we adopted unconditional multivariate logistic regression analysis to estimate the association between LIG3 SNP genotypes and gastric cancer risk. In all, no positive association was found between the three LIG3 SNPs and gastric cancer risk in single locus analysis or combined risk genotypes analysis. However, compared with participants with rs4796030 AA genotype, participants with the AC/CC had a decreased risk of developing tumors from cardia at an adjusted OR of 0.68 (95% CI = 0.48-0.96, P = 0.026). In addition, we found that participants harboring 2-3 risk genotypes were at a significantly increased risk of developing tumor from cardia (adjusted OR = 1.63, 95% CI = 1.16-2.28, P = 0.005). These results suggest that genetic variations in LIG3 gene may play a weak role in modifying the risk of gastric cancer. Future functional studies should be performed to elucidate the biological role of LIG3 polymorphisms in gastric cancer carcinogenesis.

Yang MW, Fu XL, Jiang YS, et al.
Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas.
World J Gastroenterol. 2019; 25(14):1684-1696 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown.
AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.
METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1
RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1
CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.

Yu J, Yan Y, Hua C, Ming L
Upregulation of lncRNA SNHG1 is associated with metastasis and poor prognosis in cancers: A meta-analysis.
Medicine (Baltimore). 2019; 98(16):e15196 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidence suggested that the expression level of long noncoding RNA small nucleolar RNA host gene 1 (lncRNA SNHG1) was upregulated in various cancers, and high expression of SNHG1 was associated with metastasis and prognosis in patients with cancer.The relationship between SNHG1 expression and metastasis or prognosis in malignant tumors was investigated in this meta-analysis.
METHODS: A systematic search was performed in PubMed, Web of Science, and Cochrane Library from inception until May 31, 2018. Hazard ratio (HR) or odds ratio (OR) with 95% confidence intervals (95% CIs) were calculated to demonstrate prognostic value of SNHG1 using Stata 12.0 software.
RESULTS: A total of 10 studies including 1129 patients were finally enrolled in the meta-analysis based on the inclusion and exclusion criteria. Increased SNHG1 expression was significantly associated with lymph node metastasis (OR = 3.28, 95% CI = 2.02-5.33) and advanced TNM stage (OR = 0.26, 95% CI = 0.16-0.43). Moreover, high expression of SNHG1 could predict poor overall survival (HR = 2.32, 95% CI = 1.90-2.83), event-free survival (HR = 1.58, 95% CI = 1.06-2.35), recurrence-free survival (HR = 2.15, 95% CI = 1.23-3.77), progression-free survival (HR = 2.75, 95% CI = 1.70-4.46), and disease-free survival (HR = 1.93, 95% CI = 1.10-3.40) in patients with cancer.
CONCLUSION: The present meta-analysis demonstrated that upregulation of lncRNA SNHG1 might serve as a useful prognostic biomarker in various cancers.

Hua L, Wang G, Wang Z, et al.
Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth.
J Neurooncol. 2019; 143(1):35-47 [PubMed] Related Publications
PURPOSE: Glioma is a highly aggressive and lethal brain tumor. Signal transducers and activators of transcription (STAT) pathway are widely implicated in glioma carcinogenesis. Our previous study found that the Fynrelated kinase (FRK) gene, plays as a tumor suppressor in the development and progression of glioma. This study aimed to investigate the role of FRK in the activation pathway of STATs and its effect on the growth of glioma.
METHODS: The U251 and U87 cells with stable FRK overexpression were generated by lentivirus technique. The effects of FRK on the related proteins of STAT signaling pathway were detected by western blotting. Coimmunoprecipitation was used to detect the association of FRK and STAT1. The effects of STAT1 on the proliferation of glioma cells were detected by CCK8 or Edu cell proliferation assays. The expressions and correlation of FRK and p-STAT1 in glioma tissues were detectd by western blotting or immunohistochemistry. The effect of FRK on the growth of glioma was investigated in vivo mouse model.
RESULTS: The level of p-JAK2 and p-STAT1 increased after FRK overexpression, while they decreased after FRK downregulation both in U251 and U87 cells. However, FRK had no effect on STAT3 phosphorylation. FRK-induced STAT1 activation was not dependent on JAK2. FRK associated with STAT1, induced STAT1 nuclear translocation and regulated the expressions of STAT1-related target genes. STAT1 overexpression suppressed the proliferation of glioma cells. In contrast, STAT1 knockdown by siRNA promoted glioma cell growth. Importantly, down-regulation of STAT1 partially attenuated FRK-induced growth suppression. The clinical sample-based study indicated that the expression of FRK was significantly correlated with the expression of p-STAT1. FRK significantly inhibited glioma tumor growth in vivo.
CONCLUSIONS: Our findings highlighted a critical role of FRK in tumor suppression ability through promoting STAT1 activation, and provided a potential therapeutic target for glioma.

Zhu H, Gan X, Jiang X, et al.
ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2.
J Exp Clin Cancer Res. 2019; 38(1):163 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ALKBH5 regulated the malignant behavior of breast cancer and glioblastoma. However, the expression and function of ALKBH5 in epithelial ovarian cancer have not yet been determined. In the present study, we investigated the expression and function of ALKBH5 in epithelial ovarian cancer with respect to its potential role in the tumorigenesis of the disease as well as an early diagnostic marker.
METHODS: Immunohistochemistry and western blot were used to detect protein expression. Gene silencing and over-expression experiment were used to study gene function. Cell proliferation assay and Matrigel invasion assays were used to detect cell proliferation and invasion, respectively. The nude mouse tumor formation experiment was used to evaluate the growth of cells in vivo.
RESULTS: The expression of ALKBH5 was found to be increased in epithelial ovarian cancer tissue as compared to the normal ovarian tissues. The silencing of ALKBH5 in SKOV3 cells enhanced the autophagy and inhibited the proliferation and invasion in vitro and in vivo, whereas the ectopic expression of ALKBH5 in A2780 cells exerted an opposite effect. Mechanical study revealed that ALKBH5 physically interacted with HuR. ALKBH5 activated EGFR-PIK3CA-AKT-mTOR signaling pathway. Also, ALKBH5 enhanced the stability of BCL-2 mRNA and promoted the interaction between Bcl-2 and Beclin1.
CONCLUSION: Overall, the present study identified ALKBH5 as a candidate oncogene in epithelial ovarian cancer and a potential target for ovarian cancer therapy.

Wang Z, Shen J, Sun W, et al.
Antitumor activity of Raddeanin A is mediated by Jun amino-terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma.
Cancer Sci. 2019; 110(5):1746-1759 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A (RA) is an active oleanane-type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose- and time-dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species (ROS) generation and JNK and ERK1/2 activation. Apoptosis induction was evaluated by the activation of caspase-3, caspase-8, and caspase-9 and poly-ADP ribose polymerase (PARP) cleavage. RA-induced cell death was significantly restored by the ROS scavenger glutathione (GSH), the pharmacological inhibitor of JNK SP600125, or specific JNK knockdown by shRNA. Additionally, signal transducer and activator of transcription 3 (STAT3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH, SP600125, and JNK-shRNA. Further investigation showed that STAT3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK/c-Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

Xi Y, Zhang X, Yang Z, et al.
Prognositic significance of P-cadherin expression in breast cancer: Protocol for a meta-analysis.
Medicine (Baltimore). 2019; 98(12):e14924 [PubMed] Related Publications
BACKGROUND: P-cadherin is a calcium-dependent cell-cell adhesion glycoprotein. It has been implicated in invasiveness and metastasis. However, the clinical prognostic value of overexpression of P-cadherin in patients with breast cancer (BC) remains unsettled.
METHODS: A systematic literature search will be performed in all available databases to quantitatively review eligible studies and identify all relevant data, which could be used to detect the relationship between overexpression of P-cadherin and overall survival (OS), disease-free survival (DFS), and clinicopathological parameters. Hazard ratio and 95% confidence intervals (CIs) or P value will be employed as effect measures to estimate the correlation between P-cadherin and the oncologic outcomes including overall survival (OS), disease-free survival (DFS). Odds ratios (ORs) and the 95% CIs will be evaluated for the pooled analysis of the correlation between P-cadherin expression and clinicopathological features. We will use the Review Manager (Revman) 5.3.5 software (Cochrane Community, London, United Kingdom) and STATA 14 software (version 14.0; Stata Corp, College Station, TX) to perform the meta-analysis to calculate the data.
RESULTS: The review will provide a high-quality synthesis of current evidence of the prognostic role of P-cadherin in BCs. The results will be published in a peer-reviewed journal.
CONCLUSION: We hope that the results of this study will provide significant evidence to assess whether the expression of P-cadherin is associated with poor prognosis in patients with BC.
PROSPERO REGISTRATION NUMBER: This meta-analysis protocol has been registered in the PROSPERO network with registration number: CRD42019119880.

Dong J, Zhang RY, Sun N, et al.
Bio-Inspired NanoVilli Chips for Enhanced Capture of Tumor-Derived Extracellular Vesicles: Toward Non-Invasive Detection of Gene Alterations in Non-Small Cell Lung Cancer.
ACS Appl Mater Interfaces. 2019; 11(15):13973-13983 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Tumor-derived extracellular vesicles (EVs) present in bodily fluids are emerging liquid biopsy markers for non-invasive cancer diagnosis and treatment monitoring. Because the majority of EVs in circulation are not of tumor origin, it is critical to develop new platforms capable of enriching tumor-derived EVs from the blood. Herein, we introduce a biostructure-inspired NanoVilli Chip, capable of highly efficient and reproducible immunoaffinity capture of tumor-derived EVs from blood plasma samples. Anti-EpCAM-grafted silicon nanowire arrays were engineered to mimic the distinctive structures of intestinal microvilli, dramatically increasing surface area and enhancing tumor-derived EV capture. RNA in the captured EVs can be recovered for downstream molecular analyses by reverse transcription Droplet Digital PCR. We demonstrate that this assay can be applied to monitor the dynamic changes of ROS1 rearrangements and epidermal growth factor receptor T790M mutations that predict treatment responses and disease progression in non-small cell lung cancer patients.

Hua M, Qin Y, Sheng M, et al.
miR‑145 suppresses ovarian cancer progression via modulation of cell growth and invasion by targeting CCND2 and E2F3.
Mol Med Rep. 2019; 19(5):3575-3583 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
MicroRNAs (miRNA/miRs) have been demonstrated to be critical post‑transcriptional modulators of gene expression during tumorigenesis. Numerous miRNAs have been revealed to be downregulated in human epithelial ovarian cancer (EOC). In the present study, it was observed that the expression of miR‑145 was decreased in EOC tissues and cell lines. Overexpression of miR‑145 inhibited the proliferation, migration and invasion of EOC cells. The D‑type cyclin 2, cyclin D2 (CCND2), and E2F transcription factor 3 (E2F3) were confirmed to be targets of miR‑145. In addition, restoration of these 2 genes significantly reversed the tumor suppressive effects of miR‑145. Collectively, the results indicated that miR‑145 serves a critical role in suppressing the biological behavior of EOC cells by targeting CCND2 and E2F3. Therefore, miR‑145 was suggested to be a potential miRNA‑based therapeutic target in ovarian cancer.

Bai X, Hua S, Zhang J, Xu S
The MicroRNA Family Both in Normal Development and in Different Diseases: The miR-17-92 Cluster.
Biomed Res Int. 2019; 2019:9450240 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
An increasing number of research studies over recent years have focused on the function of microRNA (miRNA) molecules which have unique characteristics in terms of structure and function. They represent a class of endogenous noncoding single-strand small molecules. An abundance of miRNA clusters has been found in the genomes of various organisms often located in a polycistron. The miR-17-92 family is among the most famous miRNAs and has been identified as an oncogene. The functions of this cluster, together with the seven individual molecules that it comprises, are most related to cancers, so it would not be surprising that they are considered to have involvement in the development of tumors. The miR-17-92 cluster is therefore expected not only to be a tumor marker, but also to perform an important role in the early diagnosis of those diseases and possibly also be a target for tumor biotherapy. The miR-17-92 cluster affects the development of disease by regulating many related cellular processes and multiple target genes. Interestingly, it also has important roles that cannot be ignored in disease of the nervous system and circulation and modulates the growth and development of bone. Therefore, it provides new opportunities for disease prevention, clinical diagnosis, prognosis, and targeted therapy. Here we review the role of the miR-17-92 cluster that has received little attention in relation to neurological diseases, cardiac diseases, and the development of bone and tumors.

Li S, Zhang W, Jiang K, et al.
Nanobody against the E7 oncoprotein of human papillomavirus 16.
Mol Immunol. 2019; 109:12-19 [PubMed] Related Publications
The persistent infection of high-risk human papillomavirus (HPV) is one of the most common causes of cervical cancer. It is well documented that expression of two oncogenes (E6/E7) plays a key role in tumor progression. HPV16E7 -targeting via nanobody (Nb) therefore could be beneficial for HPV16-associated cancer diagnosis and therapy. In this work, phage-display approach was employed to select the high affinity HPV16E7-specific Nb. Firstly; a high-quality immune library was constructed. After three round of biopanning, high-affinity HPV16 E7-specific nanobodies were retrieved. By phage ELISA and sequencing, four different sequences of anti- HPV16E7 nanobodies were selected. Then recombinant nanobody Nb2 was cloned and expressed in E. coli, and the specificity and thermal stability of purified Nb2 was evaluated. To examine the potential of Nb2 as an inhibitor of E7 function, Nb2 was expressed within HPV16 positive cells. Proliferation assay showed that the intracellular expressed Nb2 as an intrabody can decrease the growth of HPV16-positive cells. The results indicate that Nb2 as an intracellular antibody directed towards HPV oncoprotein E7 has great promise in applications for the therapy of HPV16-associated disease.

Zhang Z, Dong Y, Hua J, et al.
A five-miRNA signature predicts survival in gastric cancer using bioinformatics analysis.
Gene. 2019; 699:125-134 [PubMed] Related Publications
Abnormal expression of miRNAs is critical for gastric cancer progression. Here, we aimed to identify the differential expression of miRNAs in normal and cancerous gastric tissues and build a nomogram for effectively predicting the survival of patients with gastric cancer. We used high-throughput miRNA data in The Cancer Genome Atlas (TCGA) database for this study. The discriminative capabilities and predictive accuracy of the nomogram depended on the calibration curve and concordance index (C-index), and comparisons were made between the nomogram and current gastric cancer staging systems. Data of 87 patients collected from TCGA as bootstrap resamples were used to validate the results. In total, 129 miRNAs were differential expressed, of which, prognostic function was associated with five miRNAs using Kaplan-Meier analysis. Functional enrichment analysis showed that the target genes of these miRNAs were involved in various cancer-related pathways. Age, metastasis, lymph node status, T stage and the five-miRNA signature were selected as independent survival variables, in the nomogram for primary cohort multivariate analysis. According to the survival probability calibration curve, the nomogram predictions were consistent with the actual observations. The survival predicting nomogram showed a C-index of 0.72 (95% CI, 0.64 to 0.78), which was significantly higher than the C-index of the American Joint Committee on Cancer (AJCC) seventh edition (0.60; P < 0.001). We suggest that the proposed nomogram could be used to accurately predict the prognosis of patients with gastric cancer.

Mou T, Xie F, Zhong P, et al.
MiR-345-5p functions as a tumor suppressor in pancreatic cancer by directly targeting CCL8.
Biomed Pharmacother. 2019; 111:891-900 [PubMed] Related Publications
BACKGROUND: Increasing evidence has demonstrated that microRNAs (miRNAs) are key regulators of human diseases and can serve as prognostic markers for several cancers, such as pancreatic ductal adenocarcinoma (PDAC). Previous studies have revealed various functions for miR-345-5p in several cancers. However, the role and potential mechanism of miR-345-5p in PDAC have not been resolved.
METHODS: Quantitative RT-PCR was performed to investigate the expression levels of miR-345-5p in pancreatic cancer tissues and cell lines, and the effect of miR-345-5p on the proliferation and invasiveness of pancreatic cancer was examined in Transwell assays with miR-345-5p overexpression. We used Western blot assay to explore the underlying mechanisms. Immunofluorescence staining was performed to examine changes in the cytoskeleton of PANC-1 cells in response to miR-345-5p. Luciferase assays were used to clarify the target and regulation mechanism of miR-345-5p.
RESULTS: miR-345-5p expression was downregulated in PDAC cells and tissues. Upregulated miR-345-5p expression inhibited the proliferation and metastasis of PDAC cells. We identified CCL8 as a direct target of miR-345-5p and found CCL8 expression was inversely correlated with miR-345-5p expression in PDAC samples. CCL8 could activate the NF-κB signaling pathway to promote the proliferation and invasiveness of PDAC cells. These results suggested that miR-345-5p inhibited PDAC progression by inactivating NF-κB signaling.
CONCLUSIONS: Here we demonstrated that miR-345-5p was a tumor-suppressive miRNA in pancreatic cancer progression by targeting CCL8. Our results suggest miR-345-5p may be a potential therapeutic biomarker for pancreatic cancer treatment.

Yao Y, Hua Q, Zhou Y, Shen H
CircRNA has_circ_0001946 promotes cell growth in lung adenocarcinoma by regulating miR-135a-5p/SIRT1 axis and activating Wnt/β-catenin signaling pathway.
Biomed Pharmacother. 2019; 111:1367-1375 [PubMed] Related Publications
Circular RNAs (circRNAs) are involved in the tumorigenesis and progression of human cancers. However, little is known about the biological role and mechanism of circRNAs in lung adenocarcinoma (LAC). In the present study, we applied microarray analysis to screen for LAC-specific circRNAs. Top ten upregulated circRNAs were chosen for qRT-PCR analysis. Among them, circ_0001946 was significantly overexpressed in both LAC tissues and cell lines. In addition, the expression level of circ_0001946 was positively correlated with TNM stage and tumor size. Using Kaplan-Meier analysis, we found that circ_0001946 expression was negatively related with the overall survival of LAC patients. Next, we treated LAC cells with circ_0001946-specific shRNAs and found that knockdown of circ_0001946 inhibited LAC cell growth in vitro and in vivo. Mechanism investigation revealed that circ_0001946 was located in the cytoplasm of LAC cells and acted as a molecular sponge of miR-135a-5p to upregulate Sirtuin 1 (SIRT1) expression. Rescue assays further validated the role of circ_0001946-miR-135a-5p-SIRT1 axis in LAC progression. Additionally, SIRT1 has been demonstrated to be a positive regulator of Wnt/β-catenin signaling pathway. Western blot analysis revealed that circ_0001946 regulated SIRT1/Wnt/β-catenin signaling pathway. In conclusion, our findings suggested that circ_0001946 might be a potential biomarker for the diagnosis or treatment of LAC.

Hua F, Tian Y, Gao Y, et al.
Colony‑stimulating factor 1 receptor inhibition blocks macrophage infiltration and endometrial cancer cell proliferation.
Mol Med Rep. 2019; 19(4):3139-3147 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Tumor‑associated macrophages (TAMs) promote the progression of endometrial cancer (EC), but the mechanism of TAM in EC cell proliferation remains unclear. It was found that colony stimulating factor (CSF)‑1 and CSF‑1 receptor (CSF‑1R) were highly expressed in EC tissues of patients and two EC cell lines (ECC‑1 and HEC‑1A). Using wound‑healing and chemotactic migration assays to evaluate the role of EC cells in the induction of macrophage migration, it was found that the supernatant of EC cells promoted macrophage cell line (U937) migration; however, the migration capacity of U937 weakened when CSF‑1R was blocked. Subsequently, inhibition of CSF‑1 expression in EC cells also restrained U937 migration. Additionally, blocking CSF‑1R by PLX3397 treatment in U937 cells inhibited EC cell proliferation in a co‑culture system by inhibiting the expression of proliferation‑associated proteins (Janus kinase‑1, phosphoinositide 3‑kinase, AKT, cyclin kinase 2, 4 and retinoblastoma‑associated protein). Together, these results demonstrated that CSF‑1 secreted by EC cells promoted macrophage migration; similarly, CSF‑1‑stimulated macrophages promoted EC cell proliferation. These results suggested that the interaction between CSF‑1 and its receptor served an important role in promoting macrophage infiltration and progression of EC.

Jiang W, Jin G, Cai F, et al.
Extracellular signal-regulated kinase 5 increases radioresistance of lung cancer cells by enhancing the DNA damage response.
Exp Mol Med. 2019; 51(2):19 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Radiotherapy is a frequent mode of cancer treatment, although the development of radioresistance limits its effectiveness. Extensive investigations indicate the diversity of the mechanisms underlying radioresistance. Here, we aimed to explore the effects of extracellular signal-regulated kinase 5 (ERK5) on lung cancer radioresistance and the associated mechanisms. Our data showed that ERK5 is activated during solid lung cancer development, and ectopic expression of ERK5 promoted cell proliferation and G2/M cell cycle transition. In addition, we found that ERK5 is a potential regulator of radiosensitivity in lung cancer cells. Mechanistic investigations revealed that ERK5 could trigger IR-induced activation of Chk1, which has been implicated in DNA repair and cell cycle arrest in response to DNA double-strand breaks (DSBs). Subsequently, ERK5 knockdown or pharmacological inhibition selectively inhibited colony formation of lung cancer cells and enhanced IR-induced G2/M arrest and apoptosis. In vivo, ERK5 knockdown strongly radiosensitized A549 and LLC tumor xenografts to inhibition, with a higher apoptotic response and reduced tumor neovascularization. Taken together, our data indicate that ERK5 is a novel potential target for the treatment of lung cancer, and its expression might be used as a biomarker to predict radiosensitivity in NSCLC patients.

Chen X, Li X, Wang X, et al.
MUC16 impacts tumor proliferation and migration through cytoplasmic translocation of P120-catenin in epithelial ovarian cancer cells: an original research.
BMC Cancer. 2019; 19(1):171 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
BACKGROUND: Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic cancers, and its pathogenetic mechanism remains unclear. Here we show that MUC16 promotes the translocation of p120-catenin (p120ctn) to the cytoplasm and consequently activates ras homolog (Rho) GTPases RhoA/Cdc42 activation to modulate the proliferation and migration abilities of EOC cells.
METHODS: We collect 94 ovarian cancer (OC) patients' tissue samples to constitute tissue microarray (TMA) and analyze the MUC16 and p120ctn expression levels. Lentivirus transfection is used to overexpress cytoplasmic tail domain (CTD) of MUC16 and CRISPR/Cas9 genome-editing system is firstly used to knock out MUC16 in EOC cells. The proliferation or migration ability of cells is analyzed by MTS or migration assay.
RESULTS: We find that MUC16 and p120ctn are aberrantly overexpressed in 94 clinical OC samples compared with benign ovarian tumors (BOT). MUC16 is a critical inducer of the proliferation and migration of EOC cells and the CTD of MUC16 plays an important role during this process. In addition, we reveal the relationship between MUC16 and p120ctn, which has not previously been studied. We show that MUC16 promotes the translocation of p120ctn to the cytoplasm and consequently activates Rho GTPases to modulate the proliferation and migration abilities of EOC cells. The cell proliferation and migration abilities induced by MUC16 are mediated by p120ctn through RhoA/Cdc42 activation.
CONCLUSIONS: The highly expressed MUC16 promotes the translocation of p120ctn to the cytoplasm, where it activates RhoA/Cdc42 to modulate the proliferation and migration abilities of EOC cells. These findings may provide new targets for the treatment of EOC.

Huang WC, Jang TH, Tung SL, et al.
A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing β5-integrin/c-met signaling pathway.
J Exp Clin Cancer Res. 2019; 38(1):89 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
BACKGROUND: Targeting the c-Met signaling pathway has become a therapeutic strategy in multiple types of cancer. We unveiled a novel c-Met regulating mechanism that could be applied as a modality for oral squamous cell carcinoma (OSCC) therapy.
METHODS: Upregulation of keratin 16 (KRT16) was found by comparing isogenic pairs of low and high invasive human OSCC lines via microarray analysis. OSCC cells with ectopic expression or silencing of KRT16 were used to scrutinize functional roles and associated molecular mechanisms.
RESULTS: We observed that high KRT16 expression significantly correlated with poorer pathological differentiation, advanced stages, increased lymph nodes metastasis, and decreased survival rate from several Taiwanese OSCC patient cohorts. We further revealed that miR-365-3p could target ETS homologous factor (EHF), a KRT16 transcription factor, to decrease migration, invasion, metastasis and chemoresistance in OSCC cells via inhibition of KRT16. Under confocal microscopic examination, c-Met was found possibly partially associates with KRT16 through β5-integrin. Colocalization of these three proteins may facilitate c-Met and β5-integrin-mediated signaling in OSCC cells. Depletion of KRT16 led to increased protein degradation of β5-integrin and c-Met through a lysosomal pathway leading to inhibition of their downstream Src/STAT3/FAK/ERK signaling in OSCC cells. Knockdown of KRT16 enhanced chemosensitivity of OSCC towards 5-fluorouracil (5-FU). Various combination of c-Met inhibitor (foretinib), protein tyrosine kinase inhibitor (genistein), β5-integrin antibody, and 5-FU markedly augmented cytotoxic effects in OSCC cells as well as tumor killing effects in vitro and in vivo.
CONCLUSIONS: Our data indicate that targeting a novel miR-365-3p/EHF/KRT16/β5-integrin/c-Met signaling pathway could improve treatment efficacy in OSCC.

Hua TNM, Kim MK, Vo VTA, et al.
Inhibition of oncogenic Src induces FABP4-mediated lipolysis via PPARγ activation exerting cancer growth suppression.
EBioMedicine. 2019; 41:134-145 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
BACKGROUND: c-Src is a driver oncogene well-known for tumorigenic signaling, but little for metabolic function. Previous reports about c-Src regulation of glucose metabolism prompted us to investigate its function in other nutrient modulation, particularly in lipid metabolism.
METHODS: Oil-red O staining, cell growth assay, and tumor volume measurement were performed to determine lipid amount and growth inhibitory effect of treatments in lung cancer cells and xenograft model. Gene expression was evaluated by immunoblotting and relative RT-PCR. Transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) was assessed by luciferase assay. Reactive oxygen species (ROS) was measured using ROS sensing dye. Oxygen consumption rate was evaluated by Seahorse XF Mito Stress Test. Clinical relevance of candidate proteins was examined using patient samples and public database analysis.
FINDINGS: Inhibition of Src induced lipolysis and increased intracellular ROS. Src inhibition derepressed PPARγ transcriptional activity leading to induced expression of lipolytic gene fatty acid binding protein (FABP) 4 which accompanies reduced lipid droplets and decreased tumor growth. The reverse correlation of Src and FABP4 was confirmed in pair-matched lung cancer patient samples, and further analysis using public datasets revealed upregulation of lipolytic genes is associated with better prognosis of cancer patients.
INTERPRETATION: This study provides an insight of how oncogenic factor Src concurrently regulates both cellular signaling pathways and metabolic plasticity to drive cancer progression. FUND: National Research Foundation of Korea and Korea Health Industry Development Institute.

Lukosiute-Urboniene A, Jasukaitiene A, Silkuniene G, et al.
Human antigen R mediated post-transcriptional regulation of inhibitors of apoptosis proteins in pancreatic cancer.
World J Gastroenterol. 2019; 25(2):205-219 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
AIM: To determine the association of human antigen R (HuR) and inhibitors of apoptosis proteins (IAP1, IAP2) and prognosis in pancreatic cancer.
METHODS: Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreatic ductal adenocarcinoma (PDAC) were compared with normal pancreatic tissue. The correlations among IAP1/IAP2 and HuR as well as their respective correlations with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for survival analysis. Immunoprecipitation assay was performed to demonstrate HuR binding to IAP1, IAP2 mRNA. PANC1 cells were transfected with either anti-HuR siRNA or control siRNA for 72 h and quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot analysis was carried out.
RESULTS: RT-PCR analysis revealed that HuR, IAP1, IAP2 mRNA expression were accordingly 3.3-fold, 5.5-fold and 8.4 higher in the PDAC when compared to normal pancreas (
CONCLUSION: HuR mediated overexpression of IAP1 significantly correlates with poor outcomes and early progression of pancreatic cancer. Further studies are needed to assess the underlying mechanisms.

Taş İ, Han J, Park SY, et al.
Physciosporin suppresses the proliferation, motility and tumourigenesis of colorectal cancer cells.
Phytomedicine. 2019; 56:10-20 [PubMed] Related Publications
BACKGROUND: Lichens, which represent symbiotic associations of fungi and algae, are potential sources of numerous natural products. Physciosporin (PHY) is a potent secondary metabolite found in lichens and was recently reported to inhibit the motility of lung cancer cells via novel mechanisms.
PURPOSE: The present study investigated the anticancer potential of PHY on colorectal cancer (CRC) cells.
METHODS: PHY was isolated from lichen extract by preparative TLC. The effect of PHY on cell viability, motility and tumourigenicity was elucidated by MTT assay, hoechst staining, flow cytometric analysis, transwell invasion and migration assay, soft agar colony formation assay, Western blotting, qRT-PCR and PCR array in vitro as well as tumorigenicity study in vivo.
RESULTS: PHY decreased the viability of various CRC cell lines (Caco2, CT26, DLD1, HCT116 and SW620). Moreover, PHY elicited cytotoxic effects by inducing apoptosis at toxic concentrations. At non-toxic concentrations, PHY dose-dependently suppressed the invasion, migration and colony formation of CRC cells. PHY inhibited the motility of CRC cells by suppressing epithelial-mesenchymal transition and downregulating actin-based motility markers. In addition, PHY downregulated β-catenin and its downstream target genes cyclin-D1 and c-Myc. Moreover, PHY modulated KAI1 C-terminal-interacting tetraspanin and KAI1 expression, and downregulated the downstream transcription factors c-jun and c-fos. Finally, PHY administration showed considerable bioavailability and effectively decreased the growth of CRC xenografts in mice without causing toxicity.
CONCLUSION: PHY suppresses the growth and motility of CRC cells via novel mechanisms.

Lv Z, He K, Shi L, et al.
Interaction between C2ORF68 and HuR in human colorectal cancer.
Oncol Rep. 2019; 41(3):1918-1928 [PubMed] Related Publications
The detailed molecular mechanisms underlying the carcinogenesis of colorectal carcinoma (CRC) remain unknown. Therefore, the present study was designed to investigate the effect of the relationship between C2ORF68 and HuR in regards to the carcinogenesis of CRC. Immunohistochemistry, immunofluorescence, flow cytometry, Transwell migration and CCK‑8 assays, co‑immunoprecipitation, qRT‑PCR and western blot analysis were performed. The results revealed that expression of C2ORF68 was significantly upregulated in the cytoplasm and nucleus in rectal cancer, and upregulation of the expression of C2ORF68 was associated with lymph node metastasis and pathological grade. C2ORF68 and HuR were found to be mainly localized in the nucleus in both SW480 and LoVo cells. In LoVo+c2orf68,‑HuR and LoVo+c2orf68 cells, the cell apoptosis rate was significantly decreased, cell proliferation rate was significantly increased, and the cell migration rate was only significantly increased in the LoVo+c2orf68 cells. In SW480‑c2orf68,‑HuR, SW480‑c2orf68 and SW480‑HuR, the cell apoptosis rate was significantly increased. At the same time, cell proliferation and the cell migration rate were significantly decreased. The mRNA and protein expression levels of C2orf68, HuR, Bcl‑2, c‑Myc, cyclin D and cyclin A were upregulated, while the expression of Bax was downregulated in LoVo+c2orf68 and LoVo+c20rf68,‑HuR cells. Expression levels of C2orf68, HuR, Bcl‑2, c‑Myc, cyclin D and cyclin A were downregulated while Bax was upregulated in the SW480‑c2orf68,‑HuR, SW480‑c2orf68 and SW480‑HuR cells. In conclusion, it is suggested that c2orf68 is a potential carcinogenesis factor in rectal cancer. Furthermore, c2orf68 may have a synergistic effect with HuR in the onset and development of CRC.

Guo H, Ci X, Ahmed M, et al.
ONECUT2 is a driver of neuroendocrine prostate cancer.
Nat Commun. 2019; 10(1):278 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.

Lei WY, Hsiung SC, Wen SH, et al.
Total HLA Class I Antigen Loss with the Downregulation of Antigen-Processing Machinery Components in Two Newly Established Sarcomatoid Hepatocellular Carcinoma Cell Lines.
J Immunol Res. 2018; 2018:8363265 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Limited information is currently available concerning HLA class I antigen abnormalities in sarcomatoid hepatocellular carcinoma (sHCC). Here, we have analyzed the growth characteristics and HLA class I antigen status of four sHCC cell lines (sHCC29, sHCC63, sHCC74, and SAR-HCV); the first three were newly established in this study. Among the four, sHCC29 showed the highest growth rate

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