VIP

Gene Summary

Gene:VIP; vasoactive intestinal peptide
Aliases: PHM27
Location:6q25.2
Summary:The protein encoded by this gene belongs to the glucagon family. It stimulates myocardial contractility, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. The protein also acts as an antimicrobial peptide with antibacterial and antifungal activity. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Nov 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:VIP peptides
Source:NCBIAccessed: 16 March, 2017

Ontology:

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

Research Indicators

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

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Latest Publications: VIP (cancer-related)

Lu Y, Li Y, Chai X, et al.
Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia.
Gene. 2017; 607:41-46 [PubMed] Related Publications
Aberrant expression of long noncoding RNA (lncRNA) HULC is associated with various human cancers. However, the role of HULC in chronic myeloid leukemia (CML) is unknown. In this study, we found that HULC was remarkably overexpressed in both leukemia cell lines and primary hematopoietic cells derived from CML patients. The increase in HULC expression was positively correlated with clinical stages in CML. Moreover, the knockdown of HULC significantly inhibited CML cell proliferation and induced apoptosis by repressing c-Myc and Bcl-2. Furthermore, inhibition of HULC enhanced imatinib-induced apoptosis of CML cells. Further experiments demonstrated that HULC silencing markedly suppressed the phosphorylation of PI3K and AKT, indicating that enhancement of imatinib-induced apoptosis by HULC inhibition is related with the reduction of c-Myc expression and inhibition of PI3K/Akt pathway activity. Furthermore, HULC could modulate c-Myc and Bcl-2 by miR-200a as an endogenous sponge. Taken together, these results reveal that HULC promotes oncogenesis in CML and suggest a potential strategy for the CML treatment.

Li Y, Peng Y, Jiang X, et al.
Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome.
Eur J Endocrinol. 2017; 176(2):187-194 [PubMed] Related Publications
OBJECTIVE: Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing.
DESIGN AND METHODS: Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform.
RESULTS: We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1-24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors.
CONCLUSIONS: Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.

Liang P, Song Z, Chen D, et al.
GINS2 regulates matrix metallopeptidase 9 expression and cancer stem cell property in human triple negative Breast cancer.
Biomed Pharmacother. 2016; 84:1568-1574 [PubMed] Related Publications
GINS2, a subunit of GINS complex, is critical for the initiation of DNA replication and DNA replication fork progression. The expression of GINS2 is misregulated in many malignant tumors, such as leukemia, breast cancer and melanoma. However, the role of GINS in breast cancer remains poorly characterized. We investigate the possible effect and particular mechanism of GINS in breast cancer cells. We showed that expression of GINS2 is enriched in triple negative breast cancer (TNBC) cell lines. Furthermore, GINS2 knockdown decreased the growth, invasive ability and stem-like property of TNBC cells. Mechanistically, silencing of GINS2 in TNBC cells caused dramatic decrease of matrix metalloproteinase-9 (MMP9). Finally, the abundance of GINS2 correlated with the advance stages of tumor in human TNBC patients. Our studies provided insight into the molecular regulation of TNBC progression and invasion. More importantly, our data suggest that GINS2 could be an outstanding therapeutic target for inhibiting invasive TNBC growth and metastasis.

Wang FF, Wang S, Xue WH, Cheng JL
microRNA-590 suppresses the tumorigenesis and invasiveness of non-small cell lung cancer cells by targeting ADAM9.
Mol Cell Biochem. 2016; 423(1-2):29-37 [PubMed] Related Publications
microRNAs (miRNAs), a family of small non-coding RNA molecules, are implicated in cancer growth and progression. In the present study, we examined the expression and biological roles of miR-590 in non-small cell lung cancer (NSCLC). Compared to normal lung tissues, miR-590 expression was downregulated in primary NSCLCs and, to a greater extent, in corresponding brain metastases. NSCLC cell lines with high metastatic potential had significantly (P < 0.05) lower levels of miR-590 than those with low metastatic potential. Re-expression of miR-590 suppressed NSCLC cell proliferation, colony formation, migration, and invasion in vitro and tumorigenesis in vivo. In contrast, inhibition of miR-590 enhanced the migration and invasion of NSCLC cells. Mechanistic studies revealed that a disintegrin and metalloproteinase 9 (ADAM9) was a direct target of miR-590. Delivery of miR-590 mimic was found to decrease endogenous ADAM9 expression in NSCLC cells. Enforced expression of a miRNA-resistant form of ADAM9 significantly restored the aggressive behaviors in miR-590-overexpressing NSCLC cells. Taken together, our data reveal miR-590 as a tumor suppressor in NSCLC, which is at least partially mediated through targeting of ADAM9. Restoration of miR-590 may provide a promising therapeutic strategy for NSCLC.

Li C, Chen L, Zhao Y, et al.
Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model.
Gene. 2017; 598:20-26 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) causes female subfertility with ovarian disorders and may be associated with increased rate of early-pregnancy failure. Rat PCOS models were established using letrozole to understand the uterine pathogenesis of PCOS. The differential expression of microRNAs (miRNAs) was observed in rat uterus with PCOS. After estrous cycles were disrupted, significantly abnormal ovarian morphology and hormone level were observed in rats with PCOS. A total of 148 miRNAs differentially expressed were identified in the uterus from the letrozole-induced rat model compared with the control. These miRNAs included 111 upregulated miRNAs and 37 downregulated miRNAs. The differential expression of miR-484, miR-375-3p, miR-324-5p, and miR-223-3p was further confirmed by quantitative reverse transcription polymerase chain reaction. Bioinformatic analysis showed that these four miRNAs were predicted to regulate a large number of genes with different functions. Pathway analysis supported that target genes of miRNAs were involved in insulin secretion and signaling pathways, such as wnt, AMPK, PI3K-Akt, and Ras. These data indicated that miRNAs differentially expressed in rat uterus with PCOS may be associated with PCOS pathogenesis in the uterus. Our findings can help clarify the mechanism of uterine defects in PCOS.

Wang XZ, Cheng Y, Wang KL, et al.
Peperomin E reactivates silenced tumor suppressor genes in lung cancer cells by inhibition of DNA methyltransferase.
Cancer Sci. 2016; 107(10):1506-1519 [PubMed] Free Access to Full Article Related Publications
Advanced lung cancer has poor prognosis owing to its low sensitivity to current chemotherapy agents. Therefore, discovery of new therapeutic agents is urgently needed. In this study, we investigated the antitumor effects of peperomin E, a secolignan isolated from Peperomia dindygulensis, a frequently used Chinese folk medicine for lung cancer treatment. The results indicate that peperomin E has antiproliferative effects, promoting apoptosis and cell cycle arrest in non-small-cell lung cancer (NSCLC) cell lines in a dose-dependent manner, while showing lower toxicity against normal human lung epidermal cells. Peperomin E inhibited tumor growth in A549 xenograft BALB/c nude mice without significant secondary adverse effects, indicating that it may be safely used to treat NSCLC. Furthermore, the mechanisms underlying the anticancer effects of peperomin E have been investigated. Using an in silico target fishing method, we observed that peperomin E directly interacts with the active domain of DNA methyltransferase 1 (DNMT1), potentially affecting its genome methylation activity. Subsequent experiments verified that peperomin E decreased DNMT1 activity and expression, thereby decreasing global methylation and reactivating the epigenetically silenced tumor suppressor genes including RASSF1A, APC, RUNX3, and p16INK4, which in turn activates their mediated pro-apoptotic and cell cycle regulatory signaling pathways in lung cancer cells. The observations herein report for the first time that peperomin E is a potential chemotherapeutic agent for NSCLC. The anticancer effects of peperomin E may be partly attributable to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes through direct inhibition of the activity and expression of DNMT1.

Georg B, Falktoft B, Fahrenkrug J
PKA, novel PKC isoforms, and ERK is mediating PACAP auto-regulation via PAC1R in human neuroblastoma NB-1 cells.
Neuropeptides. 2016; 60:83-89 [PubMed] Related Publications
The neuropeptide PACAP is expressed throughout the central and peripheral nervous system where it modulates diverse physiological functions including neuropeptide gene expression. We here report that in human neuroblastoma NB-1 cells PACAP transiently induces its own expression. Maximal PACAP mRNA expression was found after stimulation with PACAP for 3h. PACAP auto-regulation was found to be mediated by activation of PACAP specific PAC1Rs as PACAP had >100-fold higher efficacy than VIP, and the PAC1R selective agonist Maxadilan potently induced PACAP gene expression. Experiments with pharmacological kinase inhibitors revealed that both PKA and novel but not conventional PKC isozymes were involved in the PACAP auto-regulation. Inhibition of MAPK/ERK kinase (MEK) also impeded the induction, and we found that PKA, novel PKC and ERK acted in parallel and were thus not part of the same pathways. The expression of the transcription factor EGR1 previously ascribed as target of PACAP signalling was found to be transiently induced by PACAP and pharmacological inhibition of either PKC or MEK1/2 abolished PACAP mediated EGR1 induction. In contrast, inhibition of PKA mediated increased PACAP mediated EGR1 induction. Experiments using siRNA against EGR1 to lower the expression did however not affect the PACAP auto-regulation indicating that this immediate early gene product is not part of PACAP auto-regulation in NB-1 cells. We here reveal that in NB-1 neuroblastoma cells, PACAP induces its own expression by activation of PAC1R, and that the signalling is different from the PAC1R signalling mediating induction of VIP in the same cells. PACAP auto-regulation depends on parallel activation of PKA, novel PKC isoforms, and ERK, while EGR1 does not seem to be part of the PACAP auto-regulation.

Gong C, Tan W, Chen K, et al.
Prognostic Value of a BCSC-associated MicroRNA Signature in Hormone Receptor-Positive HER2-Negative Breast Cancer.
EBioMedicine. 2016; 11:199-209 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Breast cancer patients with high proportion of cancer stem cells (BCSCs) have unfavorable clinical outcomes. MicroRNAs (miRNAs) regulate key features of BCSCs. We hypothesized that a biology-driven model based on BCSC-associated miRNAs could predict prognosis for the most common subtype, hormone receptor (HR)-positive, HER2-negative breast cancer patients.
PATIENTS AND METHODS: After screening candidate miRNAs based on literature review and a pilot study, we built a miRNA-based classifier using LASSO Cox regression method in the training group (n=202) and validated its prognostic accuracy in an internal (n=101) and two external validation groups (n=308).
RESULTS: In this multicenter study, a 10-miRNA classifier incorporating miR-21, miR-30c, miR-181a, miR-181c, miR-125b, miR-7, miR-200a, miR-135b, miR-22 and miR-200c was developed to predict distant relapse free survival (DRFS). With this classifier, HR+HER2- patients were scored and classified into high-risk and low-risk disease recurrence, which was significantly associated with 5-year DRFS of the patients. Moreover, this classifier outperformed traditional clinicopathological risk factors, IHC4 scoring and 21-gene Recurrence Score (RS). The patients with high-risk recurrence determined by this classifier benefit more from chemotherapy.
CONCLUSIONS: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This model may facilitate personalized therapy-decision making for HR+HER2- individuals.

Zhu M, Li M, Wang T, et al.
MicroRNA-137 represses FBI-1 to inhibit proliferation and in vitro invasion and migration of hepatocellular carcinoma cells.
Tumour Biol. 2016; 37(10):13995-14008 [PubMed] Related Publications
The pro-oncogene factor that binds to inducer of short transcripts-1 (FBI-1), which is encoded by ZBTB7A gene and belongs to POK (POZ/BTB and KrÜppel) protein family, has been shown to enhance hepatocellular carcinoma (HCC) cells proliferation and multi-drug resistance (MDR) process. However, the possibility that FBI-1 is a therapeutic target for further HCC treatment remains poorly determined. In the current study, two microRNA (miRNA) target prediction programs (TargetScan and MiRanda) were used to identify miR-137 as a potential regulator of FBI-1. Our results showed that expression of miR-137 was downregulated, while FBI-1 was upregulated in clinical HCC specimens, compared with paired non-tumor specimens. Overexpression of miR-137 via adenoviral vector inhibited the proliferation and anchorage-independent growth of HCC cells, HepG2 and MHCC-97H. Our data also showed that miR-137 repressed endogenous expression level of FBI-1, as well as Notch-1 and Survivin. MiR-137 also inhibited in vitro invasion and migration of HCC cells and attenuated their epithelial-mesenchymal transition (EMT) process. Moreover, miR-137 suppressed the growth rate of HepG2 cells in nude mice model. Overexpression of miR-137 via its adenoviral vector enhanced the sensitivity of HepG2 cells to anti-tumor drugs and attenuated the MDR process of a resistance cell line HepG2/adriamycin (ADR). Thus, FBI-1 downregulation mediated by miR-137 overexpression may be a potential strategy for HCC treatment.

Zhao Y, Zhang B, Lei Y, et al.
Knockdown of USP39 induces cell cycle arrest and apoptosis in melanoma.
Tumour Biol. 2016; 37(10):13167-13176 [PubMed] Related Publications
The spliceosome machinery composed of multimeric protein complexes guides precursor messenger RNAs (mRNAs) (pre-mRNAs) splicing in eukaryotic cells. Spliceosome components have been shown to be downregulated in cancer and could be a promising molecular target for anticancer therapy. The ubiquitin-specific protease 39 (USP39) is essential for pre-mRNA splicing, and upregulated USP39 expression is noted in a variety of cancers. However, the role of USP39 in the development and progression of melanoma remains unclear. In the present study, USP39 expression was found to be increased in melanoma tissues compared with that in nevus tissues. USP39 silencing via lentivirus-mediated short hairpin RNA (shRNA) significantly suppressed melanoma cell proliferation, induced G0/G1 cell cycle phase arrest, and increased apoptosis in vitro. Moreover, USP39 knockdown suppressed melanoma tumor growth in a xenograft model. In addition, USP39 silencing was associated with the increased expressions of p21, p27, and Bax. Furthermore, the inhibition of USP39 expression decreased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, indicating that ERK signaling pathways might be involved in the regulation of melanoma cell proliferation by USP39. Our findings suggest that USP39 may play crucial roles in the development and pathogenesis of melanoma, and it may serve as a potential therapeutic target for melanoma.

Zhang Q, Liu F, Wang B, et al.
HER-2 expression in biopsy and surgical specimen on prognosis of osteosarcoma: A systematic review and meta-analysis of 16 studies.
Medicine (Baltimore). 2016; 95(23):e3661 [PubMed] Free Access to Full Article Related Publications
Numerous original clinical studies have attempted to investigate the prognostic value of HER-2 overexpression in osteosarcoma, but the results of these studies are not consistent. This meta-analysis and systematic review was performed to further assess the correlation between HER-2 expression and prognosis in patients with osteosarcoma. A detailed search of relevant publications was conducted using 7 electronic databases: PubMed, Embase, the Cochrane library, the Wanfang database, the China National Knowledge Internet (CNKI) database, the Chinese VIP database, and the Chinese Biological Medical (CBM) Database for publications through August 1, 2015, using the following keywords (HER-2 OR ErbB-2 OR C-erbB-2 OR neu) AND (osteosarcoma OR osteogenic tumor). The bibliographies of potentially relevant articles and identified articles were then searched by hand. Eligible studies were those that enrolled participants with osteosarcoma and provided survival outcome in HER-2 positive and negative groups. The hazard ratio (HR) and 95% confidence interval (CI) for each individual study was calculated and pooled to obtain integrated estimates, using random effects modeling. Sixteen studies involving 934 participants with osteosarcoma met our inclusion criteria. HER-2 overexpression was documented in 42.2% of patients with osteosarcoma. Compared with patients without HER-2 overexpression, those overexpressing HER-2 had decreased overall survival (HR = 2.03, 95% CI: 1.36-3.03, P < 0.001). Statistical associations between HER-2 overexpression and unfavorable overall survival (OS) were observed for both biopsy and surgical removal specimens (HR = 2.07, 95%CI: 1.16-3.72, P = 0.014; and HR = 2.02, 95%CI: 1.10-3.71, P = 0.024). Results for disease-free survival (DFS) were similar. Overexpression of HER-2 is significantly associated with poor outcome for patients with osteosarcoma and should be assessed at diagnosis and after surgery as a prognostic factor. However, larger-scale multicenter clinical studies are needed to further support these findings.

Wang Y, Sun Y, Huang Y, et al.
Association study between Van der Woude Syndrome causative gene GRHL3 and nonsyndromic cleft lip with or without cleft palate in a Chinese cohort.
Gene. 2016; 588(1):69-73 [PubMed] Related Publications
Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects worldwide and is characterized by abnormalities of the orofacial structure. Syndromic CL/P is mainly caused by Mendelian disorders such as Van der Woude Syndrome (VWS). However, >70% of CL/P cases are nonsyndromic, characterized by isolated orofacial cleft without any known syndrome. The etiology of nonsyndromic CL/P (NSCL/P) remains elusive, but it has been suggested that causative genes of syndromic CL/P might also contribute to NSCL/P. As such, the VWS causative gene IRF6 has been extensively studied in NSCL/P. Recently, GRHL3 was identified as another VWS causative gene. Thus, it may be a novel candidate gene for NSCL/P. In the present study, we genotyped 10 tag SNPs covering GRHL3 and performed association analysis with NSCL/P in 504 cases and 455 healthy controls. Our preliminary results identified rs10903078, rs4638975, and a haplotype rs10903078-rs6659209 of GRHL3 that exceeded the significance threshold (p<0.05), though none survived Bonferroni correction for multiple comparisons. As the first study between GRHL3 and NSCL/P, the contribution of this gene to NSCL/P etiology should be interpreted with caution based on existing evidence. Further, the robustness of association between GRHL3 and NSCL/P should be further validated in expanded cohorts.

Lv B, Xie F, Zhao P, et al.
Promotion of Cellular Growth and Motility Is Independent of Enzymatic Activity of Fibroblast Activation Protein-α.
Cancer Genomics Proteomics. 2016 May-Jun; 13(3):201-8 [PubMed] Related Publications
BACKGROUND: Fibroblast activation protein-alpha (FAPα) is a type-II integral membrane serine protease and is expressed in most stromal fibroblasts. Recent studies showed that FAPα is also expressed in certain cancer cells but its role is still uncertain.
MATERIALS AND METHODS: We analyzed the non-enzymatic activity of FAPα in breast cancer cells by introducing an enzymatic mutant FAPα (FAPS624A), in which the serine catalytic triad was destroyed. FAPα overexpression and knockdown cells were generated as controls.
RESULTS: Cellular growth and motility were markedly increased in MCF-7 cells overexpressing FAPα and enzymatic-mutant FAPS624A. This is consistent with observations in FAPα-silenced BT549 cells. Western blotting showed activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and matrix metalloproteinase (MMP) 2/9 in both wild-type FAPα-overexpressing and enzymatic-mutant FAPS624A-overexpressing cells.
CONCLUSION: Promotion of cellular growth and motility is independent of the enzymatic activity of FAPα in breast cancer cells. The PI3K/AKT and MMP2/9 signaling pathways might be involved in such regulation.

Han JC, Xu F, Chen N, et al.
Promoter methylations of RASSF1A and p16 is associated with clinicopathological features in lung cancers.
J Cancer Res Ther. 2016 Jan-Mar; 12(1):340-9 [PubMed] Related Publications
UNLABELLED: Objection: The aim of this study is to investigate the association between promoter methylation of RASSF1A and p16 and the clinicopathological features in lung cancers.
MATERIALS AND METHODS: PubMed, EBSCO, Ovid, Wiley, Web of Science, Wanfang, and VIP databases were searched using combinations of keywords related to RASSF1A, p16, methylation, and lung cancers. After screening for relevant studies, following a strict inclusion and exclusion criteria; the selected studies were incorporated into the present meta.analysis conducted using Comprehensive Meta Analysis 2.0. (CMA 2.0).
RESULTS: We initially retrieved 402 studies, out which 13 studies met the inclusion and exclusion criteria for this meta.analysis, and contained a total of 1,259. patients with lung cancers. The results of this meta.analysis showed that the differences in promoter methylation ratio between the lung cancer patients in tumor, node, metastasis. (TNM) I.II and III.IV were not statistically significant. Based on histological types, patients with adenocarcinoma. (AC) and squamous cell carcinoma. (SCC) showed no significant differences in the promoter methylation ratios of RASSF1A, while the promoter methylation ratio of p16 was significantly higher in SCC patients compared to AC patients. Based on smoking status, the promoter methylation ratios of both RASSF1A and p16 was significantly higher in lung cancer patients with smoking history compared to nonsmokers.
CONCLUSION: The present meta.analysis provides convincing evidence that the promoter methylation ratio of RASSF1A and p16 is associated with clinicopathological features in lung cancers, and could be used as effective biomarkers in early diagnosis in lung cancers.

Cheng S, Zhang X, Huang N, et al.
Down-regulation of S100A9 inhibits osteosarcoma cell growth through inactivating MAPK and NF-κB signaling pathways.
BMC Cancer. 2016; 16:253 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Osteosarcoma (OS) is well-known for poor prognosis due to its high incidence of proliferation and metastasis. Researches have provided valuable insights into the tumorigenesis of S100A9 in some cancers. We aimed to understand the expression level, functions and mechanisms of S100A9 in human osteosarcoma for the first time.
METHODS: The expression of S100A9 protein was detected in 120 human osteosarcoma tissues and 40 normal human bone tissues using tissue microarrays analysis. The knockdown of S100A9 induced by RNA interference (RNAi) method in three osteosarcoma cell lines (U2OS, 143B, MG63) was applied to analyze the effects of S100A9 on cell proliferation, cell cycle distribution, migration, invasion and xenotransplanted tumors. Moreover, MAPK-ERK1/2, MAPK-p38, NF-κB-p65, NF-κB-p50, p21, p27, CDK2 and CDK4 were tested.
RESULTS: The expression of S100A9 was increased in human osteosarcoma issues and was positively correlated with clinical classification and survival rate. Down-regulation of S100A9 inhibited OS cellular proliferation, migration, invasion and cell cycle S phase in vitro and suppressed tumor formation in vivo with the reduction on PCNA and Ki67 proliferation index. Our data also demonstrated that knockdown of S100A9 repressed the protein levels of phospho-ERK1/2, phospho-p50, phospho-p65 except phospho-p38, and prompted up-regulation of p21 and p27 leading to inactivation of cyclin dependent kinase 2(CDK2) and cyclin dependent kinase 4(CDK4).
CONCLUSIONS: S100A9 might be a significant role for predicting osteosarcoma prognosis and down-regulation of S100A9 could be used as a potential target for gene therapy.

Wang Y, Liu Z, Yao B, et al.
Long non-coding RNA TUSC7 acts a molecular sponge for miR-10a and suppresses EMT in hepatocellular carcinoma.
Tumour Biol. 2016; 37(8):11429-41 [PubMed] Free Access to Full Article Related Publications
Despite advances in the roles of long non-coding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) in cancer biology, which has been identified as a tumor suppressor by regulating cell proliferation, apoptosis, migration, invasion, cell cycle, and tumor growth, the function of TUSC7 in hepatocellular carcinoma (HCC) remains unknown. In this study, we observed that the expression of TUSC7 was immensely decreased in HCC. Clinically, the lower expression of TUSC7 predicted poorer survival and may be an independent risk factor for HCC patients. Moreover, TUSC7 inhibited cell metastasis, invasion, and epithelial-to-mesenchymal transformation (EMT) through competitively binding miR-10a. Furthermore, we found that TUSC7 could decrease the expression of Eph tyrosine kinase receptor A4 (EphA4), a downstream target of miR-10a as well as an EMT suppressor, through TUSC7-miR-10a-EphA4 axis. Taken together, we demonstrate that TUSC7 suppresses EMT through the TUSC7-miR-10a-EphA4 axis, which may be a potential target for therapeutic intervention in HCC.

Zhang YZ, Chen X, Fan XX, et al.
Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation.
Molecules. 2016; 21(3):374 [PubMed] Related Publications
Non-small-cell lung cancer (NSCLC) dominates over 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) activating mutation is a common situation in NSCLC. In the clinic, molecular-targeting with Gefitinib as a tyrosine kinase inhibitor (TKI) for EGFR downstream signaling is initially effective. However, drug resistance frequently happens due to additional mutation on EGFR, such as substitution from threonine to methionine at amino acid position 790 (T790M). In this study, we screened a traditional Chinese medicine (TCM) compound library consisting of 800 single compounds in TKI-resistance NSCLC H1975 cells, which contains substitutions from leucine to arginine at amino acid 858 (L858R) and T790M mutation on EGFR. Attractively, among these compounds there are 24 compounds CC50 of which was less than 2.5 μM were identified. We have further investigated the mechanism of the most effective one, Digitoxin. It showed a significantly cytotoxic effect in H1975 cells by causing G2 phase arrest, also remarkably activated 5' adenosine monophosphate-activated protein kinase (AMPK). Moreover, we first proved that Digitoxin suppressed microtubule formation through decreasing α-tubulin. Therefore, it confirmed that Digitoxin effectively depressed the growth of TKI-resistance NSCLC H1975 cells by inhibiting microtubule polymerization and inducing cell cycle arrest.

Liu GX, Xi HQ, Sun XY, et al.
Isoprenaline Induces Periostin Expression in Gastric Cancer.
Yonsei Med J. 2016; 57(3):557-64 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Periostin mediates critical steps in gastric cancer and is involved in various signaling pathways. However, the roles of periostin in promoting gastric cancer metastasis are not clear. The aim of this study was to investigate the relevance between periostin expression and gastric cancer progression and the role of stress-related hormones in the regulation of cancer development and progression.
MATERIALS AND METHODS: Normal, cancerous and metastatic gastric tissues were collected from patients diagnosed with advanced gastric cancer. The in vivo expression of periostin was evaluated by in situ hybridization and immunofluorescent staining. Meanwhile, human gastric adenocarcinoma cell lines MKN-45 and BGC-803 were used to detect the in vitro expression of periostin by using quantitative real-time polymerase chain reaction (PCR) and western blotting.
RESULTS: Periostin is expressed in the stroma of the primary gastric tumors and metastases, but not in normal gastric tissue. In addition, we observed that periostin is located mainly in pericryptal fibroblasts, but not in the tumor cells, and strongly correlated to the expression of α-smooth muscle actin (SMA). Furthermore, the distribution patterns of periostin were broader as the clinical staging of tumors progressed. We also identified a role of stress-related signaling in promoting cancer development and progression, and found that isoprenaline upregulated expression levels of periostin in gastric cancer cells.
CONCLUSION: These findings suggest that the distribution pattern of periostin was broader as the clinical staging of the tumor progressed and found that isoprenaline upregulated expression levels of periostin in gastric cancer cells.

Wang M, Dong Q, Wang Y
Rab23 is overexpressed in human astrocytoma and promotes cell migration and invasion through regulation of Rac1.
Tumour Biol. 2016; 37(8):11049-55 [PubMed] Related Publications
Rab23 overexpression has been implicated in several human cancers. However, its biological roles and molecular mechanism in astrocytoma have not been elucidated. The aim of this study is to explore clinical significance and biological roles of Rab23 in astrocytoma. We observed negative Rab23 staining in normal astrocytes and positive staining in 39 out of 86 (45 %) astrocytoma specimens using immunohistochemistry. The positive rate of Rab23 was higher in grades III and IV (56.5 %, 26/46) than grades I + II astrocytomas (32.5 %, 13/40, p < 0.05). Transfection of Rab23 plasmid was performed induced A172 cell proliferation, colony formation, invasion, and migration, while Rab23 depletion with siRNA reduced these abilities of U87 cells. In addition, we found that Rab23 transfection upregulated while its depletion reduced Rac1 activity. Treatment of transfected cells with a Rac1 inhibitor decreased Rac1 activity and invasion. In conclusion, Rab23 serves as an important oncoprotein in human astrocytoma by regulating cell invasion and migration through Rac1 activity.

Li L, Chen J, Chen X, et al.
Serum miRNAs as predictive and preventive biomarker for pre-clinical hepatocellular carcinoma.
Cancer Lett. 2016; 373(2):234-40 [PubMed] Related Publications
The extremely poor prognosis of patients with symptomatic hepatocellular carcinoma (HCC) diagnosed clinically at advanced stages suggests an urgent need for biomarkers that can be used for prospective surveillance and pre-clinical screening for early presence of pre-malignant lesions and tumors. In a retrospective longitudinal phase 3 biomarker study in seven medical centers of China, time-series and 6 months interval-serum samples were collected from chronic hepatitis B virus infected (CHB) patient cohorts at the pre-malignant or pre-clinical stages (average 6 months prior to clinical diagnosis) and CHB patients that did not develop cancer, and circulating miRNAs measured. A set of serum miRNAs including miR-193a-3p, miR-369-5p, miR-672, miR-429 and let-7i* were identified in pre-clinical HCC patients and have the potential to screen for CHB patients at high risk to develop HCC 6-12 months after miRNAs measurement. These circulating miRNAs combined with the conventional screening tools using α-fetoprotein and ultrasound, may have great promise for the prediction and prevention of HCC in high-risk populations.

Meng D, Yang S, Wan X, et al.
A transcriptional target of androgen receptor, miR-421 regulates proliferation and metabolism of prostate cancer cells.
Int J Biochem Cell Biol. 2016; 73:30-40 [PubMed] Related Publications
Prostate cancer is one of the most common malignancies, and microRNAs have been recognized to be involved in tumorigenesis of various kinds of cancer including prostate cancer (PCa). Androgen receptor (AR) plays a core role in prostate cancer progression and is responsible for regulation of numerous downstream targets including microRNAs. This study identified an AR-repressed microRNA, miR-421, in prostate cancer. Expression of miR-421 was significantly suppressed by androgen treatment, and correlated to AR expression in different prostate cancer cell lines. Furthermore, androgen-activated AR could directly bind to androgen responsive element (ARE) of miR-421, as predicted by bioinformatics resources and demonstrated by ChIP and luciferase reporter assays. In addition, over-expression of miR-421 markedly supressed cell viability, delayed cell cycle, reduced glycolysis and inhibited migration in prostate cancer cells. According to the result of miR-421 target genes searching, we focused on 4 genes NRAS, PRAME, CUL4B and PFKFB2 based on their involvement in cell proliferation, cell cycle progression and metabolism. The expression of these 4 downstream targets were significantly repressed by miR-421, and the binding sites were verified by luciferase assay. Additionally, we explored the expression of miR-421 and its target genes in human prostate cancer tissues, both in shared microarray data and in our own cohort. Significant differential expression and inverse correlation were found in PCa patients.

Min L, Shou C
In Situ Hybridization of Breast Cancer Markers.
Methods Mol Biol. 2016; 1406:53-9 [PubMed] Related Publications
In situ hybridization is an important technique in breast cancer research, which is widely applied in detection of specific nucleic acid sequences. Here, we describe the detailed protocol of fluorescence in situ hybridization and chromogenic in situ hybridization in detection of gene HER2/neu amplification in breast cancer tissues.

Shi Y, Peng SL, Yang LF, et al.
Co-infection of Epstein-Barr virus and human papillomavirus in human tumorigenesis.
Chin J Cancer. 2016; 35:16 [PubMed] Free Access to Full Article Related Publications
Viral infections contribute to approximately 12% of cancers worldwide, with the vast majority occurring in developing countries and areas. Two DNA viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), are associated with 38% of all virus-associated cancers. The probability of one patient infected with these two distinct types of viruses is increasing. Here, we summarize the co-infection of EBV and HPV in human malignancies and address the possible mechanisms for the co-infection of EBV and HPV during tumorigenesis.

Zhou L, Liu X, Wang X, et al.
CD123 redirected multiple virus-specific T cells for acute myeloid leukemia.
Leuk Res. 2016; 41:76-84 [PubMed] Related Publications
Hematopoietic stem cell transplantation (HSCT) has been increasingly used as a curative treatment for acute myeloid leukemia (AML). However, relapse rates after HSCT in complete remission (CR) are reported between 30% and 70%. In addition, numerous studies suggested that secondary viral infection from a variety of viruses including Epstein-Barr virus (EBV), adenovirus (Adv), and cytomegalovirus (CMV) are among the most common causes of death post-HSCT. Currently, chimeric antigen receptor (CAR)-based T cells have been developed to treat AML in clinical studies, while virus-specific cytotoxic T cells (VST) have been proven to be able to effectively prevent or treat viral infection after HSCT. Thus it would be desirable to develop T cells with the ability of simultaneously targeting AML relapse and viral infection. In this article, we now describe the generation of VST cells that are engineered to express CAR for a specific AML cell-surface antigen CD123 (CD123-CAR-VST). Using Dendritic cells (DCs) pulsed with EBV, Adv, and CMV peptides as sources of viral antigens, we generated VST from A2 donor peripheral mononuclear cells (PBMC). VST were then transduced with retroviral vector encoding CD123-CAR to generate CD123-CAR-VST. We demonstrated that CD123-CAR-VST recognized EBV, Adv, and CMV epitopes and had HLA-restricted virus-specific cytotoxic effector function against EBV target. In addition, CD123-CAR-VST retained the specificity against CD123-positive AML cell lines such as MOLM13 and THP-1 in vitro. Thus our results suggested that CD123-CAR-VST might be a valuable candidate to simultaneously prevent or treat relapse and viral infection in AML HSCT recipients.

Sun X, Li S, Shen B
Identification of Disease States and Response to Therapy in Humans by Utilizing the Biomarker EGFR for Targeted Molecular Imaging.
Curr Protein Pept Sci. 2016; 17(6):534-42 [PubMed] Related Publications
The epidermal growth factor receptor (EGFR) plays important roles in cell proliferation, suppression of apoptosis, increased motility, and recruitment of neovasculature. Overexpressed or mutated EGFR has been an important biomarker for cancer diagnosis and molecular target for many anticancer drugs because it frequently occurs in many common human cancers. Localizing and estimating the expression of EGFR can potentially identify patients who have tumors that overexpress EGFR and would, therefore, most likely benefit from a targeted treatment to avoid overtreatment and undertreatment. Traditional biopsy methods are invasive, and analysis of the specimens is not sufficient for real-time detection of the lesions or for monitoring the therapeutic efficacy of anticancer drugs. Molecular imaging, a technology of in vivo characterization and measurement of biological processes at the cellular and molecular level, can fulfill these goals. In this review, we summarize current molecular imaging techniques including optical imaging, magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography for in vivo EGFR visualization and discuss their advantages and disadvantages. Special emphasis is placed on noninvasive imaging mutant EGFR with emerging new agents and new imaging technologies to distinguish the maximum benefit to cancer patients for molecular targeted therapy.

Luo Y, Zhang X, Tan Z, et al.
Astrocyte Elevated Gene-1 as a Novel Clinicopathological and Prognostic Biomarker for Gastrointestinal Cancers: A Meta-Analysis with 2999 Patients.
PLoS One. 2015; 10(12):e0145659 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There have been numerous articles as to whether the staining index (SI) of astrocyte elevated gene-1 (AEG-1) adversely affects clinical progression and prognosis of gastrointestinal cancers. Nevertheless, controversy still exists in terms of correlations between AEG-1 SI and clinicopathological parameters including survival data. Consequently, we conducted a comprehensive meta-analysis to confirm the role of AEG-1 in clinical outcomes of gastrointestinal carcinoma patients.
METHODS: We performed a comprehensive search in PubMed, ISI Web of Science, Cochrane Central Register of Controlled Trials, EMBASE, Science Direct, Wiley Online Library, China National Knowledge Infrastructure (CNKI), WanFang and Chinese VIP databases. STATA 12.0 (STATA Corp., College, TX) was used to analyze the data extracted from suitable studies and Newcastle-Ottawa Scale was applied to assess the quality of included articles.
RESULTS: The current meta-analysis included 2999 patients and our results suggested that strong associations emerged between AEG-1 SI and histological differentiation (OR = 2.129, 95%CI: 1.377-3.290, P = 0.001), tumor (T) classification (OR = 2.272, 95%CI: 1.147-4.502, P = 0.019), lymph node (N) classification (OR = 2.696, 95%CI: 2.178-3.337, P<0.001) and metastasis (M) classification (OR = 3.731, 95%CI: 2.167-6.426, P<0.001). Furthermore, high AEG-1 SI was significantly associated with poor overall survival (OS) (HR = 2.369, 95%CI: 2.005-2.800, P<0.001) and deteriorated disease-free survival (DFS) (HR = 1.538, 95%CI: 1.171-2.020, P = 0.002). For disease-specific survival (DSS) and relapse-free survival (RFS), no statistically significant results were observed (HR = 1.573, 95%CI: 0.761-3.250, P = 0.222; HR = 1.432, 95%CI: 0.108-19.085, P = 0.786). Subgroup analysis demonstrated that high AEG-1 SI was significantly related to poor prognosis in esophageal squamous cell carcinoma (ESCC) (HR = 1.715, 95%CI: 1.211-2.410, P = 0.002), gastric carcinoma (GC) (HR = 2.255, 95%CI: 1.547-3.288, P<0.001), colorectal carcinoma (CRC) (HR = 2.922, 95%CI: 1.921-4.444, P<0.001), gallbladder carcinoma (GBC) (HR = 3.047, 95%CI: 1.685-5.509, P<0.001), hepatocellular carcinoma (HCC) (HR = 2.245, 95%CI: 1.620-3.113, P<0.001), pancreatic adenocarcinoma (PAC) (HR = 2.408, 95%CI: 1.625-3.568, P<0.001).
CONCLUSIONS: The current meta-analysis indicated that high AEG-1 SI might be associated with tumor progression and poor survival status in patients with gastrointestinal cancer. AEG-1 might play a vital role in promoting tumor aggression and could serve as a potential target for molecular treatments. Further clinical trials are needed to validate whether AEG-1 SI provides valuable insights into improving treatment decisions.

Zhou P, Zhang Q, Zhao Y, et al.
IL-17 promoted the inhibition of medulloblastoma in mice by splenocyte injection.
Eur J Med Res. 2015; 20:98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Interleukin 17 (IL-17) is a proinflammatory cytokine produced by a new subset of activated CD4+ T cells, Th17 cells. We previously showed that increased Th17 cell populations were presented in human medulloblastoma-infiltrating T cells and peripheral blood. In this study, we attempted to address the possible role of Th17 cells in the biologic activity of IL-17 for tumor control.
METHODS: We grafted fresh surgically obtained medulloblastoma into syngeneic athymic nude/nude mice. We intrapertonially injected splenocyte and murine IL-17 in mice on the second day. The tumor volume and the life spans of the mice were measured. Meanwhile, the IL-17, IL-6, IL-23, Ccl2, Ccl20 and IFN-gamma expression in the tumors was also examined by real-time PCR, Western blot and enzyme-linked immunosorbent assay.
RESULTS: We found that medulloblastoma growth in IL-17-injected mice was significantly inhibited compared to the non-IL-17 treated mice. In contrast to the IL-17 antitumor activity observed in mice injected with splenocytes, we observed that IFN-gamma, IL-6, IL-23, Ccl2, and Ccl20 proteins were significantly increased in tumor tissues of mice injected with IL-17.
CONCLUSIONS: These experiments suggest that IL-17 may promote splenocyte antitumor activity in medulloblastoma. We postulate that IL-17's antitumor activity may be related to the increased protein levels of IFN-gamma, IL-6, IL-23, Ccl2, and Ccl20.

Feng H, Zhang Z, Qing X, et al.
Promoter methylation of APC and RAR-β genes as prognostic markers in non-small cell lung cancer (NSCLC).
Exp Mol Pathol. 2016; 100(1):109-13 [PubMed] Related Publications
Aberrant promoter hypermethylations of tumor suppressor genes are promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine methylation status at APC and RAR-β promoters in primary NSCLC, and whether they have any relationship with survival. APC and RAR-β promoter methylation status were determined in 41 NSCLC patients using methylation specific PCR. APC promoter methylation was detectable in 9 (22.0%) tumor samples and 6 (14.6%) corresponding non-tumor samples (P=0.391). RAR-β promoter methylation was detectable in 13 (31.7%) tumor samples and 4 (9.8%) corresponding non-tumor samples (P=0.049) in the NSCLC patients. APC promoter methylation was found to be associated with T stage (P=0.046) and nodal status (P=0.019) in non-tumor samples, and with smoking (P=0.004) in tumor samples. RAR-β promoter methylation was found associated with age (P=0.031) in non-tumor samples and with primary tumor site in tumor samples. Patients with APC promoter methylation in tumor samples showed significantly longer survival than patients without it (Log-rank P=0.014). In a multivariate analysis of prognostic factors, APC methylation in tumor samples was an independent prognostic factor (P=0.012), as were N1 positive lymph node number (P=0.025) and N2 positive lymph node number (P=0.06). Our study shows that RAR-β methylation detected in lung tissue may be used as a predictive marker for NSCLC diagnosis and that APC methylation in tumor sample may be a useful marker for superior survival in NSCLC patients.

Pan W, Liao H
Correlations between the COMT gene rs4680 polymorphism and susceptibility to ovarian cancer.
Genet Mol Res. 2015; 14(4):16813-8 [PubMed] Related Publications
The objective of this study was to perform a systematic review of the correlations between the single nucleotide polymorphism rs4680 in the catechol-O-methyltransferase (COMT) gene and susceptibility to ovarian cancer. A computer search was carried out for relevant case-control studies published between January 2000 to January 2014 in databases such as Ovid, EBSCO, PubMed, CNKI, CBMDISC, VIP, and WanFang Data. The literature was screened based on inclusion and exclusion criteria. A meta-analysis was performed by calculating the combined odds ratios (OR) and 95% confidence intervals (CI) using the RevMan 5.0. A total of 7 case-control studies were selected, which included 1439 cases and 2927 control subjects. Meta-analysis showed that the rs4680 polymorphism was not associated with ovarian cancer [GG vs (GA+AA): OR = 1.02, 95%CI = 0.88-1.19; G vs A allele: OR = 1.0, 95%CI = 0.90-1.11]. We, therefore, conclude that the COMT rs4680 polymorphism is not associated with susceptibility to ovarian cancer.

Ma X, Sun W, Shen J, et al.
Gelsolin promotes cell growth and invasion through the upregulation of p-AKT and p-P38 pathway in osteosarcoma.
Tumour Biol. 2016; 37(6):7165-74 [PubMed] Related Publications
The gelsolin (GSN) has been involved in the regulation of tumor formation and development, but the biological role of GSN in the pathogenesis of osteosarcoma (OS) has not been well characterized. In this study, we show that high expression of GSN was observed in OS tissues and correlated with tumor size, advanced Enneking stage, and poor patient prognosis. Knockdown of GSN significantly inhibited cell proliferation and invasiveness in the OS cell lines. Furthermore, stable overexpression of GSN in OS cells resulted in a significant increase in cell growth and motility with the downregulation of p-AKT and p-P38 pathway. Finally, overexpression of GSN promoted growth of OS tumors in SCID mice. Taken together, these results provided the first evidence that GSN might contribute to OS cancer development and could be an attractive therapeutic target for patients with OS.

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