Gene Summary

Gene:VIPR1; vasoactive intestinal peptide receptor 1
Summary:This gene encodes a receptor for vasoactive intestinal peptide, a small neuropeptide. Vasoactive intestinal peptide is involved in smooth muscle relaxation, exocrine and endocrine secretion, and water and ion flux in lung and intestinal epithelia. Its actions are effected through integral membrane receptors associated with a guanine nucleotide binding protein which activates adenylate cyclase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:vasoactive intestinal polypeptide receptor 1
Source:NCBIAccessed: 01 September, 2019


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

Research Indicators

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

Literature Analysis

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

  • Consensus Sequence
  • Up-Regulation
  • Cervical Cancer
  • Oncogene Proteins
  • Molecular Sequence Data
  • DNA Primers
  • Chromosome 3
  • Insulin-Like Growth Factor Binding Protein 2
  • Immunoglobulin Heavy Chains
  • VIPR1 protein, human
  • Amino Acid Sequence
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
  • Receptors, Vasoactive Intestinal Peptide, Type II
  • RT-PCR
  • Messenger RNA
  • Gene Expression Profiling
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
  • Sequence Homology
  • Staging
  • Microarray Analysis
  • Transcription
  • Down-Regulation
  • Lung Cancer
  • Calcitonin Gene-Related Peptide
  • stearyl-norleucine(17)-vasoactive intestinal peptide
  • Exons
  • Survival Rate
  • Pituitary Hormone Receptors
  • Vasoactive Intestinal Peptide Receptors
  • Polymerase Chain Reaction
  • Adenylyl Cyclases
  • VIP
  • Neuropeptides
  • NETO2
  • Adenocarcinoma
  • VIPR1
  • SPP1
  • Base Sequence
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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

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

Latest Publications: VIPR1 (cancer-related)

Ashizawa N, Shimizu H, Sudo M, et al.
Clinical Significance of NADPH Oxidase 5 in Human Colon Cancer.
Anticancer Res. 2019; 39(8):4405-4410 [PubMed] Related Publications
BACKGROUND/AIM: Recent studies have reported the involvement of NADPH oxidases (NOXs) in tumor progression. However, the role of NOX5 in colon cancer is unclear. We examined the clinical significance of NOX5 expression in colon cancer.
PATIENTS AND METHODS: NOX5 expression was evaluated by immunohistochemistry in 119 patients with stage II or III colon cancer, and the relationship between NOX5 expression and clinicopathological data was analyzed.
RESULTS: Of all tissues, 39.5% were negative and 60.5% were positive for NOX5 expression. Positive expression was significantly associated with undifferentiated histology (p=0.037) and lymph node metastasis (p=0.023). The 5-year progression-free survival rate of NOX5-positive patients was significantly worse than that of NOX5-negative patients (p=0.046). The rates of local recurrence observed in NOX5-positive patients were higher than that in NOX5-negative patients.
CONCLUSION: NOX5 expression may be related to poor prognostic factors and could be useful as a prognostic biomarker.

Li Z, Tan H, Zhao W, et al.
Integrative analysis of DNA methylation and gene expression profiles identifies MIR4435-2HG as an oncogenic lncRNA for glioma progression.
Gene. 2019; 715:144012 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been shown to play an important role in tumor biogenesis and prognosis. The glioma is a grade classified cancer, however, we still lack the knowledge on their function during glioma progression. While previous studies have shown how lncRNAs regulate protein-coding gene epigenetically, it is still unclear how lncRNAs are regulated epigenetically. In this study, we firstly analyzed the RNA-seq data systematically across grades II, IV, and IV of glioma samples. We identified 60 lncRNAs that are significantly differentially expressed over disease progression (DElncRNA), including well-known PVT1, HOTAIR, H19 and rarely studied CARD8-AS, MIR4435-2HG. Secondly, by integrating HM450K methylation microarray data, we demonstrated that some of the lncRNAs are epigenetically regulated by methylation. Thirdly, we developed a DESeq2-GSEA-ceRNA-survival analysis strategy to investigate their functions. Particularly, MIR4435-2HG is highly expressed in high-grade glioma and may have an impact on EMT and TNFα signaling pathway by functioning as a miRNA sponge of miR-125a-5p and miR-125b-5p to increase the expression of CD44. Our results revealed the dynamic expression of lncRNAs in glioma progression and their epigenetic regulation mechanism.

Loriot Y, Necchi A, Park SH, et al.
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.
N Engl J Med. 2019; 381(4):338-348 [PubMed] Related Publications
BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (
METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified
RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.
CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with

Avgan N, Wang JI, Fernandez-Chamorro J, Weatheritt RJ
Multilayered control of exon acquisition permits the emergence of novel forms of regulatory control.
Genome Biol. 2019; 20(1):141 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The long introns of mammals are pools of evolutionary potential due to the multiplicity of sequences that permit the acquisition of novel exons. However, the permissibility of genes to this type of acquisition and its influence on the evolution of cell regulation is poorly understood.
RESULTS: Here, we observe that human genes are highly permissive to the inclusion of novel exonic regions permitting the emergence of novel regulatory features. Our analysis reveals the potential for novel exon acquisition to occur in over 30% of evaluated human genes. Regulatory processes including the rate of splicing efficiency and RNA polymerase II (RNAPII) elongation control this process by modulating the "window of opportunity" for spliceosomal recognition. DNA damage alters this window promoting the inclusion of repeat-derived novel exons that reduce the ribosomal engagement of cell cycle genes. Finally, we demonstrate that the inclusion of novel exons is suppressed in hematological cancer samples and can be reversed by drugs modulating the rate of RNAPII elongation.
CONCLUSION: Our work demonstrates that the inclusion of repeat-associated novel intronic regions is a tightly controlled process capable of expanding the regulatory capacity of cells.

Benenemissi IH, Sifi K, Sahli LK, et al.
Angiotensin-converting enzyme insertion/deletion gene polymorphisms and the risk of glioma in an Algerian population.
Pan Afr Med J. 2019; 32:197 [PubMed] Free Access to Full Article Related Publications
Introduction: Just recently, it has been established that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is linked to the pathogenesis and to the evolution of human cancers. Therefore, the present study was concerned with the investigation of an eventual association between glioma and I/D polymorphism of the ACE gene.
Methods: The expression of ACE gene was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis in 36 Algerian patients with glioma and 195 healthy controls.
Results: In glioma cases, allelic frequencies and genotypes distribution of the ACE I/D polymorphism were different from controls cases. ACE DD genotype were highly presented in glioma cases (63.9%) than controls (33.8%) and conferred 3.64-fold risk for predisposition in glioma cases (vs ID genotype, p<0.001). Recessive model (ACE II + ID genotypes vs DD) was associated with a 72% reduced risk of glioma (OR = 0.28, 95% CI: 0.13-0.60, p <0.001). Per copy D allele frequency was found higher in glioma cases (79.2%) than in controls (63.3 %), OR = 2.20, 95% CI: 1.20 - 4.03, p = 0.009.
Conclusion: The obtained data showed that the presence of the D allele might be a risk factor for the development of glioma. Further studies considering different ethnic groups with large samples are required to confirm this finding.

Jiang B, Sun Q, Tong Y, et al.
An immune-related gene signature predicts prognosis of gastric cancer.
Medicine (Baltimore). 2019; 98(27):e16273 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although the outcome of patients with gastric cancer (GC) has improved significantly with the recent implementation of annual screening programs. Reliable prognostic biomarkers are still needed due to the disease heterogeneity. Increasing pieces of evidence revealed an association between immune signature and GC prognosis. Thus, we aim to build an immune-related signature that can estimate prognosis for GC.
METHODS: For identification of a prognostic immune-related gene signature (IRGS), gene expression profiles and clinical information of patients with GC were collected from 3 public cohorts, divided into training cohort (n = 300) and 2 independent validation cohorts (n = 277 and 433 respectively).
RESULTS: Within 1811 immune genes, a prognostic IRGS consisting of 16 unique genes was constructed which was significantly associated with survival (hazard ratio [HR], 3.9 [2.78-5.47]; P < 1.0 × 10). In the validation cohorts, the IRGS significantly stratified patients into high- vs low-risk groups in terms of prognosis across (HR, 1.84 [1.47-2.30]; P = 6.59 × 10) and within subpopulations with stage I&II disease (HR, 1.96 [1.34-2.89]; P = 4.73 × 10) and was prognostic in univariate and multivariate analyses. Several biological processes, including TGF-β and EMT signaling pathways, were enriched in the high-risk group. T cells CD4 memory resting and Macrophage M2 were significantly higher in the high-risk risk group compared with the low-risk group.
CONCLUSION: In short, we developed a prognostic IRGS for estimating prognosis in GC, including stage I&II disease, providing new insights into the identification of patients with GC with a high risk of mortality.

Yan GE, Efferth T
Broad-spectrum Cross-resistance to Anticancer Drugs Mediated by Epidermal Growth Factor Receptor.
Anticancer Res. 2019; 39(7):3585-3593 [PubMed] Related Publications
BACKGROUND: The oncogenic role of epidermal growth factor receptor (EGFR) has been intensively studied. However, its emerging role in drug resistance has not been fully addressed.
MATERIALS AND METHODS: This study systematically investigated the correlation of mRNA and protein expression of EGFR, as well as gene amplification and mutations with the log-transformed half-maximal inhibitory concentration (log
RESULTS: EGFR protein expression, rather than other measurements, was most frequently associated with drug response. Log
CONCLUSION: Collectively, we showed a broad-spectrum of cross-resistance towards clinical drugs mediated by EGFR. Natural cytotoxic products may be further developed as novel drugs to overcome EGFR-associated resistance to clinically established anticancer drugs.

Wińska P, Widło Ł, Skierka K, et al.
Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells.
Anticancer Res. 2019; 39(7):3531-3542 [PubMed] Related Publications
BACKGROUND/AIM: Recently, we demonstrated the ability of inhibitors of protein kinase 2 (casein kinase II; CK2) to enhance the efficacy of 5-fluorouracil, a thymidylate synthase (TYMS)-directed drug for anticancer treatment. The present study aimed to investigate the antileukemic effect of simultaneous inhibition of dihydrofolate reductase (DHFR), another enzyme involved in the thymidylate biosynthesis cycle, and CK2 in CCRF-CEM acute lymphoblastic leukemia cells.
MATERIALS AND METHODS: The influence of combined treatment on apoptosis and cell-cycle progression, as well as the endocellular level of DHFR protein and inhibition of CK2 were determined using flow cytometry and western blot analysis, respectively. Real-time quantitative polymerase chain reaction was used to examine the influence of silmitasertib (CX-4945), a selective inhibitor of CK2 on the expression of DHFR and TYMS genes.
RESULTS: The synergistic effect was correlated with the increase of annexin V-binding cell fraction, caspase 3/7 activation and a significant reduce in the activity of CK2. An increase of DHFR protein level was observed in CCRF-CEM cells after CX-4945 treatment, with the mRNA level remaining relatively constant.
CONCLUSION: The obtained results demonstrate a possibility to improve methotrexate-based anti-leukemia therapy by simultaneous inhibition of CK2. The effect of CK2 inhibition on DHFR expression suggests the important regulatory role of CK2-mediated phosphorylation of DHFR inside cells.

Zhang H, Luo C, Zhang G
DNA Cell Biol. 2019; 38(8):857-864 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) has been reported to be one of the major tumors in the world. There is a study indicating that MCM3AP-AS1 is an oncogenic factor in HCC; however, the mechanism by which MCM3AP-AS1 regulates HCC remains not fully understood. Reverse Transcription-quantitative PCR and Western blot approaches were used to detect mRNA and protein levels of various genes. To examine invasion of HCC cells and lymphatic vessel formation of human dermal lymphatic endothelial cells (HDLECs), we employed transwell invasion assay and lymphatic vessel assay. Bioinformatic analysis and luciferase reporter assay were used to establish direct interactions between MCM3AP-AS1 and miR-455. Besides, The Cancer Genome Atlas analyses of HCCs were performed to determine the association of MCM3AP-AS1 and epidermal growth factor receptor (EGFR) with overall survival. MCM3AP-AS1 knockdown impaired invasion of HCC cells and lymphatic vessel formation of HDLECs. MCM3AP-AS1 directly interacted with miR-455. Furthermore, miR-455 inhibitor-transfected HepG2 cells enhanced the invasion and lymphatic vessel formation abilities. The rescue experiments indicated that EGFR was critical for MCM3AP-AS1- and miR-455-regulated invasion and lymphatic vessel formation. More interestingly, autophagy-related genes (Beclin1, LC3 II/I, and ATG7) were abnormally regulated in miR-455 mimic or inhibitor HepG2 cells. miR-455 mimic inhibited cell invasion and lymphatic vessel formation, which was evidently abrogated by ATG7 overexpression. Finally, we analyzed The Cancer Genome Atlas data sets to test the upregulated expression levels of MCM3AP-AS1 and EGFR. In addition, the results showed that low levels of both genes facilitate survival of HCC patients. In this study, we reveal a novel mechanism underlying MCM3AP-AS1-induced HCC metastasis by regulating miR-455. The conclusions provide more insights into understanding mechanism underlying HCC and help development of therapeutical approaches for treating HCC.

Isoda T, Morio T, Takagi M
Noncoding RNA transcription at enhancers and genome folding in cancer.
Cancer Sci. 2019; 110(8):2328-2336 [PubMed] Free Access to Full Article Related Publications
Changes of nuclear localization of lineage-specific genes from a transcriptionally inert to permissive environment are a crucial step in establishing the identity of a cell. Noncoding RNA transcription-mediated genome folding and activation of target gene expression have been found in a variety of cell types. Noncoding RNA ThymoD (thymocyte differentiation factor) transcription at superenhancers is essential for mouse T-cell lineage commitment. The cessation of ThymoD transcription abolishes transcription-mediated demethylation, recruiting looping factors such as the cohesin complex, CCCTC-binding factor (CTCF), ultimately leading to the phenotype of severe combined immunodeficiency and T-cell leukemia/lymphoma. In this review, we describe the functional role of RNA polymerase II-mediated transcription at enhancers and in genome folding. We also highlight the involvement of faulty activation or suppression of enhancer transcription and enhancer-promoter interaction in cancer development.

D'Alise AM, Leoni G, Cotugno G, et al.
Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade.
Nat Commun. 2019; 10(1):2688 [PubMed] Free Access to Full Article Related Publications
Neoantigens (nAgs) are promising tumor antigens for cancer vaccination with the potential of inducing robust and selective T cell responses. Genetic vaccines based on Adenoviruses derived from non-human Great Apes (GAd) elicit strong and effective T cell-mediated immunity in humans. Here, we investigate for the first time the potency and efficacy of a novel GAd encoding multiple neoantigens. Prophylactic or early therapeutic vaccination with GAd efficiently control tumor growth in mice. In contrast, combination of the vaccine with checkpoint inhibitors is required to eradicate large tumors. Gene expression profile of tumors in regression shows abundance of activated tumor infiltrating T cells with a more diversified TCR repertoire in animals treated with GAd and anti-PD1 compared to anti-PD1. Data suggest that effectiveness of vaccination in the presence of high tumor burden correlates with the breadth of nAgs-specific T cells and requires concomitant reversal of tumor suppression by checkpoint blockade.

Elmansy D, Koyutürk M
Cross-population analysis for functional characterization of type II diabetes variants.
BMC Bioinformatics. 2019; 20(Suppl 12):320 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As Genome-Wide Association Studies (GWAS) have been increasingly used with data from various populations, it has been observed that data from different populations reveal different sets of Single Nucleotide Polymorphisms (SNPs) that are associated with the same disease. Using Type II Diabetes (T2D) as a test case, we develop measures and methods to characterize the functional overlap of SNPs associated with the same disease across populations.
RESULTS: We introduce the notion of an Overlap Matrix as a general means of characterizing the functional overlap between different SNP sets at different genomic and functional granularities. Using SNP-to-gene mapping, functional annotation databases, and functional association networks, we assess the degree of functional overlap across nine populations from Asian and European ethnic origins. We further assess the generalizability of the method by applying it to a dataset for another complex disease - Prostate Cancer. Our results show that more overlap is captured as more functional data is incorporated as we go through the pipeline, starting from SNPs and ending at network overlap analyses. We hypothesize that these observed differences in the functional mechanisms of T2D across populations can also explain the common use of different prescription drugs in different populations. We show that this hypothesis is concordant with the literature on the functional mechanisms of prescription drugs.
CONCLUSION: Our results show that although the etiology of a complex disease can be associated with distinct processes that are affected in different populations, network-based annotations can capture more functional overlap across populations. These results support the notion that it can be useful to take ethnicity into account in making personalized treatment decisions for complex diseases.

Fischer K, Al-Sawaf O, Bahlo J, et al.
Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.
N Engl J Med. 2019; 380(23):2225-2236 [PubMed] Related Publications
BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.
METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.
RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with
CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; number, NCT02242942.).

Golan T, Hammel P, Reni M, et al.
Maintenance Olaparib for Germline
N Engl J Med. 2019; 381(4):317-327 [PubMed] Related Publications
BACKGROUND: Patients with a germline
METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline
RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.
CONCLUSIONS: Among patients with a germline

Tong H, Zhu Y, Liu Y
Incidence and risk of fatigue in cancer patients treated with MET inhibitors: A systematic review and meta-analysis.
Medicine (Baltimore). 2019; 98(22):e15522 [PubMed] Related Publications
BACKGROUND: The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) inhibitors show a surprising survival benefit in the treatment of numerous tumors especially in MET-high tumor. Besides their impressive efficacy, fatigue reduced by MET inhibitors is still the safety issue during treatment. Thus, an understanding of this risk in the context of expanding MET-inhibitors use is an important cost and patient safety issue.
METHODS: We searched PubMed, Embase, and the Cochrane Library databases for relevant studies up to October 2017. Eligibility criteria included phase II/III trials of MET inhibitors that reported adequate safety profiles of fatigue. The principal summary measures were incidence and relative risk (RR) of all-grade (grade 1-4) and high-grade (grade 3-4) fatigue, respectively. Random-effects model was applied to consider within-study and between-study variation.
RESULTS: A total of 5028 patients from 17 clinical trials were identified. The results revealed that the incidences of MET inhibitors-associated all-grade and high-grade fatigue were 41.9% and 9.6%, respectively. The RR of high-grade fatigue was (RR = 1.37; 95% confidence interval, 1.14-1.66; P = .0009), whereas the RR of all-grade fatigue was (RR = 1.02; 95% confidence interval, 0.91-1.15; P = .71).
CONCLUSION: Our meta-analysis has demonstrated that MET inhibitors-based treatment is associated with an increased risk of high-grade fatigue compared with control.

Liu JF, Gray KP, Wright AA, et al.
Results from a single arm, single stage phase II trial of trametinib and GSK2141795 in persistent or recurrent cervical cancer.
Gynecol Oncol. 2019; 154(1):95-101 [PubMed] Related Publications
BACKGROUND: Improved treatment for advanced cervical cancer is needed; currently, treatment options include combined chemotherapy and bevacizumab or pembrolizumab monotherapy for PD-L1 positive disease. PIK3CA and KRAS mutations have been reported in cervical cancers; this study therefore tested dual inhibition of PI3K and RAS signaling by combining the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 in recurrent cervical cancer.
METHODS: This was an investigator-initiated phase II study combining trametinib and GSK2141795 in patients with recurrent cervical cancer. Primary endpoint was best tumor response; secondary endpoints included progression free survival, overall survival, and safety assessment. Translational objectives included characterization of molecular alterations in PI3K and RAS signaling pathway genes.
RESULTS: Planned accrual was 35 patients; 14 patients were enrolled and received at least one dose of study drug before the study was terminated due to discontinuation of GSK2141795 development. There were no confirmed responses; 1 patient had an unconfirmed PR, 8 had stable disease, 3 had progression as best response, and 2 were unevaluable. Toxicities were mostly grade 1 and 2, although 57% of patients experienced grade 3/4 adverse events and 50% patients required a dose reduction.
CONCLUSIONS: The combination of trametinib and GSK2141795 was feasible but required dose holds and modifications for adverse events; however, anti-cancer activity was minimal, even in patients with PI3K or RAS pathway alterations. Although the study was terminated early after GSK2141795 development was halted, the findings in these 14 patients do not support further development of this combination in cervical cancer.

Forte M, Di Lorenzo M, Iachetta G, et al.
Nonylphenol acts on prostate adenocarcinoma cells via estrogen molecular pathways.
Ecotoxicol Environ Saf. 2019; 180:412-419 [PubMed] Related Publications
Estrogens play a role in the patho-physiology of the prostate. In the present work we studied the effects of nonylphenol (NP), a xenoestrogen, on human adenocarcinoma prostate cells (LNCaP). In order to understand molecular and cellular involvement, we observed the effects on cell cycle and we investigated the expression and the cellular localization of estrogen receptors and gene expression of cyclin D1, ki-67, c-myc, IL-8, IL-1β. We performed the same experiments with 17β-estradiol (E2), the most abundant estrogen circulating in nonpregnant humans in order to compare these two different substances. We demonstrated the ability of 1 × 10

Zhan T, Ambrosi G, Wandmacher AM, et al.
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer.
Nat Commun. 2019; 10(1):2197 [PubMed] Free Access to Full Article Related Publications
In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.

Voorwerk L, Slagter M, Horlings HM, et al.
Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.
Nat Med. 2019; 25(6):920-928 [PubMed] Related Publications
The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low

Nakayama Y, Mimura K, Tamaki T, et al.
Phospho‑STAT1 expression as a potential biomarker for anti‑PD‑1/anti‑PD‑L1 immunotherapy for breast cancer.
Int J Oncol. 2019; 54(6):2030-2038 [PubMed] Free Access to Full Article Related Publications
In the present study, we evaluated the mechanisms of programmed death ligand 1 (PD‑L1) expression in the breast cancer microenvironment, focusing on the role of interferon‑γ (IFN‑γ), and the clinical indications for anti‑programmed cell death 1 (PD‑1) /anti‑PD‑L1 immunotherapy. We evaluated PD‑L1 expression in 4 breast cancer cell lines in the presence of 3 types of inhibitors, as well as IFN‑γ. The expression of phosphorylated signal transducer and activator of transcription 1 (p‑STAT1), one of the IFN‑γ signaling pathway molecules, was analyzed using immunohistochemistry (IHC) in relation to PD‑L1 and human leukocyte antigen (HLA) class I expression on cancer cells and tumor‑infiltrating CD8‑positive T cells in 111 patients with stage II/III breast cancer. Using The Cancer Genome Atlas (TCGA) database, the correlation of the IFN‑γ signature with PD‑L1 expression was analyzed in breast invasive carcinoma tissues. As a result, the JAK/STAT pathway via IFN‑γ was mainly involved in PD‑L1 expression in the cell lines examined. IHC analysis revealed that the PD‑L1 and HLA class I expression levels were significantly upregulated in the p‑STAT1‑positive cases. TCGA analysis indicated that the PD‑L1 expression and IFN‑γ signature exhibited a positive correlation. On the whole, these findings suggest that PD‑L1 and HLA class I are co‑expressed in p‑STAT1‑positive breast cancer cells induced by IFN‑γ secreted from tumor infiltrating immune cells, and that p‑STAT1 expression may be a potential biomarker for patient selection for immunotherapy with anti‑PD‑1/anti‑PD‑L1 monoclonal antibodies.

Wang J, Yao Y, Zhang Q, et al.
Inflammatory responses induced by Helicobacter pylori on the carcinogenesis of gastric epithelial GES‑1 cells.
Int J Oncol. 2019; 54(6):2200-2210 [PubMed] Related Publications
Helicobacter pylori (HP) is a pathogenic bacterium associated with chronic gastritis, gastric ulcer and gastric cancer. In the present study, the primary carcinogenesis process of normal gastric epithelial cells (GES‑1) infected with HP was investigated. It was determined that infected gastric mucosal epithelial GES‑1 cells secreted increased interleukin‑8 (IL‑8) and IL‑23, and exhibited enhanced expression of inducible nitric oxide synthase and cyclooxygenase‑2, inducing inflammatory reactions and resulting in apoptosis. The bacterial infection significantly increased the expression of carcinogenesis‑associated genes, including p16, c‑Myc, p53 and p21, as well as the expression of cell surface signaling molecules cluster of differentiation 44 (CD44) and CD54 in GES‑1 cells or tissues of patients with gastritis and gastric cancer in vitro or in vivo. Simultaneously, the migration and invasion abilities of normal gastric epithelial GES‑1 cells were increased following HP infection. These observations demonstrated that the inflammatory response of HP infection could cause normal gastric epithelial cells to undergo significant cancerous reactions, indicating that HP is a risk factor for gastric cancer.

Chen HF, Wu LX, Li XF, et al.
Ginsenoside compound K inhibits growth of lung cancer cells via HIF-1α-mediated glucose metabolism.
Cell Mol Biol (Noisy-le-grand). 2019; 65(4):48-52 [PubMed] Related Publications
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. Compound K, an active metabolite of ginsenosides, is reported to exhibit anti-cancer property in various types of human malignancies. The present study investigated the role of compound K on glucose metabolism in NSCLC cells and its underlying mechanism. Our study found that compound K dose-dependently inhibited the cell viability of NSCLC cells. Moreover, administration with compound K decreased glucose uptake and lactate secretion under normoxic and hypoxic conditions. Consistently, the expression of key enzymes (HK II, PDK1 and LDHA) involved in glucose metabolism were inhibited in compound K-treated tumor cells. In addition, compound K inhibited the expression of HIF-1α and its downstream gene GLUT1. On the contrary, overexpression of HIF-1α elevated metabolic reactions and partly attenuated the inhibitory role of compound K on NSCLC cell growth. These results demonstrate that compound K suppresses NSCLC cell growth via HIF-1α mediated metabolic alteration, contributing to novel anticancer therapy by targeting glucose metabolism.

Perone Y, Farrugia AJ, Rodríguez-Meira A, et al.
SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer.
Nat Commun. 2019; 10(1):2115 [PubMed] Free Access to Full Article Related Publications
Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

Yalcin E, Kara G, Celik E, et al.
Preparation and characterization of novel albumin-sericin nanoparticles as siRNA delivery vehicle for laryngeal cancer treatment.
Prep Biochem Biotechnol. 2019; 49(7):659-670 [PubMed] Related Publications
Small interfering RNA (siRNA)-based gene silencing strategy has high potential on suppressing specific molecular targets, involved in cancer progression. However, the lack of an effective nanocarrier system that safely delivers siRNA to its target still limits the clinical applications of siRNA. This study aimed to develop albumin-sericin nanoparticles (Alb-Ser NPs) as a novel siRNA delivery system for laryngeal cancer treatment. Nanoparticle formulations composed of albumin and sericin at different ratios (1:1, 2:1, 1:2

Li J, Hu X, Su M, et al.
CDK5RAP3 Participates in Autophagy Regulation and Is Downregulated in Renal Cancer.
Dis Markers. 2019; 2019:6171782 [PubMed] Free Access to Full Article Related Publications
Renal cancer is one of the most common malignant urological tumors; however, its diagnosis and treatment are not well established. In the present study, we identified that CDK5 regulatory subunit-associated protein 3 (CDK5RAP3), a putative tumor suppressor in many cancers, was downregulated in renal cancer tissues. Through loss- and gain-of-function experiments, we observed that the action of CDK5RAP3 in renal cancer cells was different in Caki-1 and 769-P cell lines. Knockdown of endogenous CDK5RAP3 in Caki-1 slightly increased cell viability, whereas overexpression of CDK5RAP3 in 769-P cells inhibited cell viability. In addition, we observed that CDK5RAP3 participated in the regulation of autophagy in renal cancer. Knockdown of CDK5RAP3 induced significant inhibition of autophagy in Caki-1 cells but not in 769-P cells. In contrast, overexpression of CDK5RAP3 significantly activated autophagy in 769-P cells, as evidenced by increased LC3-II levels. However, the LC3-II could not be altered by CDK5RAP3 overexpression in Caki-1 cells. These findings demonstrated that CDK5RAP3 is downregulated in renal cancer and may be associated with autophagy.

Cocciardi S, Dolnik A, Kapp-Schwoerer S, et al.
Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation.
Nat Commun. 2019; 10(1):2031 [PubMed] Free Access to Full Article Related Publications
Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1

Li JP, Zhang XM, Zhang Z, et al.
Association of p53 expression with poor prognosis in patients with triple-negative breast invasive ductal carcinoma.
Medicine (Baltimore). 2019; 98(18):e15449 [PubMed] Free Access to Full Article Related Publications
TP53 gene is mutated in approximately 80% of triple-negative breast cancer (TNBC). However, the prognostic significance of immunohistochemical (IHC)-detected p53 protein expression remains controversial in TNBC. In this study, we retrospectively analyzed the association between IHC-detected p53 expression and the prognosis in a cohort of 278 patients with stage I-III triple-negative breast invasive ductal carcinoma (IDC), who received surgery at the department of breast surgery in the Fourth Hospital of Hebei Medical University from 2010-01 to 2012-12. We found a positive expression ratio of IHC-detected p53 in triple-negative breast IDC of 58.6% (163/278). Furthermore, levels of expression were significantly associated with vessel tumor emboli and higher histologic grade (P = .038, P = .043, respectively), with the highest expression level observed in G3 breast cancer (64.7%). Additionally, Kaplan-Meier analysis showed that p53 expression indicated worse overall survival (OS) in the whole cohort (79.6% vs 89.6%, Log-rank test P = .025) as well as in stratified prognostic stage II patients (90.8% vs 100%, Log-rank test P = .027). The mortality risk of p53 expression patients was 2.22 times higher than that of p53 negative patients (HR: 2.222; 95%CI: 1.147-4.308). In addition, p53 expression was also associated with poor disease-free survival (DFS) (76.7% vs 86.8%, P = .020). Cox proportional hazard ratio model showed p53 expression was an independent risk factor for OS (P = .018) and DFS (P = .018) after controlling for tumor size, lymph node status, and vessel tumor emboli. Altogether, our data showed that IHC-detected p53 expression is a promising prognostic candidate for poor survival in triple-negative breast IDC patients. However, more studies are needed to determine if p53 may be applied to clinical practice as a biomarker and/or novel therapeutic target for TNBC.

Khajehgoodari R, Khorvash F, Kheirollahi M, et al.
Correlations between the expression of hTERT and α and β splice variants in human brain tumors.
Adv Clin Exp Med. 2019; 28(4):507-513 [PubMed] Related Publications
BACKGROUND: Astrocytomas are diffusible infiltrative and aggressive brain tumors that are extensive and heterogeneous clusters of neoplastic growths in the central nervous system (CNS). Meningioma tumors are commonly benign but may demonstrate an invasive pattern with frequent recurrences. Human telomerase reverse transcriptase (hTERT) is an unfavorable prognostic factor for several types of cancers, and there are controversies about its role.
OBJECTIVES: In the present study, we investigated the relative expression of hTERT splice variants in 2 groups of brain tumors compared to non-tumor samples.
MATERIAL AND METHODS: The mRNA of 40 brain tumor samples and 4 control samples was extracted; mRNA expression of hTERT α-deletion and β-deletion variants, as well as the wild type isoform, was quantified using quantitative reverse transcription polymerase chain reaction (RT-qPCR).
RESULTS: The α-deletion variant was significantly expressed in primary benign meningeal tumors (p = 0.01). The results indicate a positive correlation between the relative expression of hTERT mRNA transcript and α-deletion and β-deletion variants in both groups of tumors (meningiomas and astrocytomas). A strong association between the expression of the full-length splice variant and the β-deletion variant was observed in astrocytoma tumors (p = 0.045). The most significant correlations were found between the hTERT full-length and β-deletion variants in high-grade meningiomas (p = 0.018, correlation coefficient (CC) = 0.964) and grade II astrocytomas (p = 0.015; CC = 0.580. In addition, in low grades of both types of tumors, the hTERT full-length variant and especially the α-deletion variant were the predominant isoforms. The overexpression of hTERT and β-deletion variants in high grades of these tumors was statistically significant. Our findings indicate that α-deletion and β-deletion isoforms are associated with high levels of full-length hTERT mRNA in both groups of brain tumor patients.
CONCLUSIONS: Changes in the splicing pattern of hTERT splice variants in brain tumors and their correlation with pathological alterations in cells could be applied as diagnostic or prognostic biomarkers, or possibly as targets for cancer therapy. However, the function and biological role of hTERT splice variants remain to be clarified.

Sammarco G, Varricchi G, Ferraro V, et al.
Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.

Tripathy S, Tripathi M, Dattagupta S, et al.
In Vivo PSMA Expression in Head and Neck Paragangliomas on 68Ga PSMA 11 PET/CT.
Clin Nucl Med. 2019; 44(6):e398-e400 [PubMed] Related Publications
Head and neck paragangliomas are rare and often asymptomatic tumors and mostly present as painless masses. We describe Ga PSMA 11 PET/CT and Ga DOTANOC PET/CT findings of a 40 year old man with triple head and neck paragangliomas with emphasis on exploring the possible theranostic options.

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